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

Pfizer641 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

641

Conditions

Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis

Interventions

Ceftazidime - Avibactam ( CAZ-AVI)DRUG

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

DoripenemDRUG

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

Either switch to oral therapy: 500 mg of Ciprofloxacin (oral)DRUG

Patients are eligible for oral switch after receiving 5 full days of IV therapy and have met protocol specified criteria for clinical improvement

Eligibility

Sex: ALLMin age: 18 YearsMax age: 90 Years

Medical Language ↔ Plain English

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

Locations (57)

Outcomes

Primary Outcomes

Patient-reported Symptomatic Response at Day 5 (mMITT Analysis Set): Non-inferiority Hypothesis Test

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)).

Time frame: At Day 5 visit. Day 5 visit is based on 24 hour periods from the first dose date and time.

Combined Patient-reported Symptomatic and Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test

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)).

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test

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.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Secondary Outcomes

Data from ClinicalTrials.gov

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or switch to oral therapy: 800 mg/160 mg of sulfamethoxazole/trimethoprim (oral)DRUG

Patients are eligible for oral switch after receiving 5 full days of IV therapy and have met protocol specified criteria for clinical improvement

Research Site

Detroit, Michigan, United States

Research Site

St Louis, Missouri, United States

Research Site

Indiana, Pennsylvania, United States

Research Site

Rosario, Argentina

Research Site

Pazardzhik, Bulgaria

Research Site

Sofia, Bulgaria

Research Site

Veliko Tarnovo, Bulgaria

Research Site

Slavonski Brod, Croatia

Research Site

Zadar, Croatia

Research Site

Zagreb, Croatia

...and 47 more locations

Per-patient Microbiological Response at EOT (IV) (mMITT Analysis Set)

Number of patients with a favorable per-patient microbiological response at EOT (IV)

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

Per-patient Microbiological Response at LFU (mMITT Analysis Set)

Number of patients with a favorable per patient microbiological response at LFU

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-patient Microbiological Response at EOT (IV) (ME at EOT (IV) Analysis Set)

Number of patients with a favorable per-patient microbiological response at EOT (IV)

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

Per-patient Microbiological Response at TOC (ME at TOC Analysis Set)

Number of patients with a favorable per patient microbiological response at TOC

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at LFU (ME at LFU Analysis Set)

Number of patients with a favorable per patient microbiological response at LFU

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-patient Microbiological Response at EOT (IV) (Extended ME at EOT (IV) Analysis Set)

Number of patients with a favorable per-patient microbiological response at EOT (IV)

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

Per-patient Microbiological Response at TOC (Extended ME at TOC Analysis Set)

Number of patients with a favorable per patient microbiological response at TOC

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at LFU (Extended ME at LFU Analysis Set)

Number of patients with a favorable per patient microbiological response at LFU

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Investigator Determined Clinical Response at EOT (IV) (mMITT Analysis Set)

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.

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

Investigator Determined Clinical Response at TOC (mMITT Analysis Set)

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.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Investigator Determined Clinical Response at LFU (mMITT Analysis Set)

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.

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

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

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.

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.

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

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.

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.

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

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.

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.

Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set)

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.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set)

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.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set)

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.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set)

Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the mMITT analysis set.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set)

Favorable per-patient microbiological response at the TOC visit for patients infected with a ceftazidime resistant pathogen in the ME at TOC analysis set.

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set)

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 frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Time to First Defervescence While on IV Study Therapy (mMITT Analysis Set)

Time to first defervescence while on IV study therapy in patients in the mMITT analysis set who have fever at study entry.

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 (ME at TOC Analysis Set)

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 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 (Extended ME at TOC Analysis Set)

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 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 (CE at TOC Analysis Set)

Time to first defervescence while on IV study therapy in patients in the CE at TOC analysis set who have fever at study entry.

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.

Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the 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

Per-pathogen Microbiological Response at TOC for Baseline Pathogen (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization

Per-pathogen Microbiological Response at LFU for Baseline Pathogen (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization

Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (Extended ME at EOT (IV) Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the 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

Per-pathogen Microbiological Response at TOC for Baseline Pathogen (Extended ME at TOC Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the 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 LFU for Baseline Pathogen (Extended ME at LFU Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (ME at EOT (IV) Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the 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

Per-pathogen Microbiological Response at TOC for Baseline Pathogen (ME at TOC Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-pathogen Microbiological Response at LFU for Baseline Pathogen (ME at LFU Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-pathogen Microbiological Response at EOT (IV) for Blood Only (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the mMITT analysis set for blood only

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

Per-pathogen Microbiological Response at TOC for Blood Only (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the mMITT analysis set for blood only

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization

Per-pathogen Microbiological Response at LFU for Blood Only (mMITT Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the mMITT analysis set for blood only

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization

Per-pathogen Microbiological Response at EOT (IV) for Blood Only (Extended ME at EOT (IV) Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the Extended ME at EOT (IV) analysis set for blood only

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

Per-pathogen Microbiological Response at TOC for Blood Only (Extended ME at TOC Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the Extended ME at TOC analysis set for blood only

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-pathogen Microbiological Response at LFU for Blood Only (Extended ME at LFU Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the Extended ME at LFU analysis set for blood only

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-pathogen Microbiological Response at EOT (IV) for Blood Only (ME at EOT (IV) Analysis Set)

Number of favorable per-pathogen microbiological responses at the EOT (IV) visit in the ME at EOT (IV) analysis set for blood only

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

Per-pathogen Microbiological Response at TOC for Blood Only (ME at TOC Analysis Set)

Number of favorable per-pathogen microbiological responses at the TOC visit in the ME at TOC analysis set for blood only

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization.

Per-pathogen Microbiological Response at LFU for Blood Only (ME at LFU Analysis Set)

Number of favorable per-pathogen microbiological responses at the LFU visit in the ME at LFU analysis set for blood only

Time frame: At LFU visit. LFU visit is 45 to 52 days from Randomization.

Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (mMITT Analysis Set)

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the 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 (Extended ME at TOC Analysis Set)

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the 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 (ME at TOC Analysis Set)

Per pathogen microbiological response at TOC by CAZ-AVI MIC for baseline pathogen in the 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 (mMITT Analysis Set)

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the 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 (Extended ME at TOC Analysis Set)

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the 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 (ME at TOC Analysis Set)

Per pathogen microbiological response at TOC by Doripenem MIC for baseline pathogen in the ME at TOC analysis set

Time frame: At TOC visit. TOC visit is 21 to 25 days from Randomization

Plasma Concentrations for Ceftazidime Within 15 Minutes Before/After Dose (PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: within 15 minutes before/after dose

Plasma Concentrations for Ceftazidime Between 30 to 90 Minutes After Dose(PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: Between 30 to 90 minutes after dose

Plasma Concentrations for Ceftazidime Between 300 to 360 Minutes After Dose(PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: Between 300 to 360 minutes after dose

Plasma Concentrations for Avibactam Within 15 Minutes Before/After Dose (PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: within 15 minutes before/after dose

Plasma Concentrations for Avibactam Between 30 to 90 Minutes After Dose(PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: Between 30 to 90 minutes after dose

Plasma Concentrations for Avibactam Between 300 to 360 Minutes After Dose(PK Analysis Set)

Blood samples were taken on Day 3 for ceftazidime (CAZ) and avibactam (AVI) plasma concentration.

Time frame: Between 300 to 360 minutes after dose