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CAZ-AVI

Phase 3

Complicated Intra-Abdominal Infection | Small molecule | Infectious Disease |Pfizer, Inc.|Last Updated: Sep 6, 2017

Success Probability

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Trial Design

RandomizedDouble-BlindACTIVE_CONTROLLED
Total Trials1
Total Enrollment493

FDA Designations

No designations recorded

Clinical trial landscape

CAZ-AVI · 5 trials · 10 indications

Phase 3 1Phase 1 4
NCT01499290Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal InfectionsComplicated Intra-Abdominal Infection
COMPLETED493 Analytics
PHASE3COMPLETED
Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections
Complicated Intra-Abdominal InfectionUnlock trial analytics

Study Endpoints

Primary Endpoints

Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA).
TOC: 28 to 35 days after start of study drug

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.

Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]).
TOC: 28 to 35 days after start of study drug

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.

Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]).
TOC: 28 to 35 days after start of study drug

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.

Safety and Tolerability:Adverse events, vital signs, ECGs, clinical laboratory measurements, physical examinations, oral body temperature
Routine safety assessments, throughout the period that subjects receive CAZ-AVI/PLACEBO up to 5 days following discontinuation of study treatment

AE: The onset of an AE relative to treatment will be calculated as the time difference between the onset (date and time) of the AE and the start time of the last dose (date and time) prior to the AE; the duration of a resolved AE will be calculated as the difference between the resolution (date and time) of the AE and the onset (date and time) of the AE. Vital signs and oral temperature:Change in BP, pulse rate and oral temperature at each post treatment time point will be calculated as the post treatment measurement value minus the baseline value observed on Day -1. Physical examination: complete physical examination and brief physical examination. ECG: heart rate, RR, PR, QRS, and QT intervals from the 12-lead ECG and the derived variable QTcF. Safety laboratory (hematology, chemistry and urinalysis): Change in laboratory test value at each post treatment time point will be calculated as the post treatment value minus the baseline value observed on Day -1 .

Changes in the intestinal flora of healthy subjects after administration of ceftazidime-avibactam (CAZ-AVI) and ceftaroline fosamil -avibactam (CXL).
Change from baseline (Day-1) at Day 2, 5, 7, 10, 14 and 21

The number and types of microorganisms in faeces.

Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: AUC
Day 1

Key PK parameters were prespecified to be calculated for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.

Pharmacokinetic Parameters of Avibactam and Ceftazidime for Cohort 1 and 2: Cmax
Day 1

Key PK parameters are shown for cohorts 1 and 2. For cohorts 3 and 4 (where children were \<6 years of age), sparse sampling scheme was used for PK samples to limit the volume of blood required. PK parameters cannot be derived from these sparse PK samples without population PK analysis. Thus the PK is not described here, but will be reported in a separate population PK report.

Profile of pharmacokinetic of ceftazidime, avibactam and metronidazole when administering CAZ-AVI plus metronidazole in combination compared to administration of individual components
CAZ-AVI: pre-dose, 0.5, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 4, 5, 7, 11, 23, 73, 73.5, 74, 74.5, 75, 75.25, 75.5, 75.75, 76, 77, 78, 80, 84 and 95 hours post-dose

Secondary Endpoints

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
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Study Design & Arms

AllocationRANDOMIZED
MaskingQUADRUPLE
ModelPARALLEL
PurposeTREATMENT

Treatment Arms

ArmTypeDescription
CAZ-AVI + MetronidazoleEXPERIMENTALIV treatment
MeropenemACTIVE_COMPARATORIV treatment
PlaceboPLACEBO_COMPARATORIV infusions of 0.9% normal saline
CAZ-AVIEXPERIMENTALIV infusion of AVI 500 mg + CAZ 2000 mg.
CAZ-AVI or CXLEXPERIMENTALCohort 1: CAZ-AVI (2000 mg ceftazidime and 500 mg avibactam) by intravenous infusion given over 2 hours, every 8 hours Cohort 2: CXL (600 mg ceftaroline fosamil and 600 mg avibactam)
CAZAVIEXPERIMENTALCAZ-AVI (2000 mg ceftazidime/500 mg avibactam)
MetronidazoleACTIVE_COMPARATORMetronidazole (500 mg)
CAZAVI+metronidazoleACTIVE_COMPARATORCAZ-AVI (2000mg ceftazidime/500 mg avibactam) + metronidazole (500 mg)

Interventions

NameTypeDescription
CAZ-AVIDRUGCeftazidime 2000 mg and 500 mg of avibactam
MetronidazoleDRUG500 mg of Metronidazole
MeropenemDRUG1 gram of Meropenem
0.9% Normal SalineDRUGA single 120 minute IV infusion on Day 1, followed by three times daily (every 8 hours, q8h) as 120 minute IV infusions for 7 days (Day 2 to Day 8), and one single 120 minute IV infusion on Day 9.
CXLDRUGIV infusion
CAZ-AVI + metronidazoleDRUGInfusion
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Eligibility Criteria

Age Range18 Years to 90 Years
SexALL
Healthy VolunteersNo
Study Sites56

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 exogeno...

Countries:United StatesArgentinaBulgariaCroatiaCzechiaHungaryIndiaIsraelLatviaMalaysiaMexicoNetherlandsPeruRomaniaRussiaSouth AfricaSpainTaiwanThailandUkraineChinaSweden
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Frequently asked questions about CAZ-AVI

What is CAZ-AVI used for?

CAZ-AVI, also known as ceftazidime-avibactam, is an investigational small molecule being studied for complicated intra-abdominal infections, systemic infections, and pharmacokinetic effects in healthy volunteers. It is a combination antibiotic being developed by Pfizer, Inc. for the treatment of serious bacterial infections.

What does CAZ-AVI target?

CAZ-AVI is a combination of ceftazidime, a cephalosporin antibiotic, and avibactam, a beta-lactamase inhibitor. It works by inhibiting bacterial cell wall synthesis and protecting ceftazidime from degradation by beta-lactamase enzymes, thereby restoring its activity against resistant bacteria.

Who makes CAZ-AVI?

CAZ-AVI is being developed by Pfizer, Inc., a pharmaceutical company listed on the New York Stock Exchange under the ticker symbol PFE. Pfizer is conducting clinical trials to evaluate the safety and efficacy of this combination antibiotic for various infectious disease indications.

What phase is CAZ-AVI in?

CAZ-AVI has completed Phase 3 clinical trials for complicated intra-abdominal infections. It has also completed Phase 1 trials for healthy volunteers, pharmacokinetics, and systemic infections. The drug is investigational and still in clinical development, with no approval status indicated.

What clinical trials is CAZ-AVI in?

CAZ-AVI has completed four clinical trials. NCT01499290 was a Phase 3 study comparing ceftazidime-avibactam plus metronidazole versus meropenem in 493 adults with complicated intra-abdominal infections. NCT01534247 and NCT01789528 were Phase 1 pharmacokinetic studies in healthy volunteers. NCT01893346 was a Phase 1 safety study in pediatric patients with systemic infections.

Is CAZ-AVI the same as ceftazidime-avibactam?

Yes, CAZ-AVI is the same as ceftazidime-avibactam. The drug is a fixed-dose combination of ceftazidime and avibactam, and it is referred to by the abbreviation CAZ-AVI in clinical trial documentation and research literature.