Clinical trial NCT01644643: Ceftazidime-Avibactam for the Treatment of Infections Due to Ceftazidime Resistant Pathogens
Official title: An Open-Label, Randomized, Multicenter, Phase III Study of Ceftazidime Avibactam (CAZ-AVI, Formerly CAZ104) and Best Available Therapy for the Treatment of Infections Due to Ceftazidime Resistant Gram Negative Pathogens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Urinary Tract Infection
Complicated Intra-abdominal Infection
Keywords: Ceftazidime,
avibactam,
metronidazone,
Anti-Infectives
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Forest Laboratories
First posted: 2012-07-19
Enrollment: 345
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: To Evaluate the Effects of Ceftazidime-Avibactam and Best Available Therapy in patients with complicated urinary tract infections and complicated intra-abdominal infections.

Detailed description: An Open-Label, Randomized, Multicenter, Phase III Study of Ceftazidime Avibactam (CAZ-AVI, formerly CAZ104) and Best Available Therapy for the Treatment of Infections Due to Ceftazidime Resistant Gram Negative Pathogens

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Clinical Response at Test of Cure (TOC) in Microbiological Modified Intent-to-treat (mMITT) Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Secondary outcomes:
measure: Clinical Response at End of Treatment (EOT) in mMITT Analysis Set.
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Clinical Response at Follow-up 1 (FU1) in mMITT Analysis Set
timeFrame: cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
measure: Clinical Response at Follow-up 2 (FU2) in mMITT Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Clinical Response at EOT in Extended Microbiologically Evaluable (EME) at EOT Analysis Set.
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Clinical Response at TOC in EME at TOC Analysis Set.
timeFrame: 6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.
measure: Clinical Response at FU1 in EME at FU1 Analysis Set.
timeFrame: cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
measure: Clinical Response at FU2 in EME at FU2 Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Clinical Cure at TOC by Baseline Gram-negative Pathogen in mMITT Analysis Set
timeFrame: 6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.
measure: Clinical Cure at TOC by Baseline Gram-negative Pathogen in EME at TOC Analysis Set
timeFrame: 6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.
measure: Clinical Cure at TOC by Previously Failed Treatment Class in mMITT Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Clinical Cure at EOT by Previously Failed Treatment Class in EME at EOT Analysis Set
timeFrame: 28 hours after completion of last infusion of study therapy.Duration of study therapy was 5 to 21 days.
measure: Clinical Cure at TOC by Previously Failed Treatment Class in EME at TOC Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Clinical Cure at FU1 by Previously Failed Treatment Class in EME at FU1 Analysis Set
timeFrame: cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
measure: Clinical Cure at FU2 by Previously Failed Treatment Class in EME at FU2 Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Per-patient Microbiological Response at EOT in mMITT Analysis Set
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-patient Microbiological Response at TOC in mMITT Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-patient Microbiological Response at FU1 in mMITT Analysis Set
timeFrame: cUTI: 20-27 calendar days from randomization/cIAI: 27-37 calendar days from randomization
measure: Per-patient Microbiological Response at FU2 in mMITT Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Per-patient Microbiological Response at EOT in EME at EOT Analysis Set
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-patient Microbiological Response at TOC in EME at TOC Analysis Set
timeFrame: 6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.
measure: Per-patient Microbiological Response at FU1 in EME at FU1 Analysis Set
timeFrame: cUTI: 20-27 calendar days from randomization/cIAI: 27-37 calendar days from randomization
measure: Per-patient Microbiological Response at FU2 in EME at FU2 Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at EOT in mMITT Analysis Set
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC in mMITT Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at FU1 in mMITT Analysis Set
timeFrame: cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at FU2 in mMITT Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at EOT in EME at EOT Analysis Set
timeFrame: 28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC in EME at TOC Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at FU1 in EME at FU1 Analysis Set
timeFrame: cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at FU2 in EME at FU2 Analysis Set
timeFrame: At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC by CAZ-AVI MIC in mMITT Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC by CAZ-AVI MIC in EME at TOC Analysis Set
timeFrame: 6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: The Reason for Treatment Change/Discontinuation in mMITT Analysis Set
timeFrame: From first infusion to last infusion of study therapy. Duration of study therapy was 5 to 21 days.
measure: The 28 Days All Cause Mortality Rate in mMITT Analysis Set
timeFrame: From first infusion to Day 28
measure: The 28 Days All Cause Mortality Rate in EME at TOC Analysis Set
timeFrame: From first infusion to Day 28
measure: Plasma Concentrations for Ceftazidime and Avibactam - cIAI in PK Analysis Set
timeFrame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 to 90 minutes after stopping study drug, anytime between 300 to 360 minutes after stopping study drug
measure: Plasma Concentrations for Ceftazidime and Avibactam - cUTI in PK Analysis Set
timeFrame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 to 90 minutes after stopping study drug, anytime between 300 to 360 minutes after stopping study drug
Other outcomes:
Locations:
city: Shreveport
country: United States
facility: Research Site
state: Louisiana
city: Lima
country: United States
facility: Research Site
state: Ohio
city: El Talar
country: Argentina
facility: Research Site
city: La Plata
country: Argentina
facility: Research Site
city: Pazardzhik
country: Bulgaria
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Veliko Turnovo
country: Bulgaria
facility: Research Site
city: Slavonski Brod
country: Croatia
facility: Research Site
city: Zagreb
country: Croatia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Tours
country: France
facility: Research Site
city: Nazareth
country: Israel
facility: Research Site
city: Petach Tikva
country: Israel
facility: Research Site
city: Ramat-Gan
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Guadalajara
country: Mexico
facility: Research Site
city: Mexico, Distrito Federal
country: Mexico
facility: Research Site
city: Cusco
country: Peru
facility: Research Site
city: Surco
country: Peru
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Irkutsk
country: Russian Federation
facility: Research Site
city: Krasnodar
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Penza
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: St.-Petersburg,
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Antalya
country: Turkey
facility: Research Site
city: Diyarbakir
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Kharkiv
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: 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.
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: 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.
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, 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.