Study to Assess Efficacy and Safety of PF-06947386 in Japanese Adult Patients With Complicated Intra-abdominal Infection

Study Overview
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Brief Summary
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Study C3591036 is a Phase 3 study to assess the efficacy and safety of PF-06947386 in Japanese adult patients with complicated intra-abdominal infection requiring hospitalization. This is a multicenter, open-label, single-arm study. All eligible participants will receive intravenous infusion of PF-06947386 followed by intravenous infusion of metronidazole.

Official Title
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A PHASE 3, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO ASSESS THE EFFICACY AND SAFETY OF CEFTAZIDIME-AVIBACTAM (PF-06947386) PLUS METRONIDAZOLE IN JAPANESE ADULT PATIENTS WITH COMPLICATED INTRA-ABDOMINAL INFECTION REQUIRING HOSPITALIZATION

Conditions
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Complicated Intra-abdominal Infection

Intervention / Treatment
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* Drug: PF-06947386
* Drug: Metronidazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant who is capable of giving signed, dated and timed informed consent (or by their legally acceptable representative) Participant aged 20 years or older Participant who is willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures Confirmation of infection by surgical intervention within 24 hours of entry: evidence of systemic inflammatory response; physical findings consistent with intra-abdominal infection; supportive radiologic imaging findings of intra-abdominal infections Intraoperative/postoperative enrollment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis Exclusion Criteria: Participant will undergo surgery for traumatic bowel perforation within 12 hours or perforation of gastroduodenal ulcers within 24 hours. Other intra-abdominal processes that are not infectious. Participant has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation Participant whose surgery will include staged abdominal repair, or open abdomen technique, or marsupialization. Participant has evidence of sepsis with shock not responding to IV fluid challenge or anticipated to require the administration of vasopressors for >24 hours Participant has suspected intra-abdominal infections due to fungus, parasites (eg, amebic liver abscess), virus, or tuberculosis Participant is considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness Participant is pregnant or breastfeeding. Participant has received systemic antibacterial agents within the 72-hour period prior to study entry except for cases specified in the protocol such that participant is considered to have failed the previous treatment regimen, or participant has received systemic antibiotic agents no more than 24 hours (no more than one daily dose) within the 72-hour period prior to study entry, etc. Estimated CrCL ≤50 mL/min calculated by Cockcroft-Gault method.

Ages Eligible for Study
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Minimum Age: 20 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: PF-06947386 + Metronidazole<br>Multiple intravenous infusion of ceftazidime-avibactam followed by intravenous infusion of metronidazole, repeated every 8 hours for 5-14 days. | Drug: PF-06947386<br>* Ceftazidime-Avibactam powder for concentrate for solution for infusion 2.0 g/ 0.5 g. Dosage will be adjusted based on renal function after enrollment.<br>Drug: Metronidazole<br>* Metronidazole 0.5 g solution for injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants in clinically evaluable (CE) analysis set having clinical cure | The percentage of participants in CE analysis set having clinical cure will be calculated as the primary estimand of the primary endpoint. As an efficacy evaluation criterion, it will be confirmed that the point estimate of proportion of patients with clinical cure at TOC visit in the CE analysis set (the primary analysis) is ≥78%. | Test of Cure (TOC) on study Day 28-35 | 
| The percentage of participants in modified intent-to-treat (MITT) analysis set having clinical cure | The percentage of participants in MITT analysis set having clinical cure will be calculated as the supportive estimand of the primary endpoint. | TOC on study Day 28-35 | 
| The percentage of participants in microbiological modified intent-to-treat (mMITT) analysis set having clinical cure | The percentage of participants in mMITT analysis set having clinical cure will be calculated as the supportive estimand of the primary endpoint. | TOC on study Day 28-35 | 
| The percentage of participants in microbiologically evaluable (ME) analysis set having clinical cure | The percentage of participants in ME analysis set having clinical cure will be calculated as the supportive estimand of the primary endpoint. | TOC on study Day 28-35 | 
| The percentage of participants in extended microbiologically evaluable (eME) analysis set having clinical cure | The percentage of participants eME analysis set having clinical cure will be calculated as the supportive estimand of the primary endpoint | TOC on study Day 28-35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of participants in CE analysis set having clinical cure | The percentage of participants in CE analysis set having clinical cure will be calculated. | End of Treatment (EOT, within 24 hours after completion of last IV infusion) and LFU (Late Follow-Up) on study Day 42-49 | 
| The percentage of participants in MITT analysis set having clinical cure | The percentage of participants in MITT analysis set having clinical cure will be calculated. | EOT (within 24 hours after completion of last IV infusion) and LFU on study Day 42-49 | 
| The percentage of participants in mMITT analysis set having clinical cure | The percentage of participants in mMITT analysis set having clinical cure will be calculated. | EOT (within 24 hours after completion of last IV infusion) and LFU on study Day 42-49 | 
| The percentage of participants in ME analysis set having clinical cure | The percentage of participants in ME analysis set having clinical cure will be calculated. | EOT (within 24 hours after completion of last IV infusion) and LFU on study Day 42-49 | 
| The percentage of participants in eME analysis set having clinical cure | The percentage of participants in eME analysis set having clinical cure will be calculated. | EOT (within 24 hours after completion of last IV infusion) and LFU on study Day 42-49 | 
| The percentage of participants in mMITT analysis set having favorable microbiological response per-patient | The percentage of participants in mMITT analysis set having favorable microbiological response per-patient will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in ME analysis set having favorable microbiological response per-patient | The percentage of participants in ME analysis set having favorable microbiological response per-patient will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in eME analysis set having favorable microbiological response per-patient | The percentage of participants in eME analysis set having favorable microbiological response per-patient will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in mMITT analysis set having favorable microbiological response per-pathogen | The percentage of participants in mMITT analysis set having favorable microbiological response per-pathogen will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in ME analysis set having favorable microbiological response per-pathogen | The percentage of participants in ME analysis set having favorable microbiological response per-pathogen will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in eME analysis set having favorable microbiological response per-pathogen | The percentage of participants in eME analysis set having favorable microbiological response per-pathogen will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in mMITT analysis set having favorable microbiological response per-pathogen by MIC categories | The percentage of participants in mMITT analysis set having favorable microbiological response per-pathogen by MIC categories will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in ME analysis set having favorable microbiological response per-pathogen by MIC categories | The percentage of participants in ME analysis set having favorable microbiological response per-pathogen by MIC categories will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in eME analysis set having favorable microbiological response per-pathogen by MIC categories | The percentage of participants in eME analysis set having favorable microbiological response per-pathogen by MIC categories will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| Percentage of participants experiencing Adverse Events | Safety and tolerability profile of PF-06947386 plus metronidazole in the treatment of patients with cIAIs will be evaluated. | Up to a minimum of approximately 28 days after the last administration of the study drug | 
| Percentage of participants experiencing Serious Adverse Events | Safety and tolerability profile of PF-06947386 plus metronidazole in the treatment of patients with cIAIs will be evaluated. | Up to a minimum of approximately 28 days after the last administration of the study drug | 
| Ceftazidime plasma concentrations by nominal sampling window | Pharmacokinetics of ceftazidime in patients with cIAIs will be evaluated. | Day 3, Day 4 | 
| Avibactam plasma concentrations by nominal sampling window | Pharmacokinetics of avibactam in patients with cIAIs will be evaluated. | Day 3, Day 4 | 
| The percentage of participants in the sepsis population having clinical cure | The percentage of participants in the sepsis population having clinical cure will be calculated. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in the sepsis population having favorable microbiological response per-patient | The percentage of participants in the sepsis population having favorable microbiological response per-patient will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in the sepsis population having favorable microbiological response per-pathogen | The percentage of participants in the sepsis population having favorable microbiological response per-pathogen will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| The percentage of participants in the sepsis population having favorable microbiological response per-pathogen by MIC categories | The percentage of participants in the sepsis population having favorable microbiological response per-pathogen by MIC categories will be calculated. Participants with Indeterminate are not included in the denominator. | EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49 | 
| Percentage of participants experiencing Adverse Events in the sepsis population | Safety and tolerability profile of PF-06947386 plus metronidazole in the sepsis population will be evaluated. | Up to a minimum of approximately 28 days after the last administration of the study drug | 
| Percentage of participants experiencing Serious Adverse Events in the sepsis population | Safety and tolerability profile of PF-06947386 plus metronidazole in the sepsis population will be evaluated. | Up to a minimum of approximately 28 days after the last administration of the study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ceftazidime-avibactam,, Metronidazole,, complicated intra-abdominal infection