Trial Outcomes & Findings for Dinutuximab and Irinotecan Versus Irinotecan to Treat Subjects With Relapsed or Refractory Small Cell Lung Cancer (NCT NCT03098030)

Last Updated: 2020-12-09

Results Overview

OS will be derived as: (date of death - date of randomization) + 1. Subjects who are alive or permanently lost to follow-up at the cut-off date for the analysis will be censored at the last date the subject was known to be alive.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

483 participants

Primary outcome timeframe

Up to approximately 2.5 years

Results posted on

2020-12-09

Participant Flow

Participant milestones

Participant milestones
Measure	Part 1: Dinutuximab + Irinotecan Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Dinutuximab + Irinotecan Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Overall Study STARTED	12	187	190	94
Overall Study COMPLETED	2	24	24	9
Overall Study NOT COMPLETED	10	163	166	85

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Dinutuximab + Irinotecan Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Dinutuximab + Irinotecan Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Overall Study Death	10	156	156	82
Overall Study Withdrawal by Subject	0	7	8	2
Overall Study Lost to Follow-up	0	0	2	1

Baseline Characteristics

Dinutuximab and Irinotecan Versus Irinotecan to Treat Subjects With Relapsed or Refractory Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Dinutuximab + Irinotecan n=12 Participants Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Dinutuximab + Irinotecan n=187 Participants Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=190 Participants Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=94 Participants Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection	Total n=483 Participants Total of all reporting groups
Age, Continuous	67.9 years STANDARD_DEVIATION 8.8 • n=5 Participants	61.3 years STANDARD_DEVIATION 8.7 • n=7 Participants	61.5 years STANDARD_DEVIATION 9.0 • n=5 Participants	62.5 years STANDARD_DEVIATION 8.4 • n=4 Participants	61.6 years STANDARD_DEVIATION 8.7 • n=21 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	45 Participants n=7 Participants	43 Participants n=5 Participants	26 Participants n=4 Participants	118 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	142 Participants n=7 Participants	147 Participants n=5 Participants	68 Participants n=4 Participants	365 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	11 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants n=5 Participants	137 Participants n=7 Participants	142 Participants n=5 Participants	72 Participants n=4 Participants	355 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants	45 Participants n=7 Participants	46 Participants n=5 Participants	18 Participants n=4 Participants	117 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	28 Participants n=7 Participants	34 Participants n=5 Participants	18 Participants n=4 Participants	80 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	113 Participants n=7 Participants	106 Participants n=5 Participants	54 Participants n=4 Participants	277 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants	45 Participants n=7 Participants	47 Participants n=5 Participants	19 Participants n=4 Participants	119 Participants n=21 Participants
Region of Enrollment Southeast Asia	0 Participants n=5 Participants	27 Participants n=7 Participants	39 Participants n=5 Participants	16 Participants n=4 Participants	82 Participants n=21 Participants
Region of Enrollment North America	4 Participants n=5 Participants	31 Participants n=7 Participants	32 Participants n=5 Participants	16 Participants n=4 Participants	83 Participants n=21 Participants
Region of Enrollment Europe	8 Participants n=5 Participants	129 Participants n=7 Participants	119 Participants n=5 Participants	62 Participants n=4 Participants	318 Participants n=21 Participants
ECOG Performance Status Performance Status = 0	3 Participants n=5 Participants	37 Participants n=7 Participants	40 Participants n=5 Participants	19 Participants n=4 Participants	99 Participants n=21 Participants
ECOG Performance Status Performance Status = 1	9 Participants n=5 Participants	150 Participants n=7 Participants	150 Participants n=5 Participants	75 Participants n=4 Participants	384 Participants n=21 Participants
Tobacco Use No	0 Participants n=5 Participants	22 Participants n=7 Participants	12 Participants n=5 Participants	12 Participants n=4 Participants	46 Participants n=21 Participants
Tobacco Use Yes	12 Participants n=5 Participants	165 Participants n=7 Participants	178 Participants n=5 Participants	82 Participants n=4 Participants	437 Participants n=21 Participants
Body Surface Area (m^2)	26.40 m^2 STANDARD_DEVIATION 4.42 • n=5 Participants	25.84 m^2 STANDARD_DEVIATION 5.01 • n=7 Participants	25.95 m^2 STANDARD_DEVIATION 4.91 • n=5 Participants	25.54 m^2 STANDARD_DEVIATION 4.89 • n=4 Participants	25.82 m^2 STANDARD_DEVIATION 4.94 • n=21 Participants

PRIMARY outcome

Timeframe: Up to approximately 2.5 years

Population: The analysis population was based on the Intent to Treat (ITT) Analysis Set, which per the Statistical Analysis Plan was defined as all subjects randomized in Part 2 of the study, as assigned to treatment (i.e., n = 471). As such, these results do not include the subjects enrolled in Part 1 of the study.

Outcome measures

Outcome measures
Measure	Part 2: Dinutuximab + Irinotecan n=187 Participants Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=190 Participants Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=94 Participants Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Overall Survival (OS)	6.9 months Interval 6.0 to 7.6	7.0 months Interval 5.6 to 8.9	7.4 months Interval 6.1 to 9.3

SECONDARY outcome

Timeframe: Up to approximately 2.5 years

PFS will be defined as the time from the date of randomization to the date of first documentation of tumor progression or death from any cause, whichever occurs first.

Outcome measures

Outcome measures
Measure	Part 2: Dinutuximab + Irinotecan n=187 Participants Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=190 Participants Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=94 Participants Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Progression-free Survival (PFS)	3.5 months Interval 2.8 to 4.2	3.0 months Interval 2.7 to 4.2	3.4 months Interval 2.8 to 4.2

SECONDARY outcome

Timeframe: Up to approximately 2.5 years

The ORR is the percentage of subjects with best overall response of either complete response (CR) or partial response (PR); ORR = CR + PR. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters as confirmed by CT or MRI.

Outcome measures

Outcome measures
Measure	Part 2: Dinutuximab + Irinotecan n=187 Participants Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=190 Participants Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=94 Participants Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Objective Response Rate (ORR)	32 Participants	36 Participants	19 Participants

SECONDARY outcome

Timeframe: Up to approximately 2.5 years

The CBR is defined as the percentage of subjects with either a CR, PR, or stable disease (SD), relative to the number of subjects in the treatment group. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study, as confirmed by CT or MRI .

Outcome measures

Outcome measures
Measure	Part 2: Dinutuximab + Irinotecan n=187 Participants Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=190 Participants Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=94 Participants Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Clinical Benefit Rate (CBR)	126 Participants	112 Participants	64 Participants

Adverse Events

Part 1: Dinutuximab + Irinotecan

Serious events: 5 serious events

Other events: 12 other events

Deaths: 10 deaths

Part 2: Dinutuximab + Irinotecan

Serious events: 74 serious events

Other events: 183 other events

Deaths: 158 deaths

Part 2: Irinotecan

Serious events: 76 serious events

Other events: 183 other events

Deaths: 159 deaths

Part 2: Topotecan

Serious events: 39 serious events

Other events: 86 other events

Deaths: 84 deaths

Serious adverse events

Other adverse events

Additional Information

Program Manager, Oncology

United Therapeutics Corporation

Phone: 919-485-8350

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Prior to submission for any public disclosure of the data or results, the Institution and Principal Investigator shall provide Sponsor with at least 60 days for review of the Publication. In addition, the Institution and Principal Investigator agree that the first Publication of the results shall be made as a joint, multicenter publication coordinated by Sponsor, with investigators and institutions from all participating sites contributing data.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Part 1: Dinutuximab + Irinotecan n=12 participants at risk Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Dinutuximab + Irinotecan n=183 participants at risk Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=187 participants at risk Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=88 participants at risk Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Vascular disorders Hypotension	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.4% 8/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.1% 17/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.4% 3/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Neutropenia	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.8% 7/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.7% 7/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.5% 4/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Anemia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.2% 4/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.8% 6/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Atrial fibrillation	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Diarrhea	16.7% 2/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.4% 8/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.1% 17/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Leukocytosis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Leukopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Lymphopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Acute coronary syndrome	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Pancytopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	8.0% 7/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Bradycardia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Cardio-respiratory arrest	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Coronary artery disease	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Endocarditis noninfective	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Myocardial infarction	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Pericardial effusion	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Acute myocardial infarction	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Atrial flutter	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Cardiac failure	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Supraventricular tachycardia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Vomiting	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.3% 6/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.8% 9/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal pain	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.2% 4/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.3% 2/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal pain upper	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Nausea	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal distension	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Colitis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Constipation	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Dysphagia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Gastrointestinal toxicity	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Neutropenic colitis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Pancreatitis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Duodenal perforation	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Enteritis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Ileus	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Oesophagitis	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Asthenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.2% 4/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Chest pain	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).

Other adverse events
Measure	Part 1: Dinutuximab + Irinotecan n=12 participants at risk Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Dinutuximab + Irinotecan n=183 participants at risk Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV. Dinutuximab: Dinutuximab injection, for intravenous (IV) use Irinotecan: Irinotecan injection, IV infusion	Part 2: Irinotecan n=187 participants at risk Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Irinotecan: Irinotecan injection, IV infusion	Part 2: Topotecan n=88 participants at risk Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle. Topotecan: Topotecan for injection
Blood and lymphatic system disorders Anaemia	25.0% 3/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	36.6% 67/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	29.4% 55/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	65.9% 58/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Neutropenia	33.3% 4/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	32.2% 59/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	25.1% 47/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	51.1% 45/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Leukopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	16.4% 30/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	11.8% 22/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	13.6% 12/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.8% 18/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	7.0% 13/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	25.0% 22/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.0% 11/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.6% 18/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.5% 4/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Cardiac disorders Atrial fibrillation	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Diarrhoea	83.3% 10/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	64.5% 118/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	62.0% 116/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	14.8% 13/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal pain	41.7% 5/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	44.8% 82/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	12.8% 24/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	10.2% 9/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Nausea	58.3% 7/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	44.3% 81/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	47.1% 88/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	25.0% 22/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Vomiting	41.7% 5/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	35.5% 65/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	30.5% 57/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.8% 6/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal pain upper	16.7% 2/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	16.4% 30/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.9% 11/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.7% 5/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Constipation	33.3% 4/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	8.7% 16/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	8.6% 16/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	14.8% 13/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Dysphagia	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.3% 6/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Gastrooesophageal reflux disease	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.2% 4/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.1% 4/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Stomatitis	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.2% 4/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.8% 9/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.8% 6/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Abdominal pain lower	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Dry mouth	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.1% 4/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Gastrointestinal disorders Flatulence	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.53% 1/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Asthenia	33.3% 4/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	24.0% 44/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	20.9% 39/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	28.4% 25/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Fatigue	25.0% 3/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	19.7% 36/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	25.7% 48/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	18.2% 16/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Non-cardiac chest pain	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	13.1% 24/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	4.3% 8/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.7% 5/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Pyrexia	16.7% 2/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	10.4% 19/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.3% 10/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	14.8% 13/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Pain	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	7.1% 13/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.7% 5/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Chest pain	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.0% 11/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.7% 5/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 1/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Chest discomfort	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.7% 5/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
General disorders Discomfort	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Infections and infestations Pneumonia	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.6% 12/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.9% 11/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	10.2% 9/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Infections and infestations Upper respiratory tract infection	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.7% 5/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.3% 10/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.3% 2/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Infections and infestations Septic shock	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.1% 2/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Infections and infestations Bronchitis	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.55% 1/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	1.6% 3/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.4% 3/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Infections and infestations Clostridium difficile colitis	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.1% 4/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	0.00% 0/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Weight decreased	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	13.1% 24/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	13.4% 25/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.1% 8/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Blood lactate dehydrogenase increased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	10.4% 19/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.2% 6/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.7% 5/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Neutrophil count decreased	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.8% 18/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	15.0% 28/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	26.1% 23/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Alanine aminotransferase increased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.6% 12/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	7.0% 13/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.1% 8/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Aspartate aminotransferase increased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.5% 10/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.9% 11/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	9.1% 8/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Platelet count decreased	8.3% 1/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.5% 10/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.2% 6/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	20.5% 18/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Blood alkaline phosphatase increased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.8% 7/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.2% 6/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.7% 5/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations White blood cell count decreased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	3.3% 6/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	6.4% 12/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	15.9% 14/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).
Investigations Lymphocyte count decreased	0.00% 0/12 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.7% 5/183 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	2.1% 4/187 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).	5.7% 5/88 • Adverse events (AEs) were collected for all enrolled subjects beginning with first dose of study medication. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent. In addition to reporting while on study therapy, adverse events were required to be reported through 30 days after the last dose of study therapy. AEs were collected via Investigator assessment and laboratory testing during routine visits as required per protocol. For the analyses, All-Cause Mortality was evaluated for all subjects enrolled in Part 1 or randomized in Part 2 of the study and assigned treatment (n = 483). All other Safety Analyses, including Serious Adverse Events and Other Adverse Events, were evaluated using the Safety Analysis Set, defined as all subjects who received at least 1 dose of study medication (n = 470).