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

• ClinicalTrials.gov Identifier: NCT01499290
• Recruitment Status: Completed
• First Posted: December 26, 2011
• Results First Posted: March 1, 2016
• Last Update Posted: September 6, 2017
• Sponsor: Pfizer
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: December 19, 2011
• First Posted Date: December 26, 2011
• Results First Submitted Date: November 6, 2015
• Results First Posted Date: March 1, 2016
• Last Update Posted Date: September 6, 2017
• Study Start Date: March 2012
• Actual Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2016)

• Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.
• Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.
• Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]). [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.

• Original Primary Outcome Measures (submitted: December 22, 2011): Clinical Cure as Measured by proportion of patients meeting cure criteria in the microbiological modified Intent-To-Treat analysis set. [ Time Frame: 28 to 35 days after start of study drug ]

Current Secondary Outcome Measures (submitted: January 29, 2016)

• Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.
• Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.
• Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT) [ Time Frame: 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 ]
  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.
• Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set [ Time Frame: 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 ]
  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).
• Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set. [ Time Frame: TOC: 28 to 35 days after start of study drug. ]
  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.
• Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set [ Time Frame: Test of Cure: 28 to 35 days after start of study drug ]
  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.
• Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set [ Time Frame: TOC: 28 to 35 days after start of study drug ]
  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.
• Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set [ Time Frame: Test of Cure: 28 to 35 days after start of study drug ]
  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).
• Number of Patients Afebrile at Last Observation in the Clinically Evaluable Analysis Set for Patients Who Have Fever at Study Entry [ Time Frame: Test of Cure: 1 to 14 days after start of study drug ]
  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.
• Plasma Concentrations for Ceftazidime and Avibactam [ Time Frame: 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

Original Secondary Outcome Measures (submitted: December 22, 2011)

• The proportion of patients with clinical cure in the microbiologically evaluable analysis set. [ Time Frame: 28 to 35 days after start of study drug ]
• The proportion of patients with clinical cure in the microbiological modified intent-to-treat and microbiologically evaluable analysis sets. [ Time Frame: within 24 hours after last dose of study drug and 42 to 49 days after start of study drug ]
• The proportion of patients with clinical cure in the clinically evaluable analysis set. [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
• The proportion of patients with a favorable per-patient microbiological response in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
• The proportion of favorable per-pathogen microbiological response in the microbiological modified intent to treat and microbiologically evaluable analysis sets. [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
• The favorable per-pathogen microbiologic response by minimum inhibitory concentration (MIC) categories in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: within 24 hours after last dose of study drug, 28 to 35 days after start of study drug and 42 to 49 days after start of study drug ]
• The favorable per-patient clinical response and favorable per-patient microbiological response for patients infected with ceftazidime-resistant pathogens in the microbiological modified intent to treat and microbiologically evaluable analysis sets. [ Time Frame: 28 to 35 days after start of study drug ]
• The proportion of patients with a favorable per-pathogen microbiological response for patients infected with ceftazidime-resistant pathogens in the microbiological modified intent to treat and microbiologically evaluable analysis sets [ Time Frame: 28 to 35 days after start of study drug ]
• The time to first defervescence in the clinically evaluable and microbiologically evaluable analysis sets for patients who have fever at study entry. [ Time Frame: 1 to 14 days after start of study drug ]
• The safety and tolerability by incidence and severity of adverse events and serious adverse events, vital signs, clinical laboratory tests, ECGs and physical exams. [ Time Frame: study duration (from screening visit (Day -1) through last follow up visit (up to 50 days) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections
• Official Title: 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
• 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
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Complicated Intra-Abdominal Infection

Intervention

• Drug: CAZ-AVI
  Ceftazidime 2000 mg and 500 mg of avibactam
• Drug: Metronidazole
  500 mg of Metronidazole
• Drug: Meropenem
  1 gram of Meropenem

Study Arms

• Experimental: CAZ-AVI + Metronidazole
  IV treatment
  Interventions:

  • Drug: CAZ-AVI
  • Drug: Metronidazole
• Active Comparator: Meropenem
  IV treatment
  Intervention: Drug: Meropenem

Publications *

• 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.
• 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). pii: 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.
• 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). pii: e02584-17. doi: 10.1128/AAC.02584-17. Print 2018 Jul.
• Mendes RE, Castanheira M, Woosley LN, Stone GG, Bradford PA, Flamm RK. Molecular β-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). pii: e02447-16. doi: 10.1128/AAC.02447-16. Print 2017 Jun.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 3, 2014): 493
• Original Estimated Enrollment (submitted: December 22, 2011): 1106
• Actual Study Completion Date: April 2014
• Actual Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Bulgaria, Croatia, Czechia, Hungary, India, Israel, Latvia, Malaysia, Mexico, Netherlands, Peru, Romania, Russian Federation, South Africa, Spain, Taiwan, Thailand, Ukraine, United States
• Removed Location Countries: Australia, Belgium, Brazil, Canada, Chile, Czech Republic, France, Germany, Greece, Italy, Lithuania, Poland, Portugal, Serbia, Slovakia, Turkey, United Kingdom

Administrative Information

• NCT Number: NCT01499290
• Other Study ID Numbers: D4280C00001; 2011-003893-97
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Forest Laboratories

Investigators

• Study Director: Paul Newell, MBBS, MRCP; AstraZeneca

• PRS Account: Pfizer
• Verification Date: August 2017