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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Complicated Intra-abdominal Infection

Intervention / Treatment
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* Drug: Ceftazidime-avibactam
* Drug: metronidazole
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftazidime-Avibactam plus metronidazole<br> | Drug: Ceftazidime-avibactam<br>* Ceftazidime-Avibactam powder for concentrate for solution for infusion 2000 mg/500 mg<br>Drug: metronidazole<br>* Metronidazole 500mg/100ml solution for infusion<br>|
| Active Comparator: Meropenem<br> | Drug: Meropenem<br>* Meropenem powder for solution for infusion 1000mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Clinically Evaluable (CE) Analysis Set. | 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. | At the test of cure visit (Day 28 to35) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Clinically Evaluable (CE) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Clinically Evaluable (CE) Analysis Set. | 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. | At late follow up (LFU) visits (Day 42 to 49) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the late follow up (LFU) (Day 42 to 49) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the late follow up (LFU) (Day 42 to 49) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | Per-patient favorable response indicates that all of the patient's baseline pathogens are eradicated or presumed eradicated. | At the late follow up (LFU) (Day 42 to 49) | 
| 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. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| 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. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set. | 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. | At the end of treatment (EOT) (within 24 hours after last IV dose) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable(ME) Analysis Set. | 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. | At the test of cure (TOC) (Day 28 to 35) | 
| The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set. | 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. | At the late follow up (LFU) (Day 42 to 49) | 
| 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. | 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). | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | 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). | At the test of cure (TOC) (Day 28 to 35) | 
| 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. | 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). | At the test of cure (TOC) (Day 28 to 35) | 
| The Time to First Defervescence in the Clinically Evaluable (CE) Analysis Set for Patients Who Have Fever at Study Entry. | 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. | while on study therapy (from Day 1 to Day 14) | 
| The Time to First Defervescence in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set for Patients Who Have Fever at Study Entry. | 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. | while on study therapy (from Day 1 to Day 14) | 
| Safety and Tolerability by Incidence and Severity of Adverse Events and Serious Adverse Events and Mortality. | Adverse event data were collected from the screening/consent visit until the late follow-up visit (i.e. Day -1/0 to Day 42). | study duration (from screening to Day 49 LFU visit) | 
| Safety and Tolerability by Incidence: Extent of Exposure. | 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. | study duration (from screening to Day 49 LFU visit) | 
| Safety and Tolerability: Clinical Laboratory Evaluation Hematology. | Potentially clinically significant (PCS) post Baseline hematology values up to LFU (Safety analysis set) | study duration (from screening to Day 49 LFU visit) | 
| Safety and Tolerability: Clinical Laboratory Evaluation Clinical Chemistry. | Potentially clinically significant (PCS) post Baseline clinical chemistry values up to LFU (Safety analysis set) | study duration (from screening to Day 49 LFU visit) | 
| Safety and Tolerability:ECG , QTcB and QTcF Intervals | Shifts in ECG interpretation and changes in QT, QTcB, and QTcF intervals , from baseline to post baseline. | EOT visit/any observation on treatment | 
| Plasma Concentrations for Ceftazidime and Avibactam | Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ceftazidime-avibactam,, Metronidazole,, Meropenem,, Anti-Bacterial Agents,, Anti-Infective Agents,, Therapeutic Uses,, Pharmacologic Actions,, Physiological Effects of Drugs