Trial Outcomes & Findings for Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (NCT NCT00878709)

NCT ID: NCT00878709

Last Updated: 2021-06-11

Results Overview

Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 2840 participants
• Primary outcome timeframe: From randomization until time of event up to 2 years
• Results posted on: 2021-06-11

Participant Flow

Participant milestones

Measure	Neratinib Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year.Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Overall Study STARTED	1420	1420
Overall Study COMPLETED	1095	1183
Overall Study NOT COMPLETED	325	237

Reasons for withdrawal

Measure	Neratinib Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year.Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Overall Study Withdrawal by Subject	197	120
Overall Study Lost to Follow-up	35	33
Overall Study Other Reasons	93	84

Baseline Characteristics

Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer

Baseline characteristics by cohort

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Total n=2840 Participants Total of all reporting groups
Age, Continuous	52.3 years STANDARD_DEVIATION 10.08 • n=5 Participants	52.3 years STANDARD_DEVIATION 10.28 • n=7 Participants	52.3 years STANDARD_DEVIATION 10.18 • n=5 Participants
Sex: Female, Male Female	1420 Participants n=5 Participants	1420 Participants n=7 Participants	2840 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	188 Participants n=5 Participants	197 Participants n=7 Participants	385 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	27 Participants n=5 Participants	47 Participants n=7 Participants	74 Participants n=5 Participants
Race/Ethnicity, Customized White	1165 Participants n=5 Participants	1135 Participants n=7 Participants	2300 Participants n=5 Participants
Race/Ethnicity, Customized Other	40 Participants n=5 Participants	41 Participants n=7 Participants	81 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2	4.7 percentage of participants with events	7.5 percentage of participants with events

PRIMARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms	94.2 percentage of participants Interval 92.6 to 95.4	91.9 percentage of participants Interval 90.2 to 93.2

SECONDARY outcome

Timeframe: Randomization until death due to any cause (up to 119 Months)

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

OS was defined as the time from randomization to death due to any cause, censored at the last date known alive.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Overall Survival (OS) 1 Year Kaplan-Meier Estimate	99.64 percentage of participants Interval 99.13 to 99.85	99.43 percentage of participants Interval 98.86 to 99.71
Overall Survival (OS) 3 Year Kaplan-Meier Estimate	96.74 percentage of participants Interval 95.62 to 97.57	96.44 percentage of participants Interval 95.3 to 97.31
Overall Survival (OS) 5 Year Kaplan-Meier Estimate	94.09 percentage of participants Interval 92.65 to 95.25	93.26 percentage of participants Interval 91.77 to 94.49
Overall Survival (OS) 7 Year Kaplan-Meier Estimate	91.36 percentage of participants Interval 89.66 to 92.79	91.29 percentage of participants Interval 89.62 to 92.7
Overall Survival (OS) 9 Year Kaplan-Meier Estimate	89.06 percentage of participants Interval 86.97 to 90.84	88.65 percentage of participants Interval 88.58 to 90.43

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2	4.7 percentage of participants with events	8.0 percentage of participants with events

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms	94.2 percentage of participants Interval 92.6 to 95.4	91.3 percentage of participants Interval 89.6 to 92.7

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2	3.8 percentage of participants with events	5.4 percentage of participants with events

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms	95.3 percentage of participants Interval 93.9 to 96.4	94.0 percentage of participants Interval 92.6 to 95.2

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 2	3.7 percentage of participants with events	5.3 percentage of participants with events

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms	95.5 percentage of participants Interval 94.1 to 96.6	94.2 percentage of participants Interval 92.8 to 95.3

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

CNS recurrence is defined as the time from randomization to CNS as the first distant recurrence. Competing events include distant recurrence at other sites as the first distant recurrence and death from any cause prior to distant recurrence.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm at Year 2	0.8 percentage of participants with events	1.1 percentage of participants with events

SECONDARY outcome

Timeframe: From randomization until time of event up to 2 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2	0.92 percentage of participants Interval 0.49 to 1.59	1.16 percentage of participants Interval 0.68 to 1.87

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5	8.2 percentage of participants with events	11.5 percentage of participants with events

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms	90.2 percentage of participants Interval 88.3 to 91.8	87.7 percentage of participants Interval 85.7 to 89.4

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5	8.5 percentage of participants with events	12.3 percentage of participants with events

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5	7.0 percentage of participants with events	9.2 percentage of participants with events

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Percentage of Participants with TTDR events is reported. TTDR is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Percentage of Participants With Time to Distant Recurrence (TTDR) Event in Neratinib Arm Compared to Placebo Arm at Year 5	6.8 percentage of participants with events	8.9 percentage of participants with events

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization until time of event up to 5 years

Population: Intent to treat (ITT) population included all participants who were randomized regardless of whether they received any study treatment.

Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).

Outcome measures

Measure	Neratinib n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1420 Participants Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5	1.3 percentage of participants Interval 0.77 to 2.06	1.82 percentage of participants Interval 1.19 to 2.68

Adverse Events

Neratinib

Serious events: 103 serious events

Other events: 1386 other events

Deaths: 0 deaths

Placebo

Serious events: 85 serious events

Other events: 1234 other events

Deaths: 0 deaths

Serious adverse events

Measure	Neratinib n=1408 participants at risk Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1408 participants at risk Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Blood and lymphatic system disorders Anaemia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Cardiac disorders Angina pectoris	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Cardiac disorders Myocardial infarction	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Cardiac disorders Atrial fibrillation	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Cardiac disorders Sinus tachycardia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Cardiac disorders Tachycardia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Ear and labyrinth disorders Vertigo	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Diarrhoea	1.6% 22/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Vomiting	0.85% 12/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Nausea	0.28% 4/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Pancreatitis	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain upper	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal strangulated hernia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Enterocele	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Periodontal disease	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Rectal cancer	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal distension	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Colitis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Colitis ischaemic	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Constipation	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Fatigue	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Non-cardiac chest pain	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Pyrexia	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Asthenia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Cholelithiasis	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Cholecystitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Cholecystitis acute	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Hypertransaminasaemia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Immune system disorders Food allergy	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Cellulitis	0.43% 6/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.28% 4/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Erysipelas	0.36% 5/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Bronchitis	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Anal abscess	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Anorectal cellulitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Appendicitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Appendicitis perforated	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Breast cellulitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Cystitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Escherichia urinary tract infection	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Gastroenteritis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Gastroenteritis salmonella	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Gastrointestinal viral infection	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Herpes zoster	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Localised infection	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Ophthalmic herpes zoster	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Pneumonia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.28% 4/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Rectal abscess	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Streptococcal sepsis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Viral infection	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Abdominal wall abscess	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Breast abscess	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Device related infection	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Diverticulitis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Incision site cellulitis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Mastitis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Septic shock	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Ankle fracture	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Fracture	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Multiple injuries	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Sternal fracture	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Wound dehiscence	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Wrist fracture	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Fall	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Injury, poisoning and procedural complications Patella fracture	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Alanine aminotransferase increased	0.28% 4/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Aspartate aminotransferase increased	0.28% 4/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Blood creatine increased	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Blood thyroid stimulating hormone increased	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Electrocardiogram T wave inversion	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Staphylococcus test positive	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Ejection fraction decreased	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Dehydration	0.64% 9/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Hypokalaemia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Hypomagnesaemia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Hyponatraemia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign female reproductive tract neoplasm	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer metastatic	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioma	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant pleural effusion	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign breast neoplasm	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast neoplasm	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to eye	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sarcoma	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sarcoma uterus	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Vascular neoplasm	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Syncope	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Ageusia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Anosmia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Cerebral haemorrhage	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Cerebral infarction	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Paresis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Brain oedema	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Carotid artery stenosis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Cerebrovascular accident	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Dizziness	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Headache	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Intercostal neuralgia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Speech disorder	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Transient ischaemic attack	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Tremor	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Psychiatric disorders Mental status changes	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Psychiatric disorders Depression	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Psychiatric disorders Anxiety	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Psychiatric disorders Mental disorder	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Renal and urinary disorders Renal failure acute	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Renal and urinary disorders Renal failure	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Renal and urinary disorders Hyperuricosuria	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Renal and urinary disorders Renal colic	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Renal and urinary disorders Bladder prolapse	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Endometrial hyperplasia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Endometrial hypertrophy	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Endometriosis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Metrorrhagia	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Ovarian cyst	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Uterine polyp	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Reproductive system and breast disorders Vulval leukoplakia	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.21% 3/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.14% 2/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Tachypnoea	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Dermatitis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Erythema	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Skin necrosis	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Skin disorder	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Surgical and medical procedures Hysterosalpingo-oophorectomy	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Vascular disorders Hypotension	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Vascular disorders Deep vein thrombosis	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Vascular disorders Hypertension	0.00% 0/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	0.07% 1/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.

Other adverse events

Measure	Neratinib n=1408 participants at risk Patients who completed prior adjuvant trastuzumab received six 40 mg neratinib tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.	Placebo n=1408 participants at risk Patients who completed prior adjuvant trastuzumab received six 40 mg placebo tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously for one year. Therapy continued until unacceptable toxicity, recurrent disease, death, or withdrawal of consent occurred.
Gastrointestinal disorders Diarrhoea	95.2% 1341/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	35.4% 499/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Nausea	43.0% 605/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	21.5% 303/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Vomiting	25.9% 364/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	8.0% 113/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain	24.1% 339/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	10.2% 144/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal pain upper	15.1% 212/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	6.8% 96/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Dyspepsia	9.9% 139/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	4.2% 59/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Constipation	8.2% 115/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	9.5% 134/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Stomatitis	6.0% 85/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	2.1% 29/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Gastrointestinal disorders Abdominal distension	5.2% 73/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	3.5% 49/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Fatigue	27.1% 381/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	20.1% 283/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Asthenia	7.6% 107/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	7.8% 110/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
General disorders Pyrexia	5.5% 77/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	3.8% 54/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Nasopharyngitis	6.0% 84/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	8.9% 126/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Infections and infestations Urinary tract infection	5.1% 72/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	1.6% 23/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Alanine aminotransferase increased	8.4% 118/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	3.2% 45/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Aspartate aminotransferase increased	7.2% 101/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	3.3% 46/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Investigations Electrocardiogram QT prolonged	3.5% 49/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	6.6% 93/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Metabolism and nutrition disorders Decreased appetite	12.1% 170/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	2.8% 40/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Muscle spasms	11.3% 159/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	3.1% 44/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Arthralgia	6.1% 86/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	11.5% 162/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Back pain	5.6% 79/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	9.5% 134/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Musculoskeletal and connective tissue disorders Pain in extremity	4.1% 58/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	7.0% 98/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Headache	19.7% 278/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	19.5% 275/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Nervous system disorders Dizziness	10.4% 146/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	9.0% 127/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Psychiatric disorders Insomnia	3.1% 44/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	5.2% 73/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.0% 71/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	1.3% 18/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Respiratory, thoracic and mediastinal disorders Cough	4.9% 69/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	6.5% 92/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Rash	15.0% 211/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	7.1% 100/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Skin and subcutaneous tissue disorders Dry skin	6.0% 85/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	2.3% 33/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.
Vascular disorders Hot flush	2.8% 40/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.	6.0% 84/1408 • From first dose through 28 days after the last dose, up to two years. The safety population included all participants who received at least one dose of investigational product.

Additional Information

Senior Director, Clinical Operations

Puma Biotechnology, Inc.

Phone: +1 (424) 248-6500

Email: clinicaltrials@pumabiotechnology.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60