Clinical trial NCT01726023: Compare Ceftazidime-Avibactam + Metronidazole vs Meropenem for Hospitalized Adults With Complicated Intra-Abd 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Intra-abdominal Infection
Keywords: Ceftazidime-avibactam,
Metronidazole,
Meropenem,
Anti-Bacterial Agents,
Anti-Infective Agents,
Therapeutic Uses,
Pharmacologic Actions,
Physiological Effects of Drugs
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2012-11-14
Enrollment: 486
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Clinically Evaluable (CE) Analysis Set.
timeFrame: At the test of cure visit (Day 28 to35)
Secondary outcomes:
measure: The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Patients With Clinical Cure at the Test of Cure (TOC) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: The Proportion of Patients With Clinical Cure at the End of Treatment (EOT) Visit in the Clinically Evaluable (CE) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Patients With Clinical Cure at the Late Follow up (LFU) Visit in the Clinically Evaluable (CE) Analysis Set.
timeFrame: At late follow up (LFU) visits (Day 42 to 49)
measure: 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.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: 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.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: 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.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: 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.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the End of Treatment (EOT) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the end of treatment (EOT) (within 24 hours after last IV dose)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the Test of Cure (TOC) Visit in the Extended Microbiologically Evaluable(ME) Analysis Set.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Proportion of Favorable Per-pathogen Microbiological Response at the Late Follow up (LFU) Visit in the Extended Microbiologically Evaluable (ME) Analysis Set.
timeFrame: At the late follow up (LFU) (Day 42 to 49)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: 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.
timeFrame: At the test of cure (TOC) (Day 28 to 35)
measure: The Time to First Defervescence in the Clinically Evaluable (CE) Analysis Set for Patients Who Have Fever at Study Entry.
timeFrame: while on study therapy (from Day 1 to Day 14)
measure: The Time to First Defervescence in the Microbiological Modified Intent-to-treat (mMITT) Analysis Set for Patients Who Have Fever at Study Entry.
timeFrame: while on study therapy (from Day 1 to Day 14)
measure: Safety and Tolerability by Incidence and Severity of Adverse Events and Serious Adverse Events and Mortality.
timeFrame: study duration (from screening to Day 49 LFU visit)
measure: Safety and Tolerability by Incidence: Extent of Exposure.
timeFrame: study duration (from screening to Day 49 LFU visit)
measure: Safety and Tolerability: Clinical Laboratory Evaluation Hematology.
timeFrame: study duration (from screening to Day 49 LFU visit)
measure: Safety and Tolerability: Clinical Laboratory Evaluation Clinical Chemistry.
timeFrame: study duration (from screening to Day 49 LFU visit)
measure: Safety and Tolerability:ECG , QTcB and QTcF Intervals
timeFrame: EOT visit/any observation on treatment
measure: Plasma Concentrations for Ceftazidime and Avibactam
timeFrame: 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.
Other outcomes:
Locations:
city: Baotou
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Fuzhou
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Guilin
country: China
facility: Research Site
city: Haikou
country: China
facility: Research Site
city: Hebei
country: China
facility: Research Site
city: Jiangyin
country: China
facility: Research Site
city: Liaocheng
country: China
facility: Research Site
city: Nan Chang
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Urumqi
country: China
facility: Research Site
city: Wenzhou
country: China
facility: Research Site
city: Wuxi
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Ansan-si
country: Korea, Republic of
facility: Research Site
city: Anyang-si
country: Korea, Republic of
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Daejeon
country: Korea, Republic of
facility: Research Site
city: Gwangju
country: Korea, Republic of
facility: Research Site
city: Jinju-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Wonju-si
country: Korea, Republic of
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Hochiminh
country: Vietnam
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Paul A Newell, MBBS, MRCP
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, Song J, Laud PJ, Stone GG, Chow JW. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017 May;49(5):579-588. doi: 10.1016/j.ijantimicag.2017.01.010. Epub 2017 Mar 29.