Ceftazidime-Avibactam Compared With Doripenem Followed by Oral Therapy for Hospitalized Adults With Complicated UTIs (Urinary Tract Infections)

• ClinicalTrials.gov Identifier: NCT01595438
• Recruitment Status: Completed
• First Posted: May 10, 2012
• Results First Posted: March 9, 2016
• Last Update Posted: September 6, 2017
• Sponsor: Pfizer
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: April 27, 2012
• First Posted Date: May 10, 2012
• Results First Submitted Date: October 28, 2015
• Results First Posted Date: March 9, 2016
• Last Update Posted Date: September 6, 2017
• Study Start Date: October 2012
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 8, 2016)

• Patient-reported Symptomatic Response at Day 5 (mMITT Analysis Set): Non-inferiority Hypothesis Test [ Time Frame: At Day 5 visit. Day 5 visit is based on 24 hour periods from the first dose date and time. ]
  Number of patients with symptomatic resolution (or return to premorbid state) of UTI-specific symptoms except flank pain (frequency/urgency/dysuria/suprapubic pain) with resolution of or improvement in flank pain based on the patient-reported symptom assessment response at the Day 5 visit in the mMITT analysis set. The sponsor will conclude noninferiority if the lower limit of the 95% CI of difference (corresponding to a 97.5% 1-sided lower bound) is greater than -12.5% for both FDA coprimary outcome variables (symptomatic resolution at day 5 or favorable combined response at test of cure (TOC)).
• Combined Patient-reported Symptomatic and Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with both a favorable per patient microbiological response and symptomatic resolution (or return to premorbid state) of all UTI-specific symptoms (frequency/urgency/dysuria/suprapubic pain/flank pain) based on the patient-reported symptom assessment response at the TOC visit in the mMITT analysis set. The sponsor will conclude noninferiority if the lower limit of the 95% CI of difference (corresponding to a 97.5% 1-sided lower bound) is greater than -12.5% for both FDA coprimary outcome variables (symptomatic resolution at day 5 or favorable combined response at test of cure (TOC)).
• Per-patient Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at TOC. The primary efficacy outcome variable for ROW is the proportion of patients with a favorable per-patient microbiological response at the TOC visit in the mMITT analysis set.

Original Primary Outcome Measures (submitted: May 8, 2012)

• The proportion of patients with resolved (or return to premorbid) UTI(Urinary Tract Infection)symptoms except flank pain and resolution or improvement in flank pain based on patient-reported symptom assessment response [ Time Frame: Day 5 after study drug start ]
• The proportion of patients with a per patient microbiological eradication and resolution (or return to premorbid) of all UTI-specified symptoms based on patient-reported symptom assessment response. [ Time Frame: 21 to 25 day after randomization ]

Current Secondary Outcome Measures (submitted: March 8, 2016)

• Per-patient Microbiological Response at EOT (IV) (mMITT Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a favorable per-patient microbiological response at EOT (IV)
• Per-patient Microbiological Response at LFU (mMITT Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at LFU
• Per-patient Microbiological Response at EOT (IV) (ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a favorable per-patient microbiological response at EOT (IV)
• Per-patient Microbiological Response at TOC (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at TOC
• Per-patient Microbiological Response at LFU (ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at LFU
• Per-patient Microbiological Response at EOT (IV) (Extended ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a favorable per-patient microbiological response at EOT (IV)
• Per-patient Microbiological Response at TOC (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at TOC
• Per-patient Microbiological Response at LFU (Extended ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a favorable per patient microbiological response at LFU
• Investigator Determined Clinical Response at EOT (IV) (mMITT Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a clinical cure at EOT (IV). The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at TOC (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a clinical cure at TOC. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at LFU (mMITT Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a clinical cure at LFU. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at EOT (IV) (ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a clinical cure at EOT (IV). The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at TOC (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a clinical cure at TOC. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at LFU (ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a clinical cure at LFU. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at EOT (IV) (Extended ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a clinical cure at EOT (IV). The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at TOC (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a clinical cure at TOC. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at LFU (Extended ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a clinical cure at LFU. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at EOT (IV) (CE at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of patients with a clinical cure at EOT (IV). The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at TOC (CE at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of patients with a clinical cure at TOC. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at LFU (CE at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of patients with a clinical cure at LFU. The investigator should consider the entirety of the patient's clinical course and current status, including an evaluation of signs and symptoms (eg, fever, dysuria, costovertebral angle tenderness) and physical examination in order to classify the patient's clinical response.
• Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the mMITT analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.
• Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the ME at TOC analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.
• Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Clinical cure at the TOC visit for patients infected with a ceftazidime resistant pathogen in the Extended ME at TOC analysis set. Includes patients infected by at least one ceftazidime-resistant Gram-negative pathogen.
• Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the mMITT analysis set.
• Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the ME at TOC analysis set.
• Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the Extended ME at TOC analysis set.
• Time to First Defervescence While on IV Study Therapy (mMITT Analysis Set) [ Time Frame: Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period. ]
  Time to first defervescence while on IV study therapy in patients in the mMITT analysis set who have fever at study entry.
• Time to First Defervescence While on IV Study Therapy (ME at TOC Analysis Set) [ Time Frame: Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period. ]
  Time to first defervescence while on IV study therapy in patients in the ME at TOC analysis set who have fever at study entry.
• Time to First Defervescence While on IV Study Therapy (Extended ME at TOC Analysis Set) [ Time Frame: Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period. ]
  Time to first defervescence while on IV study therapy in patients in the Extended ME at TOC analysis set who have fever at study entry.
• Time to First Defervescence While on IV Study Therapy (CE at TOC Analysis Set) [ Time Frame: Time to first defervescence is defined as the time (in days) from the first dose of IV study therapy to first absence of fever, which is temperature ≤ 37.8 C in a 24-hour period. ]
  Time to first defervescence while on IV study therapy in patients in the CE at TOC analysis set who have fever at study entry.
• Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (mMITT Analysis Set) [ Time Frame: At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the mMITT analysis set
• Per-pathogen Microbiological Response at TOC for Baseline Pathogen (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set
• Per-pathogen Microbiological Response at LFU for Baseline Pathogen (mMITT Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set
• Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (Extended ME at EOT (IV) Analysis Set) [ Time Frame: At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the Extended ME at EOT (IV) analysis set
• Per-pathogen Microbiological Response at TOC for Baseline Pathogen (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the Extended ME at TOC analysis set
• Per-pathogen Microbiological Response at LFU for Baseline Pathogen (Extended ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set
• Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the ME at EOT (IV) analysis set
• Per-pathogen Microbiological Response at TOC for Baseline Pathogen (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set
• Per-pathogen Microbiological Response at LFU for Baseline Pathogen (ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set
• Per-pathogen Microbiological Response at EOT (IV) for Blood Only (mMITT Analysis Set) [ Time Frame: At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the mMITT analysis set for blood only
• Per-pathogen Microbiological Response at TOC for Blood Only (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set for blood only
• Per-pathogen Microbiological Response at LFU for Blood Only (mMITT Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set for blood only
• Per-pathogen Microbiological Response at EOT (IV) for Blood Only (Extended ME at EOT (IV) Analysis Set) [ Time Frame: At EOT IV visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the Extended ME at EOT (IV) analysis set for blood only
• Per-pathogen Microbiological Response at TOC for Blood Only (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the Extended ME at TOC analysis set for blood only
• Per-pathogen Microbiological Response at LFU for Blood Only (Extended ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set for blood only
• Per-pathogen Microbiological Response at EOT (IV) for Blood Only (ME at EOT (IV) Analysis Set) [ Time Frame: At EOT (IV) visit. EOT (IV) visit is Within 24 hours after completion of the last infusion of IV study therapy and on/before the first dose for oral study therapy ]
  Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the ME at EOT (IV) analysis set for blood only
• Per-pathogen Microbiological Response at TOC for Blood Only (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set for blood only
• Per-pathogen Microbiological Response at LFU for Blood Only (ME at LFU Analysis Set) [ Time Frame: At LFU visit. LFU visit is 45 to 52 days from Randomization. ]
  Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set for blood only
• Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the mMITT analysis set
• Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the Extended ME at TOC analysis set
• Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the ME at TOC analysis set
• Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (mMITT Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the mMITT analysis set
• Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (Extended ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the Extended ME at TOC analysis set
• Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (ME at TOC Analysis Set) [ Time Frame: At TOC visit. TOC visit is 21 to 25 days from Randomization ]
  Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the ME at TOC analysis set
• Plasma Concentrations for Ceftazidime Within 15 Minutes Before/After Dose (PK Analysis Set) [ Time Frame: within 15 minutes before/after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.
• Plasma Concentrations for Ceftazidime Between 30 to 90 Minutes After Dose(PK Analysis Set) [ Time Frame: Between 30 to 90 minutes after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.
• Plasma Concentrations for Ceftazidime Between 300 to 360 Minutes After Dose(PK Analysis Set) [ Time Frame: Between 300 to 360 minutes after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.
• Plasma Concentrations for Avibactam Within 15 Minutes Before/After Dose (PK Analysis Set) [ Time Frame: within 15 minutes before/after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.
• Plasma Concentrations for Avibactam Between 30 to 90 Minutes After Dose(PK Analysis Set) [ Time Frame: Between 30 to 90 minutes after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.
• Plasma Concentrations for Avibactam Between 300 to 360 Minutes After Dose(PK Analysis Set) [ Time Frame: Between 300 to 360 minutes after dose ]
  Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Original Secondary Outcome Measures (submitted: May 8, 2012)

• The proportion of patients with a favorable per patient microbiological response in the microbiological modified Intent-To-Treat analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with a favorable per patient microbiological response in the microbiologically evaluable analysis set. [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with a favorable per patient microbiological response in the extended microbiological evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with resolution (or return to premorbid) of all UTI-specific symptoms based on the patient-reported symptom assessment response in the microbiological modified Intent-To-Treat analysis set [ Time Frame: 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of favorable per-pathogen microbiological response in the microbiological modified Intent-To-Treat analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of favorable per-pathogen microbiological response in the microbiologically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of favorable per-pathogen microbiological response in the extended microbiologically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with an investigator-determined clinical cure in the microbiological modified Intent-To-Treat analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with an investigator-determined clinical cure in the microbiologically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The proportion of patients with an investigator-determined clinical cure in the extended microbiologically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion,anytime between 21 - 25 days and anytime between 45 - 52 days after the start of the study drug ]
• The proportion of patients with an investigator-determined clinical cure in the clinically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The favorable per pathogen microbiologic response by categories of minimum inhibitory concentration in the microbiological modified Intent-To-Treat analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The favorable per pathogen microbiologic response by categories of minimum inhibitory concentration in the microbiologically evaluable analysis set [ Time Frame: Within 24 hours after IV (intravenous) completion, 21 to 25 days and 45 to 52 days after study drug start ]
• The favorable per pathogen microbiologic response by categories of minimum inhibitory concentration in the extended microbiologically evaluable analysis set [ Time Frame: 24 hours after completion of study drug, 21 to 25 days and 45 to 52 days after the start of the study drug ]
• The proportion of patients with favorable investigator clinical response assessment in patients infected with a ceftazidime resistant pathogen in the microbiological modified Intent-To-Treat analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with an investigator-determined clinical cure in patients infected with a ceftazidime resistant pathogen in the microbiologically evaluable analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with an investigator-determined clinical cure in patients infected with a ceftazidime resistant pathogen in the extended microbiologically evaluable analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with favorable per-patient microbiological response for patients infected with a ceftazidime resistant pathogen in the microbiological modified Intent-To-Treat analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with favorable per-patient microbiological response for patients infected with a ceftazidime resistant pathogen in the microbiologically evaluable analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with favorable per-patient microbiological response for patients infected with a ceftazidime resistant pathogen in the extended microbiologically evaluable analysis set [ Time Frame: 21 to 25 days after study drug start ]
• The proportion of patients with symptomatic resolution (defined in the coprimary variables) for patients infected with a ceftazidime resistant pathogen in the microbiological modified Intent-To-Treat analysis set [ Time Frame: Day 5 and 21 to 25 days after study drug start ]
• The time to first defervescence while on IV (intravenous)study therapy in patients in the microbiological modified Intent-To-Treat analysis set who have fever at study entry [ Time Frame: Any time after start of study drug to end of IV (intravenous) study therapy, which is a minimum of 5 days to a maximum of 14 days of IV study therapy ]
• The time to first defervescence while on IV (intravenous) study therapy in patients in the microbiologically evaluable analysis set who have fever at study entry [ Time Frame: Any time after start of study drug to end of IV (intravenous) study therapy, which is a minimum of 5 days to a maximum of 14 days of IV study therapy ]
• The time to first defervescence while on IV (intravenous) study therapy in patients in the extended microbiologically evaluable analysis set who have fever at study entry [ Time Frame: Any time after start of study drug to end of IV (intravenous) study therapy, which is a minimum of 5 days to a maximum of 14 days of IV study therapy ]
• The time to first defervescence while on IV (intravenous) study therapy in patients in the clinically evaluable analysis set who have fever at study entry [ Time Frame: Any time after start of study drug to end of IV (intravenous) study therapy, which is a minimum of 5 days to a maximum of 14 days of IV study therapy ]
• Profile of pharmacokinetic (PK) of the individual components of CAZ-AVI (avibactam and ceftazidime)- maximum plasma concentration (Cmax) [ Time Frame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug ]
  Cmax - Maximum plasma concentration
• Profile of pharmacokinetic (PK) of the individual components of CAZ-AVI (avibactam and ceftazidime)- minimum plasma concentration (Cmin) [ Time Frame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug ]
  Cmin - Minimum plasma concentration
• Profile of pharmacokinetic (PK) of the individual components of CAZ-AVI (avibactam and ceftazidime)- area under the plasma concentration time curve at steady state (AUCss) [ Time Frame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug ]
  AUCss - Area under the plasma concentration time curve at steady state
• Profile of pharmacokinetic (PK) of the individual components of CAZ-AVI (avibactam and ceftazidime)- terminal half-life (t½ ) [ Time Frame: Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug ]
  t½ - Terminal half-life

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ceftazidime-Avibactam Compared With Doripenem Followed by Oral Therapy for Hospitalized Adults With Complicated UTIs (Urinary Tract Infections)
• Official Title: A Phase III, Randomized, Multicenter, Double-Blind, Double Dummy, Parallel Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam (CAZ-AVI, Formerly CAZ104) Versus Doripenem Followed by Appropriate Oral Therapy in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, With a Gram Negative Pathogen in Hospitalized Adults
• Brief Summary: The purpose of this study is to evaluate the effects of Ceftazidime Avibactam compared to Doripenem for treating hospitalized patients with complicated urinary tract infections, including acute pyelonephritis
• Detailed Description: A Phase III, Randomized, Multicenter, Double-Blind, Double Dummy, Parallel Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam (CAZ-AVI, formerly CAZ104) Versus Doripenem Followed by Appropriate Oral Therapy in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, With a Gram Negative Pathogen in Hospitalized Adults
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis

Intervention

• 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: Doripenem
  500 mg of Doripenem. Patients randomized to receive Doripenem will receive an infusion of Doripenem 500 mg every 8 hours administered by intravenous (IV) infusion in a volume of 100 mL at a constant rate over 60 minutes
• Drug: Either switch to oral therapy: 500 mg of Ciprofloxacin (oral)
  Patients are eligible for oral switch after receiving 5 full days of IV therapy and have met protocol specified criteria for clinical improvement
• Drug: or switch to oral therapy: 800 mg/160 mg of sulfamethoxazole/trimethoprim (oral)
  Patients are eligible for oral switch after receiving 5 full days of IV therapy and have met protocol specified criteria for clinical improvement

Study Arms

• Experimental: Ceftazidime - Avibactam ( CAZ-AVI)
  IV treatment
  Interventions:

  • Drug: Ceftazidime - Avibactam ( CAZ-AVI)
  • Drug: Either switch to oral therapy: 500 mg of Ciprofloxacin (oral)
  • Drug: or switch to oral therapy: 800 mg/160 mg of sulfamethoxazole/trimethoprim (oral)
• Active Comparator: Doripenem
  IV treatment
  Interventions:

  • Drug: Doripenem
  • Drug: Either switch to oral therapy: 500 mg of Ciprofloxacin (oral)
  • Drug: or switch to oral therapy: 800 mg/160 mg of sulfamethoxazole/trimethoprim (oral)

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). pii: 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.
• Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, Yates K, Gasink LB. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis. 2016 Sep 15;63(6):754-762. doi: 10.1093/cid/ciw378. Epub 2016 Jun 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 8, 2016): 598
• Original Estimated Enrollment (submitted: May 8, 2012): 964
• Actual Study Completion Date: August 2014
• Actual Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 18 to 90 years of age inclusive
• 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
• Has pyuria with >/= 10 WBCs (white blood cell) and has a positive urine culture within 48 hours of enrollment containing >/=10 to the fifth CFU (colony forming unit ) /ml of a recognized uropathogen known to be susceptible to IV study therapy (CAZ-AVI and doripenem)
• Demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis.

Exclusion Criteria:

• Urine pathogen is a Gram-positive pathogen or a uropathogen resistant to CAZ-AVI or doripenem
• Patient's urine culture at study entry isolates more than 2 microorganisms regardless of colony count or patient has a confirmed fungal UTI
• Patient is receiving hemodialysis or peritoneal dialysis or had a renal transplant
• Patient is immunocompromised
• Patient is considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness including septic shock which is associated with a high risk of mortality

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Bulgaria, Croatia, Czechia, Germany, Greece, Hungary, Israel, Japan, Korea, Republic of, Mexico, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Taiwan, Turkey, Ukraine, United States
• Removed Location Countries: Belgium, Canada, Czech Republic, France, India, Puerto Rico

Administrative Information

• NCT Number: NCT01595438
• Other Study ID Numbers: D4280C00002; 2011-005721-43
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Forest Laboratories

Investigators

• Study Director: Paul Newell, MBBS, MRCP; AstraZeneca

• PRS Account: Pfizer
• Verification Date: August 2017