Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections

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

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.

Study Overview

• Status: Completed
• Conditions: Complicated Intra-Abdominal Infection
• Intervention / Treatment: Drug: CAZ-AVI; Drug: Metronidazole; Drug: Meropenem

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

• Study Type: Interventional
• Enrollment (Actual): 493
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina
    • Research Site
  • Rosario, Argentina
    • Research Site
• Bulgaria
  • Ruse, Bulgaria
    • Research Site
  • Varna, Bulgaria
    • Research Site
• Croatia
  • Zagreb, Croatia
    • Research Site
• Czechia
  • Decin, Czechia
    • Research Site
  • Hradec Kralove, Czechia
    • Research Site
  • Jihlava, Czechia
    • Research Site
  • Olomouc, Czechia
    • Research Site
  • Praha 10, Czechia
    • Research Site
  • Praha 5, Czechia
    • Research Site
  • Teplice, Czechia
    • Research Site
• Hungary
  • Budapest, Hungary
    • Research Site
  • Székesfehérvár, Hungary
    • Research Site
• India
  • Bangalore, India
    • Research Site
  • Pune, India
    • Research Site
  • Trivandrum, India
    • Research Site
  • Vadodara, India
    • Research Site
• Israel
  • Hadera, Israel
    • Research Site
  • Haifa, Israel
    • Research Site
• Latvia
  • Riga, Latvia
    • Research Site
• Malaysia
  • Alor Setar, Malaysia
    • Research Site
• Mexico
  • Durango, Mexico
    • Research Site
  • Guadalajara, Jalisco, Mexico
    • Research Site
  • Mexico City, Mexico
    • Research Site
• Netherlands
  • Enschede, Netherlands
    • Research Site
  • s-Hertogenbosch, Netherlands
    • Research Site
• Peru
  • Arequipa, Peru
    • Research Site
  • Cercardo de Lima, Peru
    • Research Site
  • Lima, Peru
    • Research Site
  • Trujillo, Peru
    • Research Site
• Romania
  • Cluj-Napoca, Romania
    • Research Site
  • Iasi, Romania
    • Research Site
• Russian Federation
  • Kemerovo, Russian Federation
    • Research Site
  • Moscow, Russian Federation
    • Research Site
  • Saratov, Russian Federation
    • Research Site
  • Vsevolozhsk, Russian Federation
    • Research Site
• South Africa
  • Pretoria, South Africa
    • Research Site
• Spain
  • Alcorcón, Spain
    • Research Site
  • Elche, Spain
    • Research Site
  • Sabadell(Barcelona), Spain
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan
    • Research Site
  • Taichung, Taiwan
    • Research Site
  • Tainan, Taiwan
    • Research Site
  • Taipei, Taiwan
    • Research Site
• Thailand
  • Bangkok, Thailand
    • Research Site
  • Khon Kaen, Thailand
    • Research Site
  • Phisanulok, Thailand
    • Research Site
• Ukraine
  • Dnipropetrovsk, Ukraine
    • Research Site
  • Ivano-Frankivsk, Ukraine
    • Research Site
  • Kharkov, Ukraine
    • Research Site
  • Kyiv, Ukraine
    • Research Site
  • Zaporizhzhya, Ukraine
    • Research Site
• United States
  • California
    • Chula Vista, California, United States
      • Research Site
    • San Diego, California, United States
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States
      • Research Site
  • New Jersey
    • Somers Point, New Jersey, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 to 90 years of age inclusive

• Female patient is authorized to participate if at least one of the following criteria are met:

  1. Surgical sterilization
  2. Age ≥50 years and postmenopausal as defined by amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments
  3. Age <50 years and postmenopausal as defined by documented LH and FSH levels in the postmenopausal range PLUS amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments
  4. Patient has a negative serum pregnancy test (serum ß-human chorionic gonadotropin [ß-hCG]) within 1 day prior to study entry, and agrees to use highly effective contraception methods during treatment and for at least 7 days after last dose of IV study therapy
• Intraoperative/postoperative enrollment with 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 response; 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
• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAZ-AVI + Metronidazole; IV treatment	Drug: CAZ-AVI; Ceftazidime 2000 mg and 500 mg of avibactam; Drug: Metronidazole; 500 mg of Metronidazole
Active Comparator: Meropenem; IV treatment	Drug: Meropenem; 1 gram of Meropenem

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA).	The number 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 is necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, death where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure. Results from two identical protocols D4280C00001 and D4280C00005 combined into a single database with agreement from FDA and EMA.	TOC: 28 to 35 days after start of study drug
Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]).	The number 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. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.	TOC: 28 to 35 days after start of study drug
Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]).	The number 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.	TOC: 28 to 35 days after start of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set	The number 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.	TOC: 28 to 35 days after start of study drug
Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set	The number 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.	TOC: 28 to 35 days after start of study drug
Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT)	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. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.	EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU: 42 to 49 days after start of study drug
Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set	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 a surgical review panel (SRP) assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU 42 to 49 days after start of study drug
Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set.	The number 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.	TOC: 28 to 35 days after start of study drug.
Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set	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.	Test of Cure: 28 to 35 days after start of study drug
Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set	The number 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.	TOC: 28 to 35 days after start of study drug
Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set	Microbiological 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).	Test of Cure: 28 to 35 days after start of study drug
Number of Patients Afebrile at Last Observation in the Clinically Evaluable 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.	Test of Cure: 1 to 14 days after start of study drug
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	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

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Forest Laboratories

Publications and helpful links

General Publications

• Cheng K, Newell P, Chow JW, Broadhurst H, Wilson D, Yates K, Wardman A. Safety Profile of Ceftazidime-Avibactam: Pooled Data from the Adult Phase II and Phase III Clinical Trial Programme. Drug Saf. 2020 Aug;43(8):751-766. doi: 10.1007/s40264-020-00934-3.
• Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.
• Nichols WW, Stone GG, Newell P, Broadhurst H, Wardman A, MacPherson M, Yates K, Riccobene T, Critchley IA, Das S. Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018 Oct 24;62(11):e02590-17. doi: 10.1128/AAC.02590-17. Print 2018 Nov.
• Stone GG, Newell P, Gasink LB, Broadhurst H, Wardman A, Yates K, Chen Z, Song J, Chow JW. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother. 2018 Sep 1;73(9):2519-2523. doi: 10.1093/jac/dky204.
• Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis. 2016 Jun 1;62(11):1380-1389. doi: 10.1093/cid/ciw133. Epub 2016 Mar 8.
• Kongnakorn T, Eckmann C, Bassetti M, Tichy E, Di Virgilio R, Baillon-Plot N, Charbonneau C. Cost-effectiveness analysis comparing ceftazidime/avibactam (CAZ-AVI) as empirical treatment comparing to ceftolozane/tazobactam and to meropenem for complicated intra-abdominal infection (cIAI). Antimicrob Resist Infect Control. 2019 Dec 21;8:204. doi: 10.1186/s13756-019-0652-x. eCollection 2019.
• Stone GG, Newell P, Bradford PA. In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections. Antimicrob Agents Chemother. 2018 Jun 26;62(7):e02584-17. doi: 10.1128/AAC.02584-17. Print 2018 Jul.
• Mendes RE, Castanheira M, Woosley LN, Stone GG, Bradford PA, Flamm RK. Molecular beta-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets. Antimicrob Agents Chemother. 2017 May 24;61(6):e02447-16. doi: 10.1128/AAC.02447-16. Print 2017 Jun.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: December 19, 2011
• First Submitted That Met QC Criteria: December 22, 2011
• First Posted (Estimate): December 26, 2011

Study Record Updates

• Last Update Posted (Actual): September 6, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Anti-Infective Agents; Metronidazole; Meropenem; Anti-Bacterial Agents; Ceftazidime; Antiparasitic Agents; Antiprotozoal Agents; cIAI, Complicated Intra-Abdominal Infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Intraabdominal Infections; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole; Meropenem
• Other Study ID Numbers: D4280C00001; 2011-003893-97

Plan for Individual participant data (IPD)

Study Data/Documents

1. Study Protocol
   Information identifier: D4280C00001 Revised CSP
   Information comments: RECLAIM 1 (D4280C00001) Revised Clinical Study Protocol