Trial Outcomes & Findings for Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008) (NCT NCT02070757)

NCT ID: NCT02070757

Last Updated: 2020-05-05

Results Overview

To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in stratified adult participants with ventilated nosocomial pneumonia (VNP) (participants with either ventilator-associated bacterial pneumonia \[VABP\] or ventilated hospital-acquired bacterial pneumonia \[HABP\]) based on the difference in all-cause mortality rates in the intent to treat (ITT) population using a non-inferiority margin of 10%. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

726 participants

Primary outcome timeframe

Day 28

Results posted on

2020-05-05

Participant Flow

A total of 263 sites were opened for enrollment with the majority of participants recruited from sites in eastern Europe.

Randomization was stratified by diagnosis (ventilator-associated bacterial pneumonia \[VABP\] or ventilated hospital-acquired bacterial pneumonia \[HABP\]) and by age (\<65 or ≥65 years). All participants randomized were included in the intent-to-treat (ITT) population.

Participant milestones

Participant milestones
Measure	Ceftolozane/Tazobactam Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Overall Study STARTED	362	364
Overall Study Treated Participants	361	359
Overall Study COMPLETED	245	250
Overall Study NOT COMPLETED	117	114

Reasons for withdrawal

Reasons for withdrawal
Measure	Ceftolozane/Tazobactam Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Overall Study Adverse Event	107	99
Overall Study Lost to Follow-up	7	4
Overall Study Protocol Violation	0	4
Overall Study Withdrawal by Subject	1	3
Overall Study Investigator Decision	0	2
Overall Study Discharged from Study Hospital	2	2

Baseline Characteristics

Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ceftolozane/Tazobactam n=362 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=364 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.	Total n=726 Participants Total of all reporting groups
Age, Continuous	60.5 Years STANDARD_DEVIATION 16.7 • n=5 Participants	59.5 Years STANDARD_DEVIATION 17.2 • n=7 Participants	60.0 Years STANDARD_DEVIATION 16.9 • n=5 Participants
Sex: Female, Male Female	100 Participants n=5 Participants	109 Participants n=7 Participants	209 Participants n=5 Participants
Sex: Female, Male Male	262 Participants n=5 Participants	255 Participants n=7 Participants	517 Participants n=5 Participants
Race/Ethnicity, Customized Asian	27 Participants n=5 Participants	23 Participants n=7 Participants	50 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	10 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized White	301 Participants n=5 Participants	300 Participants n=7 Participants	601 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian Or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized American Indian Or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Not Reported	19 Participants n=5 Participants	27 Participants n=7 Participants	46 Participants n=5 Participants
Race/Ethnicity, Customized Missing	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 28

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=362 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=364 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28	24.0 Percentage of Participants Interval 18.83 to 27.39	25.3 Percentage of Participants Interval 19.96 to 28.41

SECONDARY outcome

Timeframe: 7 to 14 days after last dose of study drug (Up to ~Day 30)

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) at the TOC visit (7 to 14 days after the end-of-therapy \[EOT\] visit) using a non-inferiority margin of 12.5%. Clinical response at the TOC visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate unless the clinical outcome at the EOT visit was failure. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=362 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=364 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population	54.4 Percentage of Participants Interval 49.47 to 59.6	53.3 Percentage of Participants Interval 48.44 to 58.54

SECONDARY outcome

Timeframe: Day 28

Population: The mITT population was a subset of the ITT population that included any participant who received any amount of study drug and had at least 1 bacterial respiratory pathogen isolated from the baseline LRT culture that was susceptible to at least 1 of the study drugs.

To compare the all cause mortality rates of participants in the ceftolozane/tazobactam versus meropenem arms in microbiological intent-to-treat (mITT) population.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=264 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=247 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28	20.1 Percentage of Participants Interval 15.12 to 24.5	25.5 Percentage of Participants Interval 18.89 to 29.35

SECONDARY outcome

Timeframe: 7 to 14 days after last dose of study drug (Up to ~Day 30)

Population: The CE population was a subset of the ITT population that included any participant who received study drug, adhered to the study protocol through the TOC visit, and had an evaluable clinical outcome (either Cure or Failure) at the TOC visit (or were classified as a clinical failure prior to the TOC visit).

To compare the clinical response rates of ceftolozane/tazobactam versus meropenem in adult participants with VNP (participants with either ventilator-associated bacterial pneumonia \[VABP\] or ventilated hospital-acquired bacterial pneumonia \[HABP\]) at the TOC visit in the CE population. Clinical response at the TOC visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate unless the clinical outcome at the EOT visit was failure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=218 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=221 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population	63.8 Percentage of Participants Interval 57.5 to 70.11	64.7 Percentage of Participants Interval 58.83 to 71.19

SECONDARY outcome

Timeframe: 7 to 14 days after last dose of study drug (Up to ~Day 30)

Population: The ME population was a subset of the mITT population that included any participants who adhered to the study protocol through the TOC visit, had an evaluable clinical outcome (Cure or Failure) at the TOC visit and had at least 1 bacterial respiratory pathogen (at the appropriate CFU/mL threshold) isolated from the baseline LRT culture.

To compare the per-participant microbiological response rates of ceftolozane/tazobactam versus meropenem at the TOC visit in the microbiologically evaluable (ME) population. The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the TOC visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=115 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=118 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Per-Participant Microbiological Response of Cure or Presumed Cure at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population	70.4 Percentage of Participants Interval 61.37 to 77.55	62.7 Percentage of Participants Interval 54.12 to 71.24

SECONDARY outcome

Timeframe: 7 to 14 days after last dose of study drug (Up to ~Day 30)

Population: The ME population included any participants in the mITT who adhered to the protocol, had an evaluable clinical outcome at TOC and at least 1 pathogen isolated from the baseline LRT culture at the appropriate CFU/mL threshold. The number analyzed per pathogen represents the number of participants in the ME population with that specific pathogen.

To compare the percentage of participants with a microbiological outcome of eradication or presumed eradication, by pathogen. The microbiological outcome was classified as "eradication", "presumed eradication", "persistence", 'presumed persistence", "indeterminate" or "recurrence." "Eradication" was defined as a ≥1- log reduction in bacterial burden of the original baseline LRT pathogen AND a per pathogen count of ≤10\^4 colony-forming unit (CFU)/mL for endotracheal aspirate (ETA) or sputum specimens, ≤10\^3 CFU/mL for a bronchoalveolar lavage (BAL) specimen, or ≤10\^2 CFU/mL for a protected brush specimen (PBS) from a follow-up LRT culture. Presumed eradication was defined as an absence of material to culture (e.g. inability to obtain a culture in an extubated patient) in a patient deemed a clinical cure.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=115 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=118 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Gram-Negative	69.9 Percentage of Participants Interval 60.91 to 77.6	62.4 Percentage of Participants Interval 53.35 to 70.64
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Pseudomonas aeruginosa	79.3 Percentage of Participants Interval 61.61 to 90.15	55.3 Percentage of Participants Interval 39.71 to 69.85
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Enterobacteriaceae	68.7 Percentage of Participants Interval 58.06 to 77.64	65.6 Percentage of Participants Interval 55.28 to 74.55
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Escherichia coli	78.3 Percentage of Participants Interval 58.1 to 90.34	73.9 Percentage of Participants Interval 53.53 to 87.45
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Klebsiella pneumoniae	71.4 Percentage of Participants Interval 56.43 to 82.83	66.7 Percentage of Participants Interval 52.54 to 78.32
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Proteus mirabilis	63.6 Percentage of Participants Interval 35.38 to 84.83	70.0 Percentage of Participants Interval 39.68 to 89.22
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Haemophilus influenzae	91.7 Percentage of Participants Interval 64.61 to 98.51	50.0 Percentage of Participants Interval 21.52 to 78.48
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Enterobacter cloacae	57.1 Percentage of Participants Interval 25.05 to 84.18	75.0 Percentage of Participants Interval 40.93 to 92.85
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Klebsiella oxytoca	87.5 Percentage of Participants Interval 52.91 to 97.76	57.1 Percentage of Participants Interval 25.05 to 84.18
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Serratia marcescens	40.0 Percentage of Participants Interval 11.76 to 76.93	50.0 Percentage of Participants Interval 18.76 to 81.24
Percentage of Participants With Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline) Acinetobacter baumannii	33.3 Percentage of Participants Interval 9.68 to 70.0	80.0 Percentage of Participants Interval 37.55 to 96.38

SECONDARY outcome

Timeframe: Day 14

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

To compare the all cause mortality rates of participants (ceftolozane/tazobactam versus meropenem arms). Participants whose Day 14 mortality outcomes are missing or unknown are analysed as deceased.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=362 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=364 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14	14.1 Percentage of Participants Interval 10.48 to 17.57	12.9 Percentage of Participants Interval 9.31 to 15.86

SECONDARY outcome

Timeframe: Within 24 hours after last dose of study drug (Up to ~Day 15)

Population: The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.

To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus meropenem. Clinical response at the EOT visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=362 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=364 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population	66.0 Percentage of Participants Interval 61.38 to 71.03	66.8 Percentage of Participants Interval 62.31 to 71.77

SECONDARY outcome

Timeframe: Within 24 hours after last dose of study drug (Up to ~Day 15)

To compare the microbiological response rates of ceftolozane/tazobactam versus meropenem at the EOT visit. The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the EOT visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=264 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=247 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Per-Participant Microbiological Response of Cure or Presumed Cure at the End-of-Therapy (EOT) Visit in the Microbiologically Evaluable (ME) Population	80.9 Percentage of Participants Interval 71.51 to 86.33	78.8 Percentage of Participants Interval 70.25 to 84.9

SECONDARY outcome

Timeframe: 28 to 35 days after the last dose of study drug (Up to ~Day 50)

To compare the clinical response rates at the Late Follow-up (LFU) visit for ceftolozane/tazobactam versus meropenem in the CE population. Clinical response at the LFU visit will be classified as sustained cure, relapse, or indeterminate only in participants deemed a clinical cure at the TOC visit. A favorable clinical response is "sustained clinical cure."

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=218 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=221 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population	52.8 Percentage of Participants Interval 90.1 to 97.99	51.6 Percentage of Participants Interval 85.86 to 95.72

SECONDARY outcome

Timeframe: Up to 35 days after last dose of study drug (Up to ~Day 50)

Population: All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=361 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=359 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants Who Report 1 or More Adverse Event (AE)	85.9 Percentage of Participants	83.3 Percentage of Participants

SECONDARY outcome

Timeframe: Up to 35 days after last dose of study drug (Up to ~Day 50)

A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment.

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=361 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=359 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants With Any Serious Adverse Event (SAE)	42.1 Percentage of Participants	35.9 Percentage of Participants

SECONDARY outcome

Timeframe: Up to 14 days after the first dose of study drug (Up to ~Day 15)

Outcome measures

Outcome measures
Measure	Ceftolozane/Tazobactam n=361 Participants Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=359 Participants Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE)	10.2 Percentage of Participants	11.7 Percentage of Participants

Adverse Events

Ceftolozane/Tazobactam

Serious events: 152 serious events

Other events: 113 other events

Deaths: 105 deaths

Meropenem

Serious events: 129 serious events

Other events: 111 other events

Deaths: 101 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Ceftolozane/Tazobactam n=361 participants at risk Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).	Meropenem n=359 participants at risk Participants receive 1000 mg meropenem administered as an IV infusion q8h.
Blood and lymphatic system disorders Anaemia	8.9% 32/361 • Number of events 32 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	10.6% 38/359 • Number of events 45 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
Gastrointestinal disorders Diarrhoea	6.4% 23/361 • Number of events 23 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	7.0% 25/359 • Number of events 28 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
Infections and infestations Urinary tract infection	6.4% 23/361 • Number of events 24 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	7.0% 25/359 • Number of events 27 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
Investigations Alanine aminotransferase increased	5.5% 20/361 • Number of events 21 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	3.9% 14/359 • Number of events 14 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
Respiratory, thoracic and mediastinal disorders Hydrothorax	4.4% 16/361 • Number of events 17 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	5.6% 20/359 • Number of events 24 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
Skin and subcutaneous tissue disorders Decubitus ulcer	6.9% 25/361 • Number of events 30 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.	4.7% 17/359 • Number of events 22 • From first dose of study drug up to 35 days after last dose of study drug (Up to ~Day 50) All safety analyses were based on a subset of the ITT population who received any amount (i.e., full or partial dose) of study drug (the Safety Population). All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor will review proposed publication within forty five (45) calendar days and reserves the right to defer such publication an additional forty five (45) calendar days to protect Sponsor's intellectual property as applicable. If a joint manuscript has not been submitted for publication within twelve (12) months of completion or termination of Trial at all participating sites, Principal Investigator is free to publish separately, subject to the other requirements of this Agreement.
Publication restrictions are in place

Restriction type: OTHER