Trial Outcomes & Findings for Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3) (NCT NCT01942135)

NCT ID: NCT01942135

Last Updated: 2024-04-04

Results Overview

PFS is the time from the date of randomization to the date of the first documentation of objective progression of disease (PD)or death due to any cause in absence of documented PD. Participants lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of a day. Participants with documentation of PD or death after a long interval (2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) =\[progression/death date(censor date) - randomization date + 1\]/30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors(RECIST v1.1) a 20% increase in the sum of diameters of target lesions and the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of existing non-target lesions or the appearance of new lesions.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 521 participants
• Primary outcome timeframe: From randomization date to date of first documentation of progression or death (assessed up to 12 months)
• Results posted on: 2024-04-04

Participant Flow

The study was conducted at 144 sites in 17 countries that randomized 521 participants. Eligible participants were to have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of recurrent (local or metastatic) disease.

The study consisted of a screening visit within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a post-treatment follow-up period during which survival and new anti-cancer therapy information was collected every 3 months for the first 9 months, then every 6 months from the last dose of study intervention.

Participant milestones

Measure	Palbociclib + Fulvestrant Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Overall Study STARTED	347	174
Overall Study Treated	345	172
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	347	174

Reasons for withdrawal

Measure	Palbociclib + Fulvestrant Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Overall Study Adverse Event	21	7
Overall Study Global Deterioration of Health Status	9	6
Overall Study Randomized Not Treated	2	2
Overall Study Death	2	1
Overall Study Objective Progression or Relapse + Progressive Disease	279	148
Overall Study Participant Refused to Continue Treatment for Reason Other than Adverse Event	10	3
Overall Study Withdrawal by Subject	4	3
Overall Study Protocol Violation	1	0
Overall Study Other	19	4

Baseline Characteristics

Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)

Baseline characteristics by cohort

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.	Total n=521 Participants Total of all reporting groups
Age, Continuous	56.9 Years STANDARD_DEVIATION 11.7 • n=5 Participants	56.8 Years STANDARD_DEVIATION 10.4 • n=7 Participants	56.9 Years STANDARD_DEVIATION 11.3 • n=5 Participants
Sex: Female, Male Female	347 Participants n=5 Participants	174 Participants n=7 Participants	521 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants n=5 Participants	11 Participants n=7 Participants	28 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	329 Participants n=5 Participants	161 Participants n=7 Participants	490 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Menopausal Status Postmenopausal	275 Participants n=5 Participants	138 Participants n=7 Participants	413 Participants n=5 Participants
Menopausal Status Pre/Perimenopausal	72 Participants n=5 Participants	36 Participants n=7 Participants	108 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization date to date of first documentation of progression or death (assessed up to 12 months)

Population: The intent-to-treat (ITT) population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

PFS is the time from the date of randomization to the date of the first documentation of objective progression of disease (PD)or death due to any cause in absence of documented PD. Participants lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of a day. Participants with documentation of PD or death after a long interval (2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) =[progression/death date(censor date) - randomization date + 1]/30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors(RECIST v1.1) a 20% increase in the sum of diameters of target lesions and the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of existing non-target lesions or the appearance of new lesions.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Progression-Free Survival (PFS) as Assessed by the Investigator	9.2 months Interval 7.5 to Not estimable based on the Brookmeyer and Crowley method, because of insufficient number of participants with events.	3.8 months Interval 3.5 to 5.5

SECONDARY outcome

Timeframe: From randomization until death (up to 4.5 years)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Participants lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = [death date (censor date) - randomization date + 1]/30.4.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Overall Survival (OS)-Number of Participants Who Died	201 Participants	109 Participants

SECONDARY outcome

Timeframe: From randomization until death (up to 4.5 years)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Participants lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = [death date (censor date) - randomization date + 1]/30.4.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Overall Survival (OS)	34.9 months Interval 28.8 to 40.0	28.0 months Interval 23.6 to 34.6

SECONDARY outcome

Timeframe: From randomization until death (assessed up to 36 months)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

One-, Two- or Three-year Survival Probability is defined as the probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. Survival time was censored to last date the participant is known to be alive.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Survival Probabilities at Year 1, Year 2, and Year 3 Survival Probability at Year 1	85.5 Survival Probability Interval 81.3 to 88.9	84.8 Survival Probability Interval 78.3 to 89.4
Survival Probabilities at Year 1, Year 2, and Year 3 Survival Probability at Year 2	65.3 Survival Probability Interval 59.9 to 70.2	57.3 Survival Probability Interval 49.2 to 64.6
Survival Probabilities at Year 1, Year 2, and Year 3 Survival Probability at Year 3	49.6 Survival Probability Interval 44.0 to 54.9	40.8 Survival Probability Interval 32.9 to 48.5

SECONDARY outcome

Timeframe: From randomization until end of treatment (assessed up to 2 years)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized. Randomized participants with measurable disease at baseline was also included.

OR is defined as the overall complete response (CR) or partial response (PR) according to the RECIST version 1.1 Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per response evaluation criteria in solid tumors criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions (longest for non-nodal and short axis for nodal target lesions); Overall Response (OR) = CR + PR.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Objective Response (OR)	21.0 percentage of participants Interval 16.9 to 25.7	8.6 percentage of participants Interval 4.9 to 13.8

SECONDARY outcome

Timeframe: From randomization until end of treatment (assessed up to 2 years)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as [the date response ended (ie, date of PD or death) - first CR or PR date + 1)]/30.4. Kaplan-Meier estimate of median of the DR is provided below. No inferential statistical analysis were done for DR. The DR was only calculated for the participants with a CR or PR.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Duration of Response (DR)	10.4 Months Interval 8.3 to Due to less follow up time and insufficient number of participants having duration response.	9.0 Months Interval 5.6 to Due to less follow up time and insufficient number of participants having duration response.

SECONDARY outcome

Timeframe: From randomization until end of treatment (assessed up to 2 years)

Population: The ITT population or full analysis set included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized. Randomized participants with measurable disease at baseline was also included.

CBR is defined as the overall complete response (CR), partial response (PR) , or stable disease (SD) ≥24 weeks according to the RECIST version 1.1. Clinical Benefit Response Rate (CBRR) is defined as the proportion of participants with CR, PR, or SD ≥24 weeks relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received antitumor treatment other than the study medication prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR and a best response of SD ≥24 weeks was counted as non-responders in the assessment of CBR. Per RECIST v1.1 for target lesions and assessed by MRI: CR, disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR.

Outcome measures

Measure	Palbociclib + Fulvestrant n=347 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=174 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Clinical Benefit Response (CBR)	66.3 percentage of participants Interval 61.0 to 71.2	39.7 percentage of participants Interval 32.3 to 47.3

SECONDARY outcome

Timeframe: Cycle 1/Day 15 and Cycle 2/Day 15

Population: The participants who were treated with Palbociclib + fulvestrant (with or without goserelin) or placebo + fulvestrant (with or without goserelin) and have at least one measured plasma drug concentration. The geometric mean and coefficient of variation was not estimable for Cycle 1/Day 15 and Cycle 2/Day 15 for the reporting arm placebo plus fulvestrant.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For palbociclib, a steady-state trough was to be defined as a predose plasma concentration following at least 8 consecutive days of 125 mg daily dose without dosing interruption and the time window for the PK collection was to be between 22 and 26 hours after the dose (the day prior to PK collection) and no more than 1 hour post-dose on the day of PK collection.

Outcome measures

Measure	Palbociclib + Fulvestrant n=325 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Observed Plasma Trough Concentration (Ctrough) for Palbociclib Cycle 1/Day 15	70.70 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 44	—
Observed Plasma Trough Concentration (Ctrough) for Palbociclib Cycle 2/Day 15	75.29 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 44	—

SECONDARY outcome

Timeframe: Cycles 2/Day 1 and Cycle 3/Day 1

Population: The 40 participants who participated in the early safety review, who are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and have at least one measured plasma drug concentration.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For fulvestrant, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose.

Outcome measures

Measure	Palbociclib + Fulvestrant n=64 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=33 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Ctrough for Fulvestrant Cycle 3/Day 1	9.90 ng/mL Geometric Coefficient of Variation 42	7.60 ng/mL Geometric Coefficient of Variation 72
Ctrough for Fulvestrant Cycle 2/Day 1	11.75 ng/mL Geometric Coefficient of Variation 41	9.31 ng/mL Geometric Coefficient of Variation 52

SECONDARY outcome

Timeframe: Cycles 2/ Day 1 and Cycle 3/ Day 1

Population: The 40 participants who participated in the early safety review, who are treated with palbociclib + fulvestrant ± goserelin or placebo + fulvestrant ± goserelin and have at least one measured plasma drug concentration.

Ctrough was defined as steady-state predose concentration. Observed directly from data. For goserelin, a steady-state trough was to be defined when a patient had received all prior planned doses and the sample was collected predose.

Outcome measures

Measure	Palbociclib + Fulvestrant n=16 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=8 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Ctrough for Goserelin Cycle 2/Day 1	295.1 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 153	302.5 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 74
Ctrough for Goserelin Cycle 3/Day 1	344.8 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 64	288.5 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 40

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Global health status / QoL	-0.9 Units on a scale 95% Confidence Interval 64.5 • Interval -2.5 to 0.7	-4.0 Units on a scale 95% Confidence Interval 26.25 • Interval -6.3 to -1.7
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Physical functioning	-0.7 Units on a scale 95% Confidence Interval 22.76 • Interval -2.1 to 0.7	-1.7 Units on a scale 95% Confidence Interval 21.24 • Interval -3.7 to 0.2
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Role functioning	-1.8 Units on a scale 95% Confidence Interval 30.70 • Interval -3.7 to 0.1	-3.7 Units on a scale 95% Confidence Interval 28.04 • Interval -6.5 to -0.9
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Emotional functioning	2.7 Units on a scale 95% Confidence Interval 25.97 • Interval 1.1 to 4.3	-1.9 Units on a scale 95% Confidence Interval 21.19 • Interval -4.2 to 0.5
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Cognitive functioning	-1.7 Units on a scale 95% Confidence Interval 20.97 • Interval -3.1 to -0.2	-2.9 Units on a scale 95% Confidence Interval 20.22 • Interval -5.0 to -0.7
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores Social functioning	-0.5 Units on a scale 95% Confidence Interval 32.07 • Interval -2.5 to 1.5	-0.6 Units on a scale 95% Confidence Interval 32.27 • Interval -3.4 to 2.3

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from "not at all" to "very much" and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Fatigue	1.8 Units on a scale 95% Confidence Interval 26.12 • Interval 0.1 to 3.5	3.3 Units on a scale 95% Confidence Interval 24.82 • Interval 0.9 to 5.8
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Nausea and vomiting	1.7 Units on a scale 95% Confidence Interval 26.06 • Interval 0.4 to 3.0	4.2 Units on a scale 95% Confidence Interval 19.71 • Interval 2.3 to 6.1
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Pain	-3.3 Units on a scale 95% Confidence Interval 29.02 • Interval -5.1 to -1.5	2.0 Units on a scale 95% Confidence Interval 30.04 • Interval -0.6 to 4.6
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Dyspnoea	2.8 Units on a scale 95% Confidence Interval 30.32 • Interval 1.0 to 4.7	3.3 Units on a scale 95% Confidence Interval 24.98 • Interval 0.6 to 6.0
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Insomnia	-2.4 Units on a scale 95% Confidence Interval 29.81 • Interval -4.4 to -0.4	-0.4 Units on a scale 95% Confidence Interval 29.30 • Interval -3.3 to 2.5
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Appetite loss	1.1 Units on a scale 95% Confidence Interval 36.43 • Interval -0.8 to 3.1	1.7 Units on a scale 95% Confidence Interval 29.61 • Interval -1.1 to 4.6
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Constipation	3.5 Units on a scale 95% Confidence Interval 32.05 • Interval 1.7 to 5.3	2.8 Units on a scale 95% Confidence Interval 26.05 • Interval 0.1 to 5.4
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Diarrhoea	1.9 Units on a scale 95% Confidence Interval 18.97 • Interval 0.6 to 3.1	2.4 Units on a scale 95% Confidence Interval 26.12 • Interval 0.5 to 4.3
Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores Financial difficulties	-3.7 Units on a scale 95% Confidence Interval 28.87 • Interval -5.6 to -1.9	-4.0 Units on a scale 95% Confidence Interval 26.30 • Interval -6.7 to -1.3

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores Future perspective	8.1 Units on a scale 95% Confidence Interval 30.63 • Interval 5.8 to 10.4	4.5 Units on a scale 95% Confidence Interval 30.00 • Interval 1.2 to 7.9
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores Body image	1.9 Units on a scale 95% Confidence Interval 28.07 • Interval 0.2 to 3.6	-0.3 Units on a scale 95% Confidence Interval 20.33 • Interval -2.8 to 2.1
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores Sexual functioning	-1.1 Units on a scale 95% Confidence Interval 16.08 • Interval -2.5 to 0.2	-0.4 Units on a scale 95% Confidence Interval 18.23 • Interval -2.3 to 1.5
Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores Sexual enjoyment	-5.2 Units on a scale 95% Confidence Interval 20.80 • Interval -8.3 to -2.1	-6.6 Units on a scale 95% Confidence Interval 25.49 • Interval -11.6 to -1.7

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represent more severe symptoms.

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores Systemic therapy side effects	3.8 Units on a scale 95% Confidence Interval 15.19 • Interval 2.6 to 4.9	3.4 Units on a scale 95% Confidence Interval 14.31 • Interval 1.8 to 5.0
Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores Breast symptoms	-2.2 Units on a scale 95% Confidence Interval 21.32 • Interval -3.2 to -1.3	-1.3 Units on a scale 95% Confidence Interval 17.49 • Interval -2.7 to 0.0
Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores Arm symptoms	-2.2 Units on a scale 95% Confidence Interval 20.59 • Interval -3.6 to -0.9	-2.0 Units on a scale 95% Confidence Interval 20.08 • Interval -4.0 to -0.1
Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores Upset by hair loss	2.9 Units on a scale 95% Confidence Interval 30.19 • Interval -1.7 to 7.4	-6.0 Units on a scale 95% Confidence Interval 20.91 • Interval -12.3 to 0.3

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a three level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/ impairment Published weights are available that allow for the creation of a single summary score called the EQ-5D index, which basically ranges from 0 to 1 with low scores representing a higher level of dysfunction and 1 as perfect health. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D)- Health Index Scores	0.006 Units on a scale Interval -0.01 to 0.03	-0.031 Units on a scale Interval -0.06 to 0.0

SECONDARY outcome

Timeframe: From Cycle 1 to 14, as of 05 December 2014.

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale	-1.8 Units on a scale 95% Confidence Interval 19.00 • Interval -3.3 to -0.3	-2.6 Units on a scale 95% Confidence Interval 23.09 • Interval -4.8 to -0.4

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment, as of 05 December 2014

Population: The PRO -evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post -baseline PRO assessment prior to end of study treatment.

A time to event analysis was pre-specified for pain. An analysis of TTD in pain defined as time between baseline and first occurrence of increase of ≥10 points in pain. Deterioration will be defined increase in score of 10 points or greater from baseline. The Kaplan-Meier estimates of quartiles (time to deterioration) with 95% CI is mentioned below.

Outcome measures

Measure	Palbociclib + Fulvestrant n=335 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=166 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Time to Deterioration (TTD) 50% quartile	8.0 Months Interval 5.6 to Due to less follow-up time and insufficient number of participants with events.	2.8 Months Interval 2.3 to 5.4
Time to Deterioration (TTD) 25% quartile	1.9 Months Interval 1.2 to 2.2	1.0 Months Interval 1.0 to 1.9

SECONDARY outcome

Timeframe: From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years).

Population: The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.

An AE is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death; is life-threatening; requires hospitalization; results in persistent or significant disability or in congenital anomaly/birth defect. Severity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.

Outcome measures

Measure	Palbociclib + Fulvestrant n=345 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=172 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) With AEs	98.8 percentage of participants	93.6 percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) With SAEs	22.6 percentage of participants	19.2 percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) With Grade 3 or 4 AEs	80.6 percentage of participants	26.7 percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) With Grade 5 AEs	2.3 percentage of participants	1.7 percentage of participants
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) Discontinued palbociclib/placebo due to AEs	7.5 percentage of participants	4.7 percentage of participants

SECONDARY outcome

Timeframe: From baseline to end of treatment/withdrawal (up to 4.5 years)

Population: The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.

Number of participants with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters Anemia, Hemoglobin increased, Neutrophil count decreased, Platelet count decreased, and White blood cell count decreased) were reported.

Outcome measures

Measure	Palbociclib + Fulvestrant n=345 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=172 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results Anemia	16 Participants	3 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results Hemoglobin increased	1 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results Neutrophil count decreased	239 Participants	1 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results Platelet count decreased	10 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Hematology Results White blood cell count decreased	167 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline to end of treatment/withdrawal (up to 4.5 years)

Population: The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received.

Number of participants with shifts from Grade ≤2 at baseline values to post-baseline values (shift to Grade 3 or 4) were reported as per NCI-CTCAE, V4.0 graded from Grade 1 to 5. Grade 1: Mild; asymptomatic/ mild symptoms; clinical/diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local/noninvasive intervention indicated. Grade 3: Severe/medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Shifts in lab parameter from Grade ≤2 at baseline to Grade 3 or 4 postbaseline (for parameters ALT increased, ALP increased, AST increased, Blood bilirubin increased, Creatinine increased, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hypoalbuminemia, Hypocalcemia, Hypokalemia, Hypomagnesemia, and Hyponatremia) were reported.

Outcome measures

Measure	Palbociclib + Fulvestrant n=345 Participants Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=172 Participants Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results ALT increased	10 Participants	1 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results ALP increased	2 Participants	2 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results AST increased	13 Participants	7 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Blood bilirubin increased	2 Participants	3 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Creatinine increased	5 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypercalcemia	1 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hyperkalemia	2 Participants	2 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypermagnesemia	7 Participants	2 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypernatremia	0 Participants	1 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypoalbuminemia	0 Participants	1 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypocalcemia	2 Participants	2 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypokalemia	0 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hypomagnesemia	0 Participants	0 Participants
Participants With Shifts From CTCAE Grade ≤2 at Baseline to CTCAE Grade 3 or 4 Postbaseline for Chemistry Results Hyponatremia	12 Participants	4 Participants

Adverse Events

Palbociclib + Fulvestrant

Serious events: 78 serious events

Other events: 341 other events

Deaths: 201 deaths

Placebo + Fulvestrant

Serious events: 33 serious events

Other events: 161 other events

Deaths: 109 deaths

Serious adverse events

Measure	Palbociclib + Fulvestrant n=345 participants at risk Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=172 participants at risk Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Febrile neutropenia	0.87% 3/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Neutropenia	1.2% 4/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Cardiac disorders Atrial fibrillation	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Cardiac disorders Pericarditis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Endocrine disorders Hyperthyroidism	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Abdominal pain	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Ascites	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Duodenal ulcer	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Intestinal obstruction	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Nausea	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Pancreatitis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Vomiting	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Chest pain	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Asthenia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Disease progression	1.2% 4/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders General physical health deterioration	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Non-cardiac chest pain	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Oedema peripheral	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Pain	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Pyrexia	1.4% 5/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Hepatobiliary disorders Cholecystitis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Hepatobiliary disorders Cholelithiasis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Hepatobiliary disorders Hepatic failure	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Bacteraemia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Cellulitis	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Erysipelas	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Gastrointestinal infection	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Otitis media acute	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Pharyngitis	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Pneumonia	0.87% 3/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Pyelonephritis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Upper respiratory tract infection	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Urinary tract infection	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Femur fracture	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Fracture	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Alanine aminotransferase increased	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Electrocardiogram QT prolonged	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Neutrophil count decreased	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Troponin increased	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Metabolism and nutrition disorders Dehydration	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Back pain	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Osteonecrosis of jaw	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Pain in extremity	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Carotid artery stenosis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Cerebral haemorrhage	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Cerebrovascular accident	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Drug withdrawal convulsions	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Facial paralysis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Migraine	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Sciatica	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Somnolence	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Depression	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Psychotic disorder	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.7% 3/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.2% 4/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Vascular disorders Deep vein thrombosis	0.87% 3/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Leukopenia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Cardiac disorders Cardiovascular insufficiency	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Endocrine disorders Hypopituitarism	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Endocrine disorders Hypothyroidism	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Eye disorders Cataract	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Eye disorders Diplopia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Crohn's disease	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Diarrhoea	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Gastric volvulus	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Hiatus hernia, obstructive	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Small intestinal obstruction	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Injection site fibrosis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Malaise	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Multiple organ dysfunction syndrome	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Hepatobiliary disorders Bile duct stone	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Immune system disorders Hypersensitivity	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Appendicitis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Atypical pneumonia	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations COVID-19	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Escherichia sepsis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Hepatitis C	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Infectious pleural effusion	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Influenza	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Lower respiratory tract infection	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Meningitis aseptic	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Nasopharyngitis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Neutropenic sepsis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Sepsis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Sinusitis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Urosepsis	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Viral infection	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Ankle fracture	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Fall	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Heat illness	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Sedation complication	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Subdural haematoma	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Blood creatinine increased	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Metabolism and nutrition disorders Hypokalaemia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Skin disorder	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Reproductive system and breast disorders Breast mass	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Suicide attempt	0.58% 2/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Product Issues Device occlusion	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Cauda equina syndrome	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Facial spasm	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Paraesthesia	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Transient ischaemic attack	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Vocal cord paresis	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Muscular weakness	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma gastric	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.58% 1/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal cancer	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial cancer	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.29% 1/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

Other adverse events

Measure	Palbociclib + Fulvestrant n=345 participants at risk Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 105 cycles.	Placebo + Fulvestrant n=172 participants at risk Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase. Maximum treatment duration was 93 cycles.
Blood and lymphatic system disorders Anaemia	31.3% 108/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	13.4% 23/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Leukopenia	32.8% 113/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Neutropenia	67.0% 231/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.3% 4/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Blood and lymphatic system disorders Thrombocytopenia	14.8% 51/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Abdominal pain	9.0% 31/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.6% 13/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Constipation	22.3% 77/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	16.9% 29/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Diarrhoea	27.5% 95/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	20.3% 35/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Dry mouth	7.8% 27/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	9.3% 16/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Dyspepsia	11.9% 41/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.2% 9/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Nausea	36.5% 126/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	29.7% 51/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Stomatitis	14.8% 51/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.9% 5/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Vomiting	22.0% 76/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	15.7% 27/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Asthenia	7.8% 27/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Chest pain	4.6% 16/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	6.4% 11/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Fatigue	43.8% 151/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	32.6% 56/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Injection site pain	7.5% 26/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	11.0% 19/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Oedema peripheral	10.4% 36/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.6% 13/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Pain	5.8% 20/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Pyrexia	12.8% 44/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.2% 9/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Nasopharyngitis	14.5% 50/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Upper respiratory tract infection	13.3% 46/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.6% 13/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Aspartate aminotransferase increased	12.2% 42/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.6% 13/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Neutrophil count decreased	24.3% 84/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Platelet count decreased	12.5% 43/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	0.00% 0/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations White blood cell count decreased	31.0% 107/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	4.1% 7/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Metabolism and nutrition disorders Decreased appetite	17.7% 61/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	10.5% 18/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Arthralgia	26.1% 90/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	24.4% 42/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Back pain	18.8% 65/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	18.6% 32/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Muscle spasms	10.1% 35/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.0% 12/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	6.1% 21/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	6.4% 11/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Myalgia	10.1% 35/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.7% 15/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Pain in extremity	18.0% 62/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	15.7% 27/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Dizziness	17.1% 59/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	10.5% 18/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Dysgeusia	5.2% 18/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.9% 5/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Headache	29.6% 102/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	22.1% 38/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Anxiety	5.8% 20/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.8% 10/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Depression	7.8% 27/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.8% 10/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Psychiatric disorders Insomnia	13.3% 46/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	9.9% 17/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Cough	22.9% 79/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	13.4% 23/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.5% 50/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.7% 15/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.2% 25/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.3% 4/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	15.4% 53/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Alopecia	19.7% 68/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	6.4% 11/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Pruritus	9.3% 32/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Rash	13.3% 46/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	4.7% 8/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Vascular disorders Hot flush	16.5% 57/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	17.4% 30/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Eye disorders Lacrimation increased	7.8% 27/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.2% 2/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Eye disorders Vision blurred	6.7% 23/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.7% 3/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Abdominal distension	6.1% 21/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.2% 9/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Abdominal pain upper	7.0% 24/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.7% 15/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Gastrointestinal disorders Gastrooesophageal reflux disease	6.7% 23/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.7% 3/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
General disorders Influenza like illness	9.9% 34/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.9% 5/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Influenza	3.5% 12/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.8% 10/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Infections and infestations Urinary tract infection	11.0% 38/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	8.1% 14/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Contusion	5.8% 20/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.3% 4/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Injury, poisoning and procedural complications Fall	5.2% 18/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	7.6% 13/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Alanine aminotransferase increased	9.3% 32/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.2% 9/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Blood alkaline phosphatase increased	3.8% 13/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	6.4% 11/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Blood creatinine increased	5.8% 20/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.7% 3/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Investigations Weight decreased	5.2% 18/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.9% 5/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Bone pain	8.1% 28/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	5.2% 9/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Musculoskeletal and connective tissue disorders Neck pain	5.2% 18/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	4.7% 8/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Nervous system disorders Paraesthesia	5.5% 19/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	2.9% 5/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Skin and subcutaneous tissue disorders Dry skin	8.4% 29/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	1.7% 3/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.
Vascular disorders Hypertension	7.5% 26/345 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.	3.5% 6/172 • From the date of randomization up to 28 calendar days (±7 days) after last dose of study intervention (up to 8.4 years). The safety analysis set for adverse events and serious adverse events included all participants who received at least 1 dose of study intervention, with treatment assignments designated according to actual study intervention received. All-cause mortality of the total number at risk included all participants who were randomized, with study intervention, regardless of whether participants received the study intervention or received a different drug from that to which they were randomized.

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
• Publication restrictions are in place

Restriction type: OTHER