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

NCT01499290 | Completed Phase 3 Results

• 2 other identifiers: D4280C000012011-003893-97
• Study Type: interventional
• Target: 493
• Locations: 20 countries
• Sites: 56

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.

Conditions

Complicated Intra-Abdominal Infection

Keywords

Ceftazidime; Meropenem; Metronidazole; Anti-Bacterial Agents; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; cIAI, Complicated Intra-Abdominal Infection

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (10)

• Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set

  TOC: 28 to 35 days after start of study drug

• Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set

  TOC: 28 to 35 days after start of study drug

• Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT)

  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

  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.

  TOC: 28 to 35 days after start of study drug.

Study Arms (2)

CAZ-AVI + Metronidazole

EXPERIMENTAL

IV treatment

Drug: CAZ-AVI; Drug: Metronidazole

Meropenem

ACTIVE COMPARATOR

IV treatment

Drug: Meropenem

Interventions

CAZ-AVI DRUG

Ceftazidime 2000 mg and 500 mg of avibactam

CAZ-AVI + Metronidazole

Metronidazole DRUG

500 mg of Metronidazole

CAZ-AVI + Metronidazole

Meropenem DRUG

1 gram of Meropenem

Meropenem

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 90 years of age inclusive
• Female patient is authorized to participate if at least one of the following criteria are met:
• Surgical sterilization
• Age ≥50 years and postmenopausal as defined by amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments
• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead
• Forest Laboratories: collaborator

Study Sites (56)

Research Site

Chula Vista, California, United States

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San Diego, California, United States

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St Louis, Missouri, United States

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Somers Point, New Jersey, United States

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Córdoba, Argentina

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Rosario, Argentina

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Rousse, Bulgaria

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Varna, Bulgaria

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Zagreb, Croatia

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Děčín, Czechia

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Hradec Králové, Czechia

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Jihlava, Czechia

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Olomouc, Czechia

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Prague, Czechia

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Teplice, Czechia

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Budapest, Hungary

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Székesfehérvár, Hungary

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Bangalore, India

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Pune, India

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Trivandrum, India

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Vadodara, India

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Hadera, Israel

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Haifa, Israel

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Riga, Latvia

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Alor Star, Malaysia

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Durango, Mexico

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Guadalajara, Jalisco, Mexico

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Mexico City, Mexico

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's-Hertogenbosch, Netherlands

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Enschede, Netherlands

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Arequipa, Peru

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Cercardo de Lima, Peru

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Lima, Peru

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Trujillo, Peru

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Cluj-Napoca, Romania

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Iași, Romania

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Kemerovo, Russia

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Moscow, Russia

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Saratov, Russia

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Vsevolozhsk, Russia

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Pretoria, South Africa

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Alcorcón, Spain

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Elche, Spain

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Sabadell(Barcelona), Spain

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Kaohsiung City, Taiwan

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Taichung, Taiwan

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Tainan, Taiwan

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Taipei, Taiwan

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Bangkok, Thailand

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Khon Kaen, Thailand

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Phisanulok, Thailand

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Dnipropetrovsk, Ukraine

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Ivano-Frankivsk, Ukraine

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Kharkiv, Ukraine

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Kyiv, Ukraine

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Zaporizhzhya, Ukraine

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Related Publications (9)

• 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.

  PMID: 26962078 BACKGROUND

• Torres A, Wible M, Tawadrous M, Irani P, Stone GG, Quintana A, Debabov D, Burroughs M, Bradford PA, Kollef M. Efficacy and safety of ceftazidime/avibactam in patients with infections caused by beta-lactamase-producing Gram-negative pathogens: a pooled analysis from the Phase 3 clinical trial programme. J Antimicrob Chemother. 2023 Nov 6;78(11):2672-2682. doi: 10.1093/jac/dkad280.

  PMID: 37700689 DERIVED

• 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.

  PMID: 32602065 DERIVED

• 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.

  PMID: 31890160 DERIVED

• 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.

  PMID: 30221827 DERIVED

• 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.

  PMID: 30061279 DERIVED

• 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.

  PMID: 29912399 DERIVED

• 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.

  PMID: 29686147 DERIVED

• 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.

  PMID: 28348155 DERIVED

MeSH Terms

Interventions

Metronidazole; Meropenem

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

This summary describes data collected from two identical CSPs (D4280C00001 and D4280C00005). With agreement from the EMA and the FDA the data have been combined into a single study database.

Results Point of Contact

• Title: Paul Newell, Medical Science Director
• Organization: AstraZeneca

paul.newell@astrazeneca.com

+44 1625 515727

Study Officials

• Paul Newell, MBBS, MRCP

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2011
• First Posted: December 26, 2011
• Study Start: March 1, 2012
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: September 6, 2017
• Results First Posted: March 1, 2016

Record last verified: 2017-08

Locations

LA (1); IL (2); HU (2); BU (2); MY (1); NL (2); RU (4); TH (3); UA (5); RO (2); PE (4); AR (2); IN (4); CR (1); ZA (1); US (4); ME (3); TW (4); CZ (6); ES (3)