Trial Outcomes & Findings for Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095) (NCT NCT00773838)

NCT ID: NCT00773838

Last Updated: 2021-04-01

Results Overview

Objective RR was defined as percentage (%) of participants with complete response (CR: disappearance of original monoclonal (M) paraprotein from blood \& urine on at least 2 determinations for at least 6 weeks (WKs) by immunofixation studies, \<5% plasma cells in bone marrow on at least 1 determination, no increase in size/number of lytic bone lesions (LBLs) \& disappearance of soft tissue plasmacytomas (STP) for at least 6 WKs on skeletal survey (SS) if available) or partial response (PR: ≥50% reduction in serum M protein for at least 2 determinations 6 WKs apart, if present, reduction in 24-hour urinary light chain excretion by ≥90% or ≤200 mg for at least 2 determinations 6 WKs apart, ≥50% reduction in STP size for at least 6 WKs, \& no increase in size/number of LBLs on SS if available) as assessed by Independent Adjudication Committee (IAC) per European Blood \& Marrow Transplant (EBMT) criteria. To report RR \& 95% confidence intervals (CIs), exact test of binomial parameter was used.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 143 participants
• Primary outcome timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)
• Results posted on: 2021-04-01

Participant Flow

Of 143 participants enrolled, 142 participants were allocated to treatment. Five participants received additional treatment for about 1 year during an extension as per investigator's discretion based on clinical benefit of the treatment received. All 5 participants discontinued extension treatment and were followed for survival up to 2 years post last dose of treatment.

Participant milestones

Measure	Vorinostat + Bortezomib Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.
Overall Study STARTED	143
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	143

Reasons for withdrawal

Measure	Vorinostat + Bortezomib Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.
Overall Study Adverse Event	29
Overall Study Lost to Follow-up	1
Overall Study Physician Decision	8
Overall Study Progressive Disease	82
Overall Study Protocol Violation	2
Overall Study Withdrawal by Subject	21

Baseline Characteristics

Study of Vorinostat (MK0683), an Histone Deacetylase (HDAC) Inhibitor in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma (MK-0683-095)

Baseline characteristics by cohort

Measure	Vorinostat + Bortezomib n=143 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.
Age, Continuous	62.1 Years STANDARD_DEVIATION 8.7 • n=5 Participants
Sex: Female, Male Female	56 Participants n=5 Participants
Sex: Female, Male Male	87 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	138 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	34 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	7 Participants n=5 Participants
Race (NIH/OMB) White	102 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)

Population: All participants who received at least one dose of study treatment

Objective RR was defined as percentage (%) of participants with complete response (CR: disappearance of original monoclonal (M) paraprotein from blood & urine on at least 2 determinations for at least 6 weeks (WKs) by immunofixation studies, <5% plasma cells in bone marrow on at least 1 determination, no increase in size/number of lytic bone lesions (LBLs) & disappearance of soft tissue plasmacytomas (STP) for at least 6 WKs on skeletal survey (SS) if available) or partial response (PR: ≥50% reduction in serum M protein for at least 2 determinations 6 WKs apart, if present, reduction in 24-hour urinary light chain excretion by ≥90% or ≤200 mg for at least 2 determinations 6 WKs apart, ≥50% reduction in STP size for at least 6 WKs, & no increase in size/number of LBLs on SS if available) as assessed by Independent Adjudication Committee (IAC) per European Blood & Marrow Transplant (EBMT) criteria. To report RR & 95% confidence intervals (CIs), exact test of binomial parameter was used.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Objective Response Rate (RR)

11.3 Percentage of Participants Interval 6.6 to 17.7

SECONDARY outcome

Timeframe: Up to approximately 22 months

Population: All participants who received at least one dose of study treatment

An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experienced an AE were reported.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Number of Participants Who Experienced an Adverse Event (AE)

142 Participants

SECONDARY outcome

Timeframe: Up to approximately 18 months

Population: All participants who received at least one dose of study treatment

An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinued study treatment due to an AE were reported.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Number of Participants Who Discontinued Study Treatment Due to an AE

28 Participants

SECONDARY outcome

Timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)

Population: All participants who received at least one dose of study treatment

TTP was defined as the time from allocation to the first documented disease progression (PD) as determined by IAC per EBMT criteria or death due to myeloma, whichever occurred first. PD: >25% increase in level of serum Mparaprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median TTP (in months) and associated 95% CIs Kaplan-Meier method was used.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Time To Disease Progression (TTP) as Determined by IAC Per EBMT Criteria

3.47 Months Interval 2.53 to 4.57

SECONDARY outcome

Timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)

Population: All participants who received at least one dose of study treatment

TTP was defined as the time from allocation to the first documented PD as assessed by investigator per EBMT criteria or death due to myeloma, whichever occurred first. PD: >25% increase in level of serum Mparaprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median TTP (in months) and associated 95% CIs Kaplan-Meier method was used.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

TTP as Assessed by Investigator Per EBMT Criteria

3.07 Months Interval 2.37 to 4.33

SECONDARY outcome

Timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)

Population: All participants who received at least one dose of study treatment

PFS was defined as the time from allocation to the first documents PD as determined by IAC per EBMT criteria or death due to any cause, whichever occurs first. PD: >25% increase in level of serum M-paraprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median PFS (in months) and associated 95%CIs Kaplan-Meier method was used.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Progression-Free Survival (PFS) as Determined by IAC Per EBMT Criteria

3.13 Months Interval 2.4 to 4.33

SECONDARY outcome

Timeframe: Up to approximately 30 months (through Final Analysis data cut-off of 16-May-2011)

Population: All participants who received at least one dose of study treatment

PFS was defined as the time from allocation to the first documents PD as assessed by investigator per EBMT criteria or death due to any cause, whichever occurs first. PD: >25% increase in level of serum M-paraprotein, which must also be an absolute increase of at least 5g/L (500 mg/dL) and confirmed on a repeat investigation or 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg/24hour and confirmed on a repeat investigation or >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which must also be an absolute increase of at least 10% or definitive increase in size of existing LBLs or STP or development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). To report the median PFS (in months) and associated 95%CIs Kaplan-Meier method was used.

Outcome measures

Measure

Vorinostat + Bortezomib n=142 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

PFS as Assessed by Investigator Per EBMT Criteria

2.83 Months Interval 2.17 to 3.77

SECONDARY outcome

Timeframe: Up to approximately 40 months (through End of Trial data cut-off of 09-Apr-2012)

Population: All allocated participants

OS was defined as the time from allocation to death due to any cause. To report the median survival (in months) and the associated 95%CIs were reported using Kaplan-Meier method was used. Participants without documented death at the time of final analysis were censored at the date of the last follow up.

Outcome measures

Measure

Vorinostat + Bortezomib n=143 Participants Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.

Overall Survival (OS)

11.23 Months Interval 8.47 to 14.43

Adverse Events

Vorinostat + Bortezomib

Serious events: 92 serious events

Other events: 140 other events

Deaths: 85 deaths

Serious adverse events

Measure	Vorinostat + Bortezomib n=142 participants at risk Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.
Blood and lymphatic system disorders Anaemia	2.8% 4/142 • Number of events 4 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Febrile neutropenia	2.1% 3/142 • Number of events 3 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Hyperviscosity syndrome	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Lymphadenitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Pancytopenia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Thrombocytopenia	4.2% 6/142 • Number of events 6 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Acute myocardial infarction	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Angina unstable	0.70% 1/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Cardiac failure	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Myocardial ischaemia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Sinus tachycardia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Cardiac disorders Tachycardia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Ear and labyrinth disorders Deafness neurosensory	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Endocrine disorders Inappropriate antidiuretic hormone secretion	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Eye disorders Blepharitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Eye disorders Cataract	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Eye disorders Conjunctivitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Diarrhoea	5.6% 8/142 • Number of events 8 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Gingival bleeding	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Inguinal hernia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Nausea	1.4% 2/142 • Number of events 3 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Vomiting	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Asthenia	4.2% 6/142 • Number of events 6 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Fatigue	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Mucosal inflammation	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Oedema	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Pain	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Pyrexia	4.9% 7/142 • Number of events 7 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Immune system disorders Immunodeficiency	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Appendicitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Bacteraemia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Bacterial sepsis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Bronchitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Bronchopneumonia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Device related infection	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Febrile infection	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Gastroenteritis	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Gastrointestinal infection	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations H1N1 influenza	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Herpes zoster	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Lobar pneumonia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Lower respiratory tract infection	2.1% 3/142 • Number of events 3 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Lung infection	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Pharyngotonsillitis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Pneumocystis jiroveci pneumonia	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Pneumonia	9.2% 13/142 • Number of events 14 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Pneumonia respiratory syncytial viral	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Pyelonephritis acute	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Respiratory tract infection	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Sepsis	3.5% 5/142 • Number of events 5 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Septic shock	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Staphylococcal infection	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Streptococcal bacteraemia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Upper respiratory tract infection	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Urinary tract infection	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Urosepsis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Accidental overdose	8.5% 12/142 • Number of events 15 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Contusion	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Femur fracture	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Head injury	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Heat stroke	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Intentional overdose	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Rib fracture	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Upper limb fracture	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Investigations Blood creatinine increased	0.70% 1/142 • Number of events 3 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Dehydration	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hypercalcaemia	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hypokalaemia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hyponatraemia	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Malnutrition	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Metabolic acidosis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Tumour lysis syndrome	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Arthritis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Back pain	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Bone pain	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Joint range of motion decreased	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Muscular weakness	0.70% 1/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Neck pain	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Pathological fracture	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	21.1% 30/142 • Number of events 31 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Altered state of consciousness	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Cerebral haemorrhage	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Convulsion	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Dizziness	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Nerve root compression	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Post herpetic neuralgia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Psychiatric disorders Delirium	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Haematuria	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Neurogenic bladder	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Renal failure	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Renal failure acute	7.0% 10/142 • Number of events 12 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Renal failure chronic	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Renal and urinary disorders Urinary retention	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	1.4% 2/142 • Number of events 2 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Vascular disorders Thrombosis	0.70% 1/142 • Number of events 1 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.

Other adverse events

Measure	Vorinostat + Bortezomib n=142 participants at risk Participants receive vorinostat 400 mg, orally, once daily (QD) on Days 1-14 of each 21-day treatment cycle and bortezomib 1.3mg/m\^2 intravenous (IV) injection QD on Days 1, 4, 8 and 11 of each 21-day treatment cycle for up to 26 cycles. Participants with progressive disease (PD) after 2 cycles of treatment or no change (NC) after 4 cycles of treatment receive additional treatment of Dexamethasone, 20 mg of total daily dose, orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle for up to 26 cycles. Eligible participants could receive additional treatment on an extension.
Blood and lymphatic system disorders Anaemia	52.1% 74/142 • Number of events 231 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Leukopenia	17.6% 25/142 • Number of events 74 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Neutropenia	37.3% 53/142 • Number of events 135 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Blood and lymphatic system disorders Thrombocytopenia	69.7% 99/142 • Number of events 582 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Eye disorders Vision blurred	7.7% 11/142 • Number of events 13 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Abdominal discomfort	5.6% 8/142 • Number of events 9 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Abdominal pain	12.7% 18/142 • Number of events 25 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Abdominal pain upper	8.5% 12/142 • Number of events 18 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Constipation	24.6% 35/142 • Number of events 47 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Diarrhoea	52.1% 74/142 • Number of events 189 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Dry mouth	7.0% 10/142 • Number of events 10 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Dyspepsia	7.7% 11/142 • Number of events 16 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Nausea	56.3% 80/142 • Number of events 162 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Gastrointestinal disorders Vomiting	37.3% 53/142 • Number of events 103 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Asthenia	21.8% 31/142 • Number of events 57 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Chest pain	9.2% 13/142 • Number of events 15 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Chills	8.5% 12/142 • Number of events 14 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Fatigue	48.6% 69/142 • Number of events 143 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Oedema peripheral	12.0% 17/142 • Number of events 18 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
General disorders Pyrexia	23.9% 34/142 • Number of events 56 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Nasopharyngitis	9.9% 14/142 • Number of events 19 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Infections and infestations Upper respiratory tract infection	12.0% 17/142 • Number of events 23 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Injury, poisoning and procedural complications Contusion	7.0% 10/142 • Number of events 12 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Investigations Blood creatinine increased	12.7% 18/142 • Number of events 31 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Investigations Platelet count decreased	10.6% 15/142 • Number of events 48 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Investigations Weight decreased	9.2% 13/142 • Number of events 21 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Decreased appetite	37.3% 53/142 • Number of events 78 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Dehydration	7.7% 11/142 • Number of events 11 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hypoalbuminaemia	7.0% 10/142 • Number of events 13 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hypokalaemia	10.6% 15/142 • Number of events 27 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Metabolism and nutrition disorders Hyponatraemia	7.7% 11/142 • Number of events 19 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Arthralgia	9.2% 13/142 • Number of events 16 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Back pain	13.4% 19/142 • Number of events 26 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Bone pain	5.6% 8/142 • Number of events 14 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Muscle spasms	8.5% 12/142 • Number of events 17 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.0% 10/142 • Number of events 11 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.2% 13/142 • Number of events 15 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Myalgia	7.7% 11/142 • Number of events 12 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Musculoskeletal and connective tissue disorders Pain in extremity	12.7% 18/142 • Number of events 22 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Dizziness	14.8% 21/142 • Number of events 26 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Headache	17.6% 25/142 • Number of events 35 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Neuralgia	9.9% 14/142 • Number of events 17 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Neuropathy peripheral	12.0% 17/142 • Number of events 27 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Nervous system disorders Peripheral sensory neuropathy	5.6% 8/142 • Number of events 14 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Psychiatric disorders Insomnia	9.2% 13/142 • Number of events 14 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Cough	19.0% 27/142 • Number of events 31 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Dyspnoea	23.2% 33/142 • Number of events 56 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Epistaxis	16.2% 23/142 • Number of events 36 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.6% 8/142 • Number of events 9 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Respiratory, thoracic and mediastinal disorders Productive cough	5.6% 8/142 • Number of events 10 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Vascular disorders Haematoma	5.6% 8/142 • Number of events 10 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Vascular disorders Hypertension	9.2% 13/142 • Number of events 17 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.
Vascular disorders Hypotension	9.9% 14/142 • Number of events 16 • Up tp approximately 22 months for non-serious adverse events (AEs). Up to approximately 40 months for serious AEs and all-cause mortality. All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all enrolled participants who received at least 1 dose of study treatment. Only serious AEs were collected for participants treated on extension.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: ClinicalTrialsDisclosure@merck.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Sponsor have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication guidelines.
• Publication restrictions are in place

Restriction type: OTHER