Clinical trial NCT01499290: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Intra-Abdominal Infection
Keywords: Ceftazidime
Meropenem
Metronidazole
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
cIAI, Complicated Intra-Abdominal Infection
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Forest Laboratories
First posted: 2011-12-26
Enrollment: 493
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:

* 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

Primary outcomes:
measure: Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA).
timeFrame: TOC: 28 to 35 days after start of study drug
measure: Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]).
timeFrame: TOC: 28 to 35 days after start of study drug
measure: Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]).
timeFrame: TOC: 28 to 35 days after start of study drug
Secondary outcomes:
measure: Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set
timeFrame: TOC: 28 to 35 days after start of study drug
measure: Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set
timeFrame: TOC: 28 to 35 days after start of study drug
measure: Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT)
timeFrame: 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
measure: Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set.
timeFrame: TOC: 28 to 35 days after start of study drug.
measure: Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set
timeFrame: Test of Cure: 28 to 35 days after start of study drug
measure: Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set
timeFrame: TOC: 28 to 35 days after start of study drug
measure: Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set
timeFrame: Test of Cure: 28 to 35 days after start of study drug
measure: Number of Patients Afebrile at Last Observation in the Clinically Evaluable Analysis Set for Patients Who Have Fever at Study Entry
timeFrame: Test of Cure: 1 to 14 days after start of study drug
measure: Plasma Concentrations for Ceftazidime and Avibactam
timeFrame: 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: Chula Vista
country: United States
facility: Research Site
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Somers Point
country: United States
facility: Research Site
state: New Jersey
city: Córdoba
country: Argentina
facility: Research Site
city: Rosario
country: Argentina
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Zagreb
country: Croatia
facility: Research Site
city: Decin
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Jihlava
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Teplice
country: Czechia
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Székesfehérvár
country: Hungary
facility: Research Site
city: Bangalore
country: India
facility: Research Site
city: Pune
country: India
facility: Research Site
city: Trivandrum
country: India
facility: Research Site
city: Vadodara
country: India
facility: Research Site
city: Hadera
country: Israel
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Alor Setar
country: Malaysia
facility: Research Site
city: Durango
country: Mexico
facility: Research Site
city: Guadalajara, Jalisco
country: Mexico
facility: Research Site
city: Mexico City
country: Mexico
facility: Research Site
city: Enschede
country: Netherlands
facility: Research Site
city: s-Hertogenbosch
country: Netherlands
facility: Research Site
city: Arequipa
country: Peru
facility: Research Site
city: Cercardo de Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Trujillo
country: Peru
facility: Research Site
city: Cluj-Napoca
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Kemerovo
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: Vsevolozhsk
country: Russian Federation
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Alcorcón
country: Spain
facility: Research Site
city: Elche
country: Spain
facility: Research Site
city: Sabadell(Barcelona)
country: Spain
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Phisanulok
country: Thailand
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkov
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Zaporizhzhya
country: Ukraine
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Paul Newell, MBBS, MRCP
role: STUDY_DIRECTOR
References:
citation: 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.
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: 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.
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: 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.
citation: 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.