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

Study Overview
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Brief Summary
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This is a Phase 3, multi-site, non-randomized, open-label study evaluating the safety and efficacy of MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) plus metronidazole 500 mg for the treatment of Complicated Intra-abdominal Infections (cIAI) in Japanese participants. Efficacy will be primarily assessed by clinical response defined as complete resolution or significant improvement in signs and symptoms of the index infection.

Official Title
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A Multicenter, Open-label, Noncomparative, Japanese Phase III Study to Assess the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) Used in Combination With Metronidazole in Japanese Patients With Complicated Intra-abdominal Infection.

Conditions
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Intra-abdominal Infection, Complicated Intra-abdominal Infection

Intervention / Treatment
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* Drug: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g)
* Drug: metronidazole 500 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has one of the following diagnoses with evidence of intra-peritoneal infection: cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or progression of the infection beyond the gallbladder wall; diverticular disease with perforation or abscess; appendiceal perforation or periappendiceal abscess; acute gastric or duodenal perforation, traumatic perforation of the intestine; peritonitis due to perforated viscus or following a prior operative procedure; or Intra-abdominal abscess (including liver and spleen). Has evidence of systemic infection Had or has plans to have surgical intervention within 24 hours of the first dose of study drug Has radiographic evidence of perforation or abscess if enrolled preoperatively Is able to have intra-abdominal specimen taken at baseline for the microbiological assessment Female participants of child bearing potential must not be pregnant (negative human chorionic gonadotropin test) or breastfeeding and must agree to use adequate contraception for the duration of the study and up to 35 days after the last dose of study drug Male participants must agree to use adequate contraception for the duration of the study and up to 75 days after the last dose of study drug Exclusion Criteria: Has simple appendicitis; abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites; acute suppurative cholangitis; infected necrotizing pancreatitis; pancreatic abscess; infectious mononucleosis; cystic fibrosis; or pelvic infections Has complicated intra-abdominal infection managed by staged abdominal repair (STAR) or open abdomen drainage Has had acute gastric or duodenal perforation (≤ 24 hours after) or traumatic perforation of the intestine (≤ 12 hours after) operated on after the perforation occurred Is expected to be cured by only surgical intervention without use of systemic antibacterial therapy Has used systemic antibacterial therapy for intra-abdominal infection for more than 24 hours prior to the first dose of study drug, unless there is a documented treatment failure with such therapy Has severe impairment of renal function (estimated CrCl < 30 mL/minute), or requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/hour urine output over 24 hours) Has a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to study drug with the exception of an antibacterial with Gram-positive activity only (vancomycin, teicoplanin, linezolid and daptomycin) Has used any postoperative non-study antibacterial therapy if enrolled preoperatively Has used more than 1 dose of non-study antibacterial therapy following surgery if enrolled postoperatively Has hepatic disease Is unlikely to survive the 4 to 5 week study period Has organic brain or spinal cord disease Has any rapidly-progressing disease or immediately life-threatening illness Has an immunocompromising condition (i.e., AIDS, hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy) or is receiving ≥ 40 mg of prednisone per day administered continuously for > 14 days prior to study start Has a history of any moderate or severe hypersensitivity or allergic reaction to any beta-lactam (β-lactam) antibacterial, including cephalosporins, carbapenems, penicillins, or β-lactamase inhibitors, or metronidazole, or nitroimidazole derivatives Is receiving or has received disulfiram within 14 days before receiving study drug or who is currently receiving probenecid Has participated in any clinical study of an investigational product within 30 days prior to the first dose of study drug Has previously participated in any study of ceftolozane or MK-7625A.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-7625A + metronidazole<br>MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days. The dose may be reduced to 750 mg (ceftolozane 500 mg/tazobactam 250 mg) for participants with a creatinine clearance (CrCl) of 30-50 mL/min. | Drug: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g)<br>* MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion<br>Drug: metronidazole 500 mg<br>* metronidazole 500 mg administered as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Test of Cure (TOC) | 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. | Day 28 (28 days after initiating study therapy) | 
| Percentage of Participants With Adverse Events (AEs) | 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. | Up to Day 42 (up to 28 days after completing study therapy) | 
| Percentage of Participants Discontinuing Study Drug Due to AEs | The percentage of participants withdrawing from study therapy due to an AE was determined. | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at End Of Therapy (EOT) | 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. | Up to Day 14 | 
| Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at Late Follow-Up (LFU) | 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. | Up to Day 42 (28 days after completing study therapy) | 
| Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at EOT | 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. | Up to Day 14 | 
| Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) at TOC | 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. | Day 28 (28 days after initiating study therapy) | 
| Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at EOT | 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. | Up to Day 14 | 
| Percentage of Participants With Microbiological Response (Eradication, Persistence, or Indeterminate) by Pathogen at TOC | 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. | Day 28 (28 days after initiating study therapy) |