Ceftazidime-Avibactam for the Treatment of Infections Due to Ceftazidime Resistant Pathogens

NCT01644643 | Completed Phase 3 Results

• 2 other identifiers: D4280C000062012-000726-21
• Study Type: interventional
• Target: 345
• Locations: 18 countries
• Sites: 43

Brief Summary

To Evaluate the Effects of Ceftazidime-Avibactam and Best Available Therapy in patients with complicated urinary tract infections and complicated intra-abdominal infections.

Conditions

Complicated Urinary Tract Infection; Complicated Intra-abdominal Infection

Keywords

Ceftazidime,; avibactam,; metronidazone,; Anti-Infectives

Outcome Measures

Primary Outcomes (1)

• Clinical Response at Test of Cure (TOC) in Microbiological Modified Intent-to-treat (mMITT) Analysis Set

  Proportion of patients with clinical cure at the TOC visit in the mMITT analysis set. Clinical cure: Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy (other than those allowed per protocol) is necessary; for cIAI patients no drainage or surgical intervention after 96 hours from randomization is necessary (ie. drainage or surgical intervention up to 96 hours from randomization is permissible).

  6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.

Secondary Outcomes (37)

• Clinical Response at End of Treatment (EOT) in mMITT Analysis Set.

  28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.

• Clinical Response at Follow-up 1 (FU1) in mMITT Analysis Set

  cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization

• Clinical Response at Follow-up 2 (FU2) in mMITT Analysis Set

  At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization

• Clinical Response at EOT in Extended Microbiologically Evaluable (EME) at EOT Analysis Set.

  28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.

• Clinical Response at TOC in EME at TOC Analysis Set.

  6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.

Study Arms (2)

Ceftazidime - Avibactam ( CAZ-AVI)

EXPERIMENTAL

IV treatment

Drug: Ceftazidime - Avibactam ( CAZ-AVI); Drug: Metronidazole

Best Available Therapy

ACTIVE COMPARATOR

IV treatment

Drug: Best Available Therapy

Interventions

Ceftazidime - Avibactam ( CAZ-AVI) DRUG

Ceftazidime 2000 mg and 500 mg of avibactam Patients randomized to receive CAZ-AVI will receive an infusion of CAZ-AVI (2000 mg ceftazidime and 500 mg avibactam) every 8 hours administered by intravenous (IV) infusion in a volume of 100 mL at a constant rate over 120 minutes

Ceftazidime - Avibactam ( CAZ-AVI)

Best Available Therapy DRUG

Patients randomized to receive Best Available Therapy will receive the best available standard of care (SOC) anti-infective therapy for their infection administered in accord with approved local label recommendation

Best Available Therapy

Metronidazole DRUG

Anti-infective, 500 mg (cIAI only) Patients randomized to receive CAZ-AVI for cIAI will also receive metronidazole (500 mg) administered by IV infusion in a volume of 100 mL at a constant rate over 60 minutes immediately following the CAZ-AVI infusion

Also known as: Flagyl

Ceftazidime - Avibactam ( CAZ-AVI)

Eligibility Criteria

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

You may qualify if:

• Patient must be ≥18 and ≤90 years of age
• Female patients can participate if they are surgically sterile or completed menopause or females capable of having children and agree not to attempt pregnancy while receiving IV study therapy and for a period of 7 days after
• Patient has a ceftazidime-resistant Gram negative pathogen that was isolated from an appropriate culture within 5 days prior to study entry (ie, within 5 days prior to Screening; the study-qualifying culture), which was determined to be the causative agent of the entry infection

You may not qualify if:

• Patient has an APACHE II score \>30 (cIAI patients only)
• Patient has an infection due to Gram negative pathogen that is unlikely to respond to CAZ-AVI treatment (eg, Acinetobacter spp., Stenotrophomonas spp.)
• Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant Patient is immunocompromised
• Patient has a rapidly progressive or terminal illness with a high risk of mortality due to any cause, including acute hepatic failure, respiratory failure or severe septic shock such that they are unlikely to survive the 4- to 5-week study period.

Sponsors & Collaborators

• Pfizer: lead
• Forest Laboratories: collaborator

Study Sites (43)

Research Site

Shreveport, Louisiana, United States

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Lima, Ohio, United States

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El Talar, Argentina

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La Plata, Argentina

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Pazardzhik, Bulgaria

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Pleven, Bulgaria

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Rousse, Bulgaria

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Sofia, Bulgaria

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Varna, Bulgaria

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Veliko Tarnovo, Bulgaria

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Slavonski Brod, Croatia

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Zagreb, Croatia

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Prague, Czechia

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Tours, France

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Nazareth, Israel

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Petah Tikva, Israel

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Ramat Gan, Israel

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Tel Aviv, Israel

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Guadalajara, Mexico

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Mexico City, Mexico

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Cusco, Peru

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Surco, Peru

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Manila, Philippines

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Szczecin, Poland

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Bucharest, Romania

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Irkutsk, Russia

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Krasnodar, Russia

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Novosibirsk, Russia

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Penza, Russia

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Saint Petersburg, Russia

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Yaroslavl, Russia

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Johannesburg, South Africa

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Seoul, South Korea

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Barcelona, Spain

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Madrid, Spain

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Ankara, Turkey (Türkiye)

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Antalya, Turkey (Türkiye)

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Diyarbakır, Turkey (Türkiye)

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Istanbul, Turkey (Türkiye)

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Dnipropetrovsk, 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 (8)

• Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, Gasink LB. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016 Jun;16(6):661-673. doi: 10.1016/S1473-3099(16)30004-4. Epub 2016 Apr 20.

  PMID: 27107460 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

• Mendes RE, Castanheira M, Woosley LN, Stone GG, Bradford PA, Flamm RK. Characterization of beta-Lactamase Content of Ceftazidime-Resistant Pathogens Recovered during the Pathogen-Directed Phase 3 REPRISE Trial for Ceftazidime-Avibactam: Correlation of Efficacy against beta-Lactamase Producers. Antimicrob Agents Chemother. 2019 May 24;63(6):e02655-18. doi: 10.1128/AAC.02655-18. Print 2019 Jun.

  PMID: 30910899 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, Bradford PA, Newell P, Wardman A. In Vitro Activity of Ceftazidime-Avibactam against Isolates in a Phase 3 Open-Label Clinical Trial for Complicated Intra-Abdominal and Urinary Tract Infections Caused by Ceftazidime-Nonsusceptible Gram-Negative Pathogens. Antimicrob Agents Chemother. 2017 Jan 24;61(2):e01820-16. doi: 10.1128/AAC.01820-16. Print 2017 Feb.

  PMID: 27872067 DERIVED

MeSH Terms

Interventions

avibactam, ceftazidime drug combination; Metronidazole

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Yunxia Lu
• Organization: AstraZeneca-PPD

Yunxia.Lu@ppdi.com

910-558-4197

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: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2012
• First Posted: July 19, 2012
• Study Start: January 1, 2013
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: September 29, 2017
• Results First Posted: December 14, 2015

Record last verified: 2017-08

Locations

TU (4); BU (6); KR (1); AR (2); FR (1); IL (4); UA (4); ES (2); ZA (1); RU (6); RO (1); CR (2); CZ (1); PL (1); ME (2); PH (1); PE (2); US (2)