Trial Outcomes & Findings for Study of Ceftolozane/Tazobactam (MK-7625A) in Combination With Metronidazole in Japanese Participants With Complicated Intra-abdominal Infection (MK-7625A-013) (NCT NCT02739997)

Results Overview

The percentage of participants with clinical responses (cure, failure, or indeterminate) at TOC was determined. Clinical cure was defined as "complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required". Clinical failure was defined as "death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care". Indeterminate was defined as "study data are not available for evaluation for any reason, including death during the study period unrelated to the index infection; or extenuating circumstances that preclude classification as cure or failure".

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

100 participants

Primary outcome timeframe

Day 28 (28 days after initiating study therapy)

Results posted on

2018-08-09

Participant Flow

Adult participants with complicated intra-abdominal infection (cIAI) were recruited at 37 study sites in Japan.

Participant milestones

Participant milestones
Measure	MK-7625A + Metronidazole MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Overall Study STARTED	100
Overall Study COMPLETED	98
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	MK-7625A + Metronidazole MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Overall Study Death	1
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Study of Ceftolozane/Tazobactam (MK-7625A) in Combination With Metronidazole in Japanese Participants With Complicated Intra-abdominal Infection (MK-7625A-013)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MK-7625A + Metronidazole n=100 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Age, Continuous	61.1 Years STANDARD_DEVIATION 16.3 • n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants
Sex: Female, Male Male	67 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	100 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 28 (28 days after initiating study therapy)

Population: Clinically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, and had a clinical response at the TOC visit within the specified visit window are included.

The percentage of participants with clinical responses (cure, failure, or indeterminate) at TOC was determined. Clinical cure was defined as "complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required". Clinical failure was defined as "death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care". Indeterminate was defined as "study data are not available for evaluation for any reason, including death during the study period unrelated to the index infection; or extenuating circumstances that preclude classification as cure or failure".

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=88 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Test of Cure (TOC) Success	92.0 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Test of Cure (TOC) Failure	8.0 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Test of Cure (TOC) Indeterminate	0.0 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 42 (up to 28 days after completing study therapy)

Population: All participants who received ≥1 dose of study therapy are included.

The percentage of participants with ≥1 AEs was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=100 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Adverse Events (AEs)	62.0 Percentage of Participants Interval 51.7 to 71.5

PRIMARY outcome

Timeframe: Up to Day 14

Population: All participants who received ≥1 dose of study therapy are included.

The percentage of participants withdrawing from study therapy due to an AE was determined.

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=100 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants Discontinuing Study Drug Due to AEs	0.0 Percentage of Participants Interval 0.0 to 3.6

SECONDARY outcome

Timeframe: Up to Day 14

Population: Clinically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, and had a clinical response at EOT visit within the specified visit window are included.

The percentage of participants with clinical responses (cure, failure, or indeterminate) at EOT was determined. Clinical cure was defined as "complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required". Clinical failure was defined as "death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care". Indeterminate was defined as "study data are not available for evaluation for any reason, including death during the study period unrelated to the index infection; or extenuating circumstances that preclude classification as cure or failure".

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=92 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at End Of Therapy (EOT) Success	94.6 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at End Of Therapy (EOT) Failure	5.4 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at End Of Therapy (EOT) Indeterminate	0.0 Percentage of Participants

SECONDARY outcome

Timeframe: Up to Day 42 (28 days after completing study therapy)

Population: Clinically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, and had a clinical response at LFU visit within the specified visit window are included.

The percentage of participants with clinical responses (cure, failure, or indeterminate) at LFU was determined. Clinical cure was defined as "complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required". Clinical failure was defined as "death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care". Indeterminate was defined as "study data are not available for evaluation for any reason, including death during the study period unrelated to the index infection; or extenuating circumstances that preclude classification as cure or failure".

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=85 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Late Follow-Up (LFU) Success	90.6 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Late Follow-Up (LFU) Failure	9.4 Percentage of Participants
Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Late Follow-Up (LFU) Indeterminate	0.0 Percentage of Participants

SECONDARY outcome

Timeframe: Up to Day 14

Population: Expanded microbiologically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, had a microbiological response at the EOT visit within the specified visit window, and have ≥1 identified intra-abdominal pathogen are included.

The percentage of participants with microbiological responses (eradication, persistence, or indeterminate) at EOT was determined. Eradication was defined as "absence of the baseline pathogen in a specimen". Persistence was defined as "presence of the baseline pathogen in a specimen". Indeterminate was defined as "Baseline culture either not obtained or has an assessment of no growth, or any other circumstance that makes it impossible to define the microbiological response".

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=65 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at EOT Eradication	93.8 Percentage of Participants
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at EOT Persistence	6.2 Percentage of Participants
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at EOT Indeterminate	0.0 Percentage of Participants

SECONDARY outcome

Timeframe: Day 28 (28 days after initiating study therapy)

Population: Expanded microbiologically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, had a microbiological response at the TOC visit within the specified visit window, and have ≥1 identified intra-abdominal pathogen are included.

The percentage of participants with microbiological response (eradication, persistence, or indeterminate) at TOC was determined. Eradication was defined as "absence of the baseline pathogen in a specimen". Persistence was defined as "presence of the baseline pathogen in a specimen". Indeterminate was defined as "Baseline culture either not obtained or has an assessment of no growth, or any other circumstance that makes it impossible to define the microbiological response".

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=61 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at TOC Eradication	90.2 Percentage of Participants
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at TOC Persistence	9.8 Percentage of Participants
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at TOC Indeterminate	0.0 Percentage of Participants

SECONDARY outcome

Timeframe: Up to Day 14

Population: Expanded microbiologically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, had a microbiological response at the EOT visit within the specified visit window, and have ≥1 identified intra-abdominal pathogen are included.

The percentage of participants with per-pathogen microbiological responses at EOT was determined. Individual pathogens were identified at baseline, and the overall percentage of participants with eradication or presumed eradication within each pathogen category are shown.

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=65 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at EOT Gram-Negative Aerobes	94.5 Percentage of Participants Interval 84.9 to 98.9
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at EOT Gram-Positive Aerobes	95.0 Percentage of Participants Interval 83.1 to 99.4
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at EOT Gram-Negative Anaerobes	97.7 Percentage of Participants Interval 88.0 to 99.9
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at EOT Gram-Positive Anaerobes	90.5 Percentage of Participants Interval 69.6 to 98.8

SECONDARY outcome

Timeframe: Day 28 (28 days after initiating study therapy)

Population: Expanded microbiologically evaluable participants were defined as those who received study therapy for ≥3 days, had 80-120% study therapy compliance, met criteria for cIAI, adhered to study procedures, had a microbiological response at the TOC visit within the specified visit window, and have ≥1 identified intra-abdominal pathogen are included.

The percentage of participants with per-pathogen microbiological responses at TOC was determined. Individual pathogens were identified at baseline, and the overall percentage of participants with eradication or presumed eradication within each pathogen category are shown.

Outcome measures

Outcome measures
Measure	MK-7625A + Metronidazole n=61 Participants MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at TOC Gram-Negative Aerobes	90.6 Percentage of Participants Interval 79.3 to 96.9
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at TOC Gram-Positive Aerobes	89.5 Percentage of Participants Interval 75.2 to 97.1
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at TOC Gram-Negative Anaerobes	95.2 Percentage of Participants Interval 83.8 to 99.4
Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at TOC Gram-Positive Anaerobes	85.0 Percentage of Participants Interval 62.1 to 96.8

Adverse Events

MK-7625A + Metronidazole

Serious events: 10 serious events

Other events: 32 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	MK-7625A + Metronidazole n=100 participants at risk MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Gastrointestinal disorders Gastrooesophageal reflux disease	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Gastrointestinal disorders Ileus	2.0% 2/100 • Number of events 2 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Hepatobiliary disorders Cholecystitis	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Infections and infestations Pneumonia	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Infections and infestations Sepsis	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Psychiatric disorders Eating disorder	1.0% 1/100 • Number of events 1 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.

Other adverse events

Other adverse events
Measure	MK-7625A + Metronidazole n=100 participants at risk MK-7625A 1.5 g (ceftolozane 1 g + tazobactam 0.5 g) plus metronidazole 500 mg was administered as an IV infusion every 8 hours for 4 to 14 days.
Gastrointestinal disorders Constipation	6.0% 6/100 • Number of events 6 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Gastrointestinal disorders Diarrhoea	7.0% 7/100 • Number of events 7 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Investigations Alanine aminotransferase increased	11.0% 11/100 • Number of events 11 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Investigations Aspartate aminotransferase increased	13.0% 13/100 • Number of events 13 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.
Psychiatric disorders Insomnia	11.0% 11/100 • Number of events 11 • Up to Day 42 An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants who received ≥1 dose of study drug are included.

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 The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.
Publication restrictions are in place

Restriction type: OTHER