Compare Ceftazidime-Avibactam + Metronidazole vs Meropenem for Hospitalized Adults With Complicated Intra-Abd Infections

Phase 3

Completed

Conditions: Complicated Intra-abdominal Infection

Interventions: Drug: Ceftazidime-avibactam
Drug: Meropenem
Drug: metronidazole

Registration Number: NCT01726023

Lead Sponsor: Pfizer

Brief Summary: The purpose of this study is to evaluate the effects of Ceftazidime Avibactam plus Metronidazole compared to Meropenem for treating hospitalized patients with complicated intra-abdominal infections.

Detailed Description: A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections In Hospitalized Adults

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 486

Inclusion Criteria

Patient must be 18 to 90 years of age, inclusive,
Female patients can participate if they are surgically sterilized or postmenopausal for at least 1 year or her sexual partner has had a vasectomy
Female of childbearing potential has had normal menstrual periods for 3 months and negative serum pregnancy test and agree to practice highly effective methods of birth control during treatment and for at least 7 days after last dose
Intraoperative/postoperative enrollment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis
Confirmation of infection by surgical intervention within 24 hours of entry: evidence of systemic inflammatory indicators; physical findings consistent with intra-abdominal infection; supportive radiologic imaging findings of intra-abdominal infections

Exclusion Criteria

Patient is diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-abdominal processes in which primary etiology is not likely to be infectious
Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation
Patients whose surgery will include staged abdominal repair, or "open abdomen" technique, or marsupialization
Patient has suspected intra-abdominal infections due to fungus, parasites, virus or tuberculosis
Patient is considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness, including septic shock that is associated with a high risk of mortality

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ceftazidime-Avibactam plus metronidazole	metronidazole	-
Ceftazidime-Avibactam plus metronidazole	Ceftazidime-avibactam	-
Meropenem	Meropenem	-

Primary Outcome Measures

Name	Time	Method
The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Clinically Evaluable (CE) Analysis Set.	At the test of cure visit (Day 28 to35)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.

Secondary Outcome Measures

Name	Time	Method
The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Clinically Evaluable (CE) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable(ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Patients With a Favorable Per Patient Microbiological Response at the Test of Cure (TOC) Visit for Patients Infected With Ceftazidime Resistant Pathogens in the Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Clinically Evaluable (CE) Analysis Set.	At late follow up (LFU) visits (Day 42 to 49)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Favorable Per-pathogen Microbiological Response in the Microbiological Response at the Test of Cure (TOC) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Test of Cure (TOC) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Patients With a Favorable Per Patient Microbiological Response at the Test of Cure (TOC) Visit for Patients Infected With Ceftazidime Resistant Pathogens in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the End of Treatment (EOT) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Patients With a Favorable Per-patient Microbiological Response at the Late Follow up (LFU) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated".
The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the end of treatment (EOT) (within 24 hours after last IV dose)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Favorable Per-pathogen Microbiological Response in the Microbiological Response at the Late Follow up (LFU) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the late follow up (LFU) (Day 42 to 49)	The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
The Time to First Defervescence in the Clinically Evaluable (CE) Analysis Set for Patients Who Have Fever at Study Entry.	while on study therapy (from Day 1 to Day 14)	Time to first defervescence was calculated for patients with a fever (\>38ºC) at baseline. Defervescence (≤37.8ºC) was defined as the absence of fever based on the highest temperature recorded on each study day. Time to first defervescence while on IV study therapy in the CE analysis set at TOC for patients who had fever at study entry is defined as time (in days) from the first dose of IV study therapy to first absence of fever.
Safety and Tolerability by Incidence and Severity of Adverse Events and Serious Adverse Events and Mortality.	study duration (from screening to Day 49 LFU visit)	Adverse event data were collected from the screening/consent visit until the late follow-up visit (i.e. Day -1/0 to Day 42).
Safety and Tolerability by Incidence: Extent of Exposure.	study duration (from screening to Day 49 LFU visit)	Duration of exposure is calculated as the difference between the last study therapy date and the first study therapy date converted to days plus 1 day. Actual calculated duration could be shorter or longer than a full day.
Safety and Tolerability: Clinical Laboratory Evaluation Hematology.	study duration (from screening to Day 49 LFU visit)	Potentially clinically significant (PCS) post Baseline hematology values up to LFU (Safety analysis set)
Safety and Tolerability:ECG , QTcB and QTcF Intervals	EOT visit/any observation on treatment	Shifts in ECG interpretation and changes in QT, QTcB, and QTcF intervals , from baseline to post baseline.
The Proportion of Patients With a Favorable Per Patient Microbiological Response at the Test of Cure (TOC) Visit for Patients Infected With Ceftazidime Resistant Pathogens in the Extended Microbiologically Evaluable (ME) Analysis Set.	At the test of cure (TOC) (Day 28 to 35)	The microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
The Time to First Defervescence in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set for Patients Who Have Fever at Study Entry.	while on study therapy (from Day 1 to Day 14)	Time to first defervescence was calculated for patients with a fever (\>38ºC) at baseline. Defervescence (≤37.8ºC) was defined as the absence of fever based on the highest temperature recorded on each study day. Time to first defervescence while on IV study therapy in the CE analysis set at TOC for patients who had fever at study entry is defined as time (in days) from the first dose of IV study therapy to first absence of fever.
Safety and Tolerability: Clinical Laboratory Evaluation Clinical Chemistry.	study duration (from screening to Day 49 LFU visit)	Potentially clinically significant (PCS) post Baseline clinical chemistry values up to LFU (Safety analysis set)
Plasma Concentrations for Ceftazidime and Avibactam	At Day 3: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug.	Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations