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

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

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

Study Overview

• Status: Completed
• Conditions: Complicated Intra-abdominal Infection; Complicated Urinary Tract Infection
• Intervention / Treatment: Drug: Ceftazidime - Avibactam ( CAZ-AVI); Drug: Metronidazole; Drug: Best Available Therapy

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

• Study Type: Interventional
• Enrollment (Actual): 345
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • El Talar, Argentina
    • Research Site
  • La Plata, Argentina
    • Research Site
• Bulgaria
  • Pazardzhik, Bulgaria
    • Research Site
  • Pleven, Bulgaria
    • Research Site
  • Ruse, Bulgaria
    • Research Site
  • Sofia, Bulgaria
    • Research Site
  • Varna, Bulgaria
    • Research Site
  • Veliko Turnovo, Bulgaria
    • Research Site
• Croatia
  • Slavonski Brod, Croatia
    • Research Site
  • Zagreb, Croatia
    • Research Site
• Czechia
  • Praha 5, Czechia
    • Research Site
• France
  • Tours, France
    • Research Site
• Israel
  • Nazareth, Israel
    • Research Site
  • Petach Tikva, Israel
    • Research Site
  • Ramat-Gan, Israel
    • Research Site
  • Tel Aviv, Israel
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Research Site
• Mexico
  • Guadalajara, Mexico
    • Research Site
  • Mexico, Distrito Federal, Mexico
    • Research Site
• Peru
  • Cusco, Peru
    • Research Site
  • Surco, Peru
    • Research Site
• Philippines
  • Manila, Philippines
    • Research Site
• Poland
  • Szczecin, Poland
    • Research Site
• Romania
  • Bucharest, Romania
    • Research Site
  • Bucuresti, Romania
    • Research Site
• Russian Federation
  • Irkutsk, Russian Federation
    • Research Site
  • Krasnodar, Russian Federation
    • Research Site
  • Novosibirsk, Russian Federation
    • Research Site
  • Penza, Russian Federation
    • Research Site
  • Saint-Petersburg, Russian Federation
    • Research Site
  • St. Petersburg, Russian Federation
    • Research Site
  • St.-Petersburg,, Russian Federation
    • Research Site
  • Yaroslavl, Russian Federation
    • Research Site
• South Africa
  • Johannesburg, South Africa
    • Research Site
• Spain
  • Barcelona, Spain
    • Research Site
  • Madrid, Spain
    • Research Site
• Turkey
  • Ankara, Turkey
    • Research Site
  • Antalya, Turkey
    • Research Site
  • Diyarbakir, Turkey
    • Research Site
  • Istanbul, Turkey
    • Research Site
• Ukraine
  • Dnipropetrovsk, Ukraine
    • Research Site
  • Kharkiv, Ukraine
    • Research Site
  • Kyiv, Ukraine
    • Research Site
  • Zaporizhzhya, Ukraine
    • Research Site
• United States
  • Louisiana
    • Shreveport, Louisiana, United States
      • Research Site
  • Ohio
    • Lima, Ohio, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftazidime - Avibactam ( CAZ-AVI); IV treatment	Drug: Ceftazidime - Avibactam ( CAZ-AVI); 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; Drug: Metronidazole; 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; Other Names: Flagyl
Active Comparator: Best Available Therapy; IV treatment	Drug: Best Available Therapy; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response at End of Treatment (EOT) in mMITT Analysis Set.	Proportion of patients with clinical cure at the EOT 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).	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	Proportion of patients with clinical cure at the FU1 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).	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	Proportion of patients with clinical cure at the FU2 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).	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.	Proportion of patients with clinical cure at the EOT visit in the EME at EOT 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).	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.	Proportion of patients with clinical cure at the TOC visit in the EME at TOC 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.
Clinical Response at FU1 in EME at FU1 Analysis Set.	Proportion of patients with clinical cure at the FU1 visit in EME at FU1 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).	cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
Clinical Response at FU2 in EME at FU2 Analysis Set	Proportion of patients with clinical cure at the FU2 visit in EME at FU2 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.	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Clinical Cure at TOC by Baseline Gram-negative Pathogen in mMITT Analysis Set	Proportion of patients with clinical cure at TOC visit by baseline pathogen (>=10% of frequency in the combined cIAI and cUTI patients) 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.
Clinical Cure at TOC by Baseline Gram-negative Pathogen in EME at TOC Analysis Set	Proportion of patients with clinical cure at TOC visit by baseline Gram-negative pathogen (>=10% of frequency in the combined cIAI and cUTI patients) in EME at TOC 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.
Clinical Cure at TOC by Previously Failed Treatment Class in mMITT Analysis Set	Proportion of patients with clinical cure at TOC visit by previously failed treatment class 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.
Clinical Cure at EOT by Previously Failed Treatment Class in EME at EOT Analysis Set	Proportion of patients with clinical cure at EOT visit by previously failed treatment class in EME at EOT 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).	28 hours after completion of last infusion of study therapy.Duration of study therapy was 5 to 21 days.
Clinical Cure at TOC by Previously Failed Treatment Class in EME at TOC Analysis Set	Proportion of patients with clinical cure at TOC visit by previously failed treatment class in EME at TOC 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.
Clinical Cure at FU1 by Previously Failed Treatment Class in EME at FU1 Analysis Set	Proportion of patients with clinical cure at FU1 visit by previously failed treatment class in EME at FU1 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).	cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
Clinical Cure at FU2 by Previously Failed Treatment Class in EME at FU2 Analysis Set	Proportion of patients with clinical cure at FU2 visit by previously failed treatment class in EME at FU2 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.	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Per-patient Microbiological Response at EOT in mMITT Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-patient Microbiological Response at TOC in mMITT Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-patient Microbiological Response at FU1 in mMITT Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	cUTI: 20-27 calendar days from randomization/cIAI: 27-37 calendar days from randomization
Per-patient Microbiological Response at FU2 in mMITT Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Per-patient Microbiological Response at EOT in EME at EOT Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-patient Microbiological Response at TOC in EME at TOC Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	6-12 days after last infusion of study therapy.Duration of study therapy was 5 to 21 days.
Per-patient Microbiological Response at FU1 in EME at FU1 Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	cUTI: 20-27 calendar days from randomization/cIAI: 27-37 calendar days from randomization
Per-patient Microbiological Response at FU2 in EME at FU2 Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cIAI patients where the clinical response was changed to indeterminate due to a Surgical Review Panel assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Per-pathogen Microbiological Response of Gram-negative Pathogen at EOT in mMITT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequency in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC in mMITT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequency in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-pathogen Microbiological Response of Gram-negative Pathogen at FU1 in mMITT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequency in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
Per-pathogen Microbiological Response of Gram-negative Pathogen at FU2 in mMITT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Per-pathogen Microbiological Response of Gram-negative Pathogen at EOT in EME at EOT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	28 hours after completion of last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC in EME at TOC Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-pathogen Microbiological Response of Gram-negative Pathogen at FU1 in EME at FU1 Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	cIAI: 27-37 calendar days from randomization/cUTI: 20-27 calendar days from randomization
Per-pathogen Microbiological Response of Gram-negative Pathogen at FU2 in EME at FU2 Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population).	At FU2, data was only collected for the cUTI Arms: 28-34 calendar days from randomization
Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC by CAZ-AVI MIC in mMITT Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population). For E.coli, MIC available values are: <=0.008, 0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 8. For K. pneumoniae, MIC available values are: 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 32, >32. For P. aeruginosa, MIC available values are: 2, 4, 8, 16, 32, >32.	6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
Per-pathogen Microbiological Response of Gram-negative Pathogen at TOC by CAZ-AVI MIC in EME at TOC Analysis Set	Proportion of patients with a favorable per-pathogen microbiological response for pathogens (>=10% of frequncy in the combined cIAI and cUTI patients): favourable microbiological response includes: Eradication Absence (or urine quantification less than 10^4 CFU/ml for cUTI patients) of causative pathogen from an appropriately obtained specimen at the site of infection. If the patient was bacteremic at Screening, the bacteremia has also resolved. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure (specific to cIAI population). For E.coli, MIC available values are: <=0.008, 0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 8. For K. pneumoniae, MIC available values are: 0.06, 0.12, 0.25, 0.5, 1, 2, 4, >32. For P. aeruginosa, MIC available values are: 2, 4, 8, 16, 32, >32.	6-12 days after last infusion of study therapy. Duration of study therapy was 5 to 21 days.
The Reason for Treatment Change/Discontinuation in mMITT Analysis Set	Proportion of patients in the mMITT analysis set for whom the assigned study treatment was changed, discontinued, or interrupted. Creatinine clearance (CrCl)	From first infusion to last infusion of study therapy. Duration of study therapy was 5 to 21 days.
The 28 Days All Cause Mortality Rate in mMITT Analysis Set	Proportion of patients with Day 28 all-cause mortality in mMITT analysis set. The death in the cIAI patient were reviewed independently by the SRP Chair.	From first infusion to Day 28
The 28 Days All Cause Mortality Rate in EME at TOC Analysis Set	Proportion of patients with Day 28 all-cause mortality in EME at TOC analysis set. The death in the cIAI patient were reviewed independently by the SRP Chair.	From first infusion to Day 28
Plasma Concentrations for Ceftazidime and Avibactam - cIAI in PK Analysis Set	Blood samples were taken on Day 3 for ceftazidime and avibactam plasma concentration.	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
Plasma Concentrations for Ceftazidime and Avibactam - cUTI in PK Analysis Set	Blood samples were taken on Day 3 for ceftazidime and avibactam plasma concentration.	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

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Forest Laboratories

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: July 18, 2012
• First Posted (Estimate): July 19, 2012

Study Record Updates

• Last Update Posted (Actual): September 29, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Ceftazidime,; avibactam,; metronidazone,; Anti-Infectives
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Intraabdominal Infections; Urinary Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; beta-Lactamase Inhibitors; Metronidazole; Avibactam; Ceftazidime
• Other Study ID Numbers: D4280C00006; 2012-000726-21

Plan for Individual participant data (IPD)

Study Data/Documents

1. Study Protocol
   Information identifier: D4280C00006
   Information comments: D4280C00006 Clinical Study Protocol
2. Study Protocol
   Information identifier: D4280C00006
   Information comments: D4280C00006 Clinical Study Protocol Amendment 2 Redacted amended
3. Study Protocol
   Information identifier: D4280C00006
   Information comments: D4280C00006 Clinical Study Protocol Amendment 3 Redacted amended