Trial Outcomes & Findings for Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN) (NCT NCT00773747)

NCT ID: NCT00773747

Last Updated: 2021-04-30

Results Overview

Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 637 participants
• Primary outcome timeframe: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)
• Results posted on: 2021-04-30

Participant Flow

This study enrolled participants with an established diagnosis of multiple myeloma based on standard criteria that have received at least 1 but not more than 3 prior anti-myeloma regimens and have demonstrated progressive disease after the most recent treatment regimen. Additional inclusion and exclusion criteria applied.

637 participants were randomized to treatment and 635 participants received at least 1 dose of MK-0683 or placebo: 315 participants were treated with vorinostat + bortezomib and 320 participants were treated with placebo + bortezomib.

Participant milestones

Measure	Vorinostat + Bortezomib Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Overall Study STARTED	317	320
Overall Study Treated	315	320
Overall Study COMPLETED	20	24
Overall Study NOT COMPLETED	297	296

Reasons for withdrawal

Measure	Vorinostat + Bortezomib Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Overall Study Lack of Efficacy	112	144
Overall Study Physician Decision	26	18
Overall Study Lost to Follow-up	0	1
Overall Study Protocol Violation	2	2
Overall Study Withdrawal by Subject	89	61
Overall Study Adverse Event	61	62
Overall Study Death	5	8
Overall Study Not Treated	2	0

Baseline Characteristics

Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)

Baseline characteristics by cohort

Measure	Vorinostat + Bortezomib n=317 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Total n=637 Participants Total of all reporting groups
Age, Continuous	60.9 Years STANDARD_DEVIATION 10.0 • n=5 Participants	62.7 Years STANDARD_DEVIATION 10.0 • n=7 Participants	61.8 Years STANDARD_DEVIATION 10.0 • n=5 Participants
Age, Customized In utero	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Preterm newborn infants (gestational age < 37 wks)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Newborns (0-27 days)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Infants and toddlers (28 days-23 months)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Children (2-11 years)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Adolescents (12-17 years)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized Adults (18-64 years)	200 Participants n=5 Participants	181 Participants n=7 Participants	381 Participants n=5 Participants
Age, Customized From 65-84 years	116 Participants n=5 Participants	137 Participants n=7 Participants	253 Participants n=5 Participants
Age, Customized 85 years and over	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Female	126 Participants n=5 Participants	134 Participants n=7 Participants	260 Participants n=5 Participants
Sex: Female, Male Male	191 Participants n=5 Participants	186 Participants n=7 Participants	377 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	32 Participants n=5 Participants	23 Participants n=7 Participants	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	285 Participants n=5 Participants	297 Participants n=7 Participants	582 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to event of disease progression or death assessed up to 32 months (final study analysis)

Population: The analysis population includes all randomized participants.

Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

Outcome measures

Measure	Vorinostat + Bortezomib n=317 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Progression-Free Survival (PFS)	7.63 Months 95% Confidence Interval 6.87 • Interval 6.87 to 8.4	6.83 Months 95% Confidence Interval 5.67 • Interval 5.67 to 7.73

SECONDARY outcome

Timeframe: Up to 722 days

Population: The analysis population includes all randomized participants who received ≥1 dose of study medication.

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade.

Outcome measures

Measure	Vorinostat + Bortezomib n=315 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) Grade 3	272 Participants	240 Participants
Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) Grade 4	108 Participants	85 Participants
Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs) Grade 5	11 Participants	17 Participants

SECONDARY outcome

Timeframe: From randomization up to 32 months (final study analysis)

Population: The analysis population includes all randomized participants.

Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.

Outcome measures

Measure	Vorinostat + Bortezomib n=317 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Overall Survival	1.7 Events/100-person Months 95% Confidence Interval 1.56 • Interval 1.56 to 1.84	1.9 Events/100-person Months 95% Confidence Interval 1.75 • Interval 1.75 to 2.05

SECONDARY outcome

Timeframe: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

Population: The analysis population includes all randomized participants.

Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

Outcome measures

Measure	Vorinostat + Bortezomib n=317 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Time to Progression	7.73 Months 95% Confidence Interval 7.00 • Interval 7.0 to 8.53	7.03 Months 95% Confidence Interval 6.33 • Interval 6.33 to 7.73

SECONDARY outcome

Timeframe: Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)

Population: The analysis population includes all randomized participants who received ≥1 dose of study medication.

Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.

Outcome measures

Measure	Vorinostat + Bortezomib n=315 Participants Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 Participants Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Objective Response Rate	56.2 Percentage of Participants 95% Confidence Interval 50.5 • Interval 50.5 to 61.7	40.6 Percentage of Participants 95% Confidence Interval 35.2 • Interval 35.2 to 46.2

Adverse Events

Vorinostat + Bortezomib

Serious events: 130 serious events

Other events: 312 other events

Deaths: 0 deaths

Placebo + Bortezomib

Serious events: 138 serious events

Other events: 306 other events

Deaths: 0 deaths

Serious adverse events

Measure	Vorinostat + Bortezomib n=315 participants at risk Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 participants at risk Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Blood and lymphatic system disorders Anaemia	1.3% 4/315 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Bone marrow failure	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Febrile neutropenia	1.3% 4/315 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Haemolysis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Neutropenia	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Thrombocytopenia	2.9% 9/315 • Number of events 13 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Acute myocardial infarction	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Arrhythmia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Atrial fibrillation	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Cardiac failure	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Cardiac failure congestive	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Cardiopulmonary failure	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Myocardial infarction	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Cardiac disorders Supraventricular tachycardia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Ear and labyrinth disorders Deafness	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Ear and labyrinth disorders Vertigo	0.32% 1/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Endocrine disorders Hyperparathyroidism primary	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Eye disorders Retinal detachment	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Abdominal pain	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Constipation	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Diarrhoea	2.9% 9/315 • Number of events 12 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	3.1% 10/320 • Number of events 10 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Gastritis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Haemorrhoids	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Ileus	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Ileus paralytic	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Melaena	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Nausea	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Odynophagia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Oesophagitis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Pneumatosis intestinalis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Vomiting	2.5% 8/315 • Number of events 8 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	2.2% 7/320 • Number of events 8 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Asthenia	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Death	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Fatigue	0.95% 3/315 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.6% 5/320 • Number of events 6 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders General physical health deterioration	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Generalised oedema	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Influenza like illness	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Multi-organ failure	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Pelvic mass	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Pyrexia	1.9% 6/315 • Number of events 7 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	2.8% 9/320 • Number of events 12 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Swelling	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Hepatobiliary disorders Hepatic necrosis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Immune system disorders Hypersensitivity	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Bronchitis	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Bronchitis pneumococcal	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Bronchopneumonia	1.3% 4/315 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Cellulitis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Clostridial infection	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Clostridium difficile colitis	0.63% 2/315 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Conjunctivitis bacterial	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Device related sepsis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Escherichia sepsis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Fungal infection	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Gastroenteritis	1.9% 6/315 • Number of events 9 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Gastroenteritis salmonella	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Gastroenteritis viral	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Gastrointestinal infection	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Gastrointestinal viral infection	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations H1N1 influenza	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Haemophilus infection	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Hepatitis B	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Herpes simplex	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Herpes zoster	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.9% 6/320 • Number of events 6 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Herpes zoster ophthalmic	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Lobar pneumonia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Lower respiratory tract infection	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Lung infection	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Pharyngitis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Pneumococcal sepsis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Pneumonia	4.4% 14/315 • Number of events 17 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.1% 13/320 • Number of events 13 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Respiratory tract infection	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Respiratory tract infection viral	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Sepsis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.6% 5/320 • Number of events 5 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Septic shock	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Skin infection	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Tracheobronchitis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Tuberculosis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Upper respiratory tract infection	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Upper respiratory tract infection bacterial	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Urinary tract infection	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.2% 4/320 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Viral infection	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Accidental overdose	10.2% 32/315 • Number of events 52 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.4% 27/320 • Number of events 43 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Rib fracture	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Road traffic accident	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Spinal compression fracture	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Tibia fracture	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Investigations Blood creatinine increased	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Decreased appetite	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Dehydration	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.6% 5/320 • Number of events 5 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hyperglycaemia	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hypoglycaemia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hypokalaemia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hyponatraemia	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Metabolic disorder	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Tumour lysis syndrome	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Back pain	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Muscular weakness	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Spondylitis	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Synovial cyst	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B-cell lymphoma	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	3.2% 10/315 • Number of events 10 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.1% 13/320 • Number of events 13 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Ataxia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Brain oedema	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Cerebral infarction	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Cerebral ischaemia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Cerebrovascular accident	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Cognitive disorder	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Diabetic coma	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Dizziness	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Haemorrhage intracranial	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Headache	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Lethargy	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Neuralgia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Paraplegia	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Spinal cord compression	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.2% 4/320 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Syncope	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Psychiatric disorders Anxiety disorder	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Psychiatric disorders Completed suicide	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Renal and urinary disorders Azotaemia	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Renal and urinary disorders Renal failure	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.2% 4/320 • Number of events 5 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Renal and urinary disorders Renal failure acute	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Renal and urinary disorders Renal impairment	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Apnoea	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Bronchitis chronic	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.63% 2/315 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Angioedema	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Decubitus ulcer	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Circulatory collapse	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Deep vein thrombosis	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Haemorrhage	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Hypertension	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Hypotension	0.32% 1/315 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.62% 2/320 • Number of events 2 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Orthostatic hypotension	1.3% 4/315 • Number of events 4 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.00% 0/320 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Shock	0.00% 0/315 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.31% 1/320 • Number of events 1 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.

Other adverse events

Measure	Vorinostat + Bortezomib n=315 participants at risk Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.	Placebo + Bortezomib n=320 participants at risk Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
Blood and lymphatic system disorders Anaemia	28.9% 91/315 • Number of events 198 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	24.7% 79/320 • Number of events 164 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Leukopenia	13.3% 42/315 • Number of events 121 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	10.0% 32/320 • Number of events 122 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Neutropenia	35.6% 112/315 • Number of events 406 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	29.7% 95/320 • Number of events 300 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Blood and lymphatic system disorders Thrombocytopenia	54.6% 172/315 • Number of events 749 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	33.1% 106/320 • Number of events 384 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Abdominal distension	2.5% 8/315 • Number of events 11 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	5.3% 17/320 • Number of events 21 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Abdominal pain	7.0% 22/315 • Number of events 37 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.4% 27/320 • Number of events 40 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Abdominal pain upper	8.3% 26/315 • Number of events 42 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.1% 13/320 • Number of events 20 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Constipation	20.3% 64/315 • Number of events 91 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	26.9% 86/320 • Number of events 132 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Diarrhoea	61.6% 194/315 • Number of events 604 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	41.6% 133/320 • Number of events 275 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Dyspepsia	7.6% 24/315 • Number of events 38 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.1% 26/320 • Number of events 40 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Nausea	61.3% 193/315 • Number of events 457 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	39.4% 126/320 • Number of events 247 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Gastrointestinal disorders Vomiting	44.4% 140/315 • Number of events 280 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	25.0% 80/320 • Number of events 127 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Asthenia	14.6% 46/315 • Number of events 89 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	12.5% 40/320 • Number of events 80 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Fatigue	39.7% 125/315 • Number of events 350 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	30.0% 96/320 • Number of events 176 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Oedema peripheral	7.6% 24/315 • Number of events 28 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	7.5% 24/320 • Number of events 27 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
General disorders Pyrexia	21.0% 66/315 • Number of events 114 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	21.9% 70/320 • Number of events 130 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Herpes zoster	7.0% 22/315 • Number of events 26 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	5.9% 19/320 • Number of events 21 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Nasopharyngitis	5.1% 16/315 • Number of events 22 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	5.6% 18/320 • Number of events 20 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Infections and infestations Upper respiratory tract infection	17.5% 55/315 • Number of events 76 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	11.9% 38/320 • Number of events 58 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Investigations Blood creatinine increased	5.4% 17/315 • Number of events 26 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	3.4% 11/320 • Number of events 14 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Investigations Weight decreased	7.0% 22/315 • Number of events 36 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	6.9% 22/320 • Number of events 30 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Decreased appetite	23.8% 75/315 • Number of events 123 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	26.6% 85/320 • Number of events 139 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hypokalaemia	11.1% 35/315 • Number of events 57 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	7.8% 25/320 • Number of events 40 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Arthralgia	8.3% 26/315 • Number of events 34 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.4% 27/320 • Number of events 40 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Back pain	15.6% 49/315 • Number of events 67 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	14.7% 47/320 • Number of events 69 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Bone pain	4.8% 15/315 • Number of events 27 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	7.5% 24/320 • Number of events 39 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Muscle spasms	6.7% 21/315 • Number of events 25 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.7% 15/320 • Number of events 17 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	5.1% 16/315 • Number of events 21 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	11.9% 38/320 • Number of events 52 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Dizziness	11.4% 36/315 • Number of events 56 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.4% 27/320 • Number of events 37 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Dysgeusia	7.3% 23/315 • Number of events 28 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	1.9% 6/320 • Number of events 8 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Headache	11.1% 35/315 • Number of events 45 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	10.6% 34/320 • Number of events 45 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Hypoaesthesia	3.2% 10/315 • Number of events 12 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	5.6% 18/320 • Number of events 26 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Neuralgia	26.0% 82/315 • Number of events 124 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	26.9% 86/320 • Number of events 125 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Neuropathy peripheral	19.7% 62/315 • Number of events 94 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	20.0% 64/320 • Number of events 97 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Paraesthesia	6.3% 20/315 • Number of events 27 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	3.8% 12/320 • Number of events 14 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Nervous system disorders Peripheral sensory neuropathy	10.5% 33/315 • Number of events 58 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.4% 27/320 • Number of events 39 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Psychiatric disorders Insomnia	8.9% 28/315 • Number of events 32 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	9.1% 29/320 • Number of events 36 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Cough	16.5% 52/315 • Number of events 71 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	15.0% 48/320 • Number of events 61 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.3% 26/315 • Number of events 36 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	8.8% 28/320 • Number of events 35 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.1% 16/315 • Number of events 17 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.1% 13/320 • Number of events 16 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Alopecia	7.6% 24/315 • Number of events 26 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	0.94% 3/320 • Number of events 3 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Rash	9.8% 31/315 • Number of events 43 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	12.5% 40/320 • Number of events 61 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Hypertension	9.2% 29/315 • Number of events 37 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	4.1% 13/320 • Number of events 16 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.
Vascular disorders Hypotension	6.0% 19/315 • Number of events 23 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.	3.8% 12/320 • Number of events 15 • Up to 722 days. Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.

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 An investigator may not independently publish the results for their study site until after the multicenter publication, or 24 months after completion of study. Sponsor must 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