Clinical trial NCT01595438: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis
Keywords: Ceftazidime, Avibactam, Doripenem, Ciprofloxacin, sulfamethoxazole/trimethoprim, Anti-Infective Agents, Complicated Urinary Tract Infection,Acute Pyelonephritis
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Forest Laboratories
First posted: 2012-05-10
Enrollment: 598
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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

Primary outcomes:
measure: Patient-reported Symptomatic Response at Day 5 (mMITT Analysis Set): Non-inferiority Hypothesis Test
timeFrame: At Day 5 visit. Day 5 visit is based on 24 hour periods from the first dose date and time.
measure: Combined Patient-reported Symptomatic and Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at TOC (mMITT Analysis Set): Non-inferiority Hypothesis Test
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
Secondary outcomes:
measure: Per-patient Microbiological Response at EOT (IV) (mMITT Analysis Set)
timeFrame: 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
measure: Per-patient Microbiological Response at LFU (mMITT Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-patient Microbiological Response at EOT (IV) (ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-patient Microbiological Response at TOC (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at LFU (ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-patient Microbiological Response at EOT (IV) (Extended ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-patient Microbiological Response at TOC (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at LFU (Extended ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Investigator Determined Clinical Response at EOT (IV) (mMITT Analysis Set)
timeFrame: 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
measure: Investigator Determined Clinical Response at TOC (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at LFU (mMITT Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Investigator Determined Clinical Response at EOT (IV) (ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Investigator Determined Clinical Response at TOC (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at LFU (ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Investigator Determined Clinical Response at EOT (IV) (Extended ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Investigator Determined Clinical Response at TOC (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at LFU (Extended ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Investigator Determined Clinical Response at EOT (IV) (CE at EOT (IV) Analysis Set)
timeFrame: 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
measure: Investigator Determined Clinical Response at TOC (CE at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at LFU (CE at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Investigator Determined Clinical Response at TOC for Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-patient Microbiological Response at TOC in Patients Infected by Ceftazidime-resistant Gram-negative Pathogen (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Time to First Defervescence While on IV Study Therapy (mMITT Analysis Set)
timeFrame: 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.
measure: Time to First Defervescence While on IV Study Therapy (ME at TOC Analysis Set)
timeFrame: 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.
measure: Time to First Defervescence While on IV Study Therapy (Extended ME at TOC Analysis Set)
timeFrame: 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.
measure: Time to First Defervescence While on IV Study Therapy (CE at TOC Analysis Set)
timeFrame: 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.
measure: Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (mMITT Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Baseline Pathogen (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at LFU for Baseline Pathogen (mMITT Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization
measure: Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (Extended ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Baseline Pathogen (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-pathogen Microbiological Response at LFU for Baseline Pathogen (Extended ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-pathogen Microbiological Response at EOT (IV) for Baseline Pathogen (ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Baseline Pathogen (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-pathogen Microbiological Response at LFU for Baseline Pathogen (ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-pathogen Microbiological Response at EOT (IV) for Blood Only (mMITT Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Blood Only (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at LFU for Blood Only (mMITT Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization
measure: Per-pathogen Microbiological Response at EOT (IV) for Blood Only (Extended ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Blood Only (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-pathogen Microbiological Response at LFU for Blood Only (Extended ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-pathogen Microbiological Response at EOT (IV) for Blood Only (ME at EOT (IV) Analysis Set)
timeFrame: 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
measure: Per-pathogen Microbiological Response at TOC for Blood Only (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization.
measure: Per-pathogen Microbiological Response at LFU for Blood Only (ME at LFU Analysis Set)
timeFrame: At LFU visit. LFU visit is 45 to 52 days from Randomization.
measure: Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at TOC by CAZ AVI MIC for Baseline Pathogen (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (mMITT Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (Extended ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Per-pathogen Microbiological Response at TOC by Doripenem MIC for Baseline Pathogen (ME at TOC Analysis Set)
timeFrame: At TOC visit. TOC visit is 21 to 25 days from Randomization
measure: Plasma Concentrations for Ceftazidime Within 15 Minutes Before/After Dose (PK Analysis Set)
timeFrame: within 15 minutes before/after dose
measure: Plasma Concentrations for Ceftazidime Between 30 to 90 Minutes After Dose(PK Analysis Set)
timeFrame: Between 30 to 90 minutes after dose
measure: Plasma Concentrations for Ceftazidime Between 300 to 360 Minutes After Dose(PK Analysis Set)
timeFrame: Between 300 to 360 minutes after dose
measure: Plasma Concentrations for Avibactam Within 15 Minutes Before/After Dose (PK Analysis Set)
timeFrame: within 15 minutes before/after dose
measure: Plasma Concentrations for Avibactam Between 30 to 90 Minutes After Dose(PK Analysis Set)
timeFrame: Between 30 to 90 minutes after dose
measure: Plasma Concentrations for Avibactam Between 300 to 360 Minutes After Dose(PK Analysis Set)
timeFrame: Between 300 to 360 minutes after dose
Other outcomes:
Locations:
city: Sylmar
country: United States
facility: Research Site
state: California
city: Royal Oak
country: United States
facility: Research Site
state: Michigan
city: Lima
country: United States
facility: Research Site
state: Ohio
city: Cordoba
country: Argentina
facility: Research Site
city: Corrientes
country: Argentina
facility: Research Site
city: Córdoba
country: Argentina
facility: Research Site
city: Mendoza
country: Argentina
facility: Research Site
city: Santa Fe
country: Argentina
facility: Research Site
city: Belo Horizonte
country: Brazil
facility: Research Site
city: Campinas/SP
country: Brazil
facility: Research Site
city: Salvador
country: Brazil
facility: Research Site
city: São José do Rio Preto - SP
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: Vila Clementino
country: Brazil
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Zagreb
country: Croatia
facility: Research Site
city: Kyjov
country: Czechia
facility: Research Site
city: Opava
country: Czechia
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Wuppertal
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Nagykanizsa
country: Hungary
facility: Research Site
city: Nyíregyháza
country: Hungary
facility: Research Site
city: Zalaegerszeg
country: Hungary
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petach-Tikva
country: Israel
facility: Research Site
city: Safed
country: Israel
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Koshigaya-shi
country: Japan
facility: Research Site
city: Kyoto-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Nara-shi
country: Japan
facility: Research Site
city: Oita-shi
country: Japan
facility: Research Site
city: Sendai-shi
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Tokushima-shi
country: Japan
facility: Research Site
city: Ueda-shi
country: Japan
facility: Research Site
city: Utsunomiya-shi
country: Japan
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Wonju
country: Korea, Republic of
facility: Research Site
city: Guadalajara, Jalisco
country: Mexico
facility: Research Site
city: Inowrocław
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Cluj
country: Romania
facility: Research Site
city: Craiova
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Arkhangelsk
country: Russian Federation
facility: Research Site
city: Krasnodar
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Penza
country: Russian Federation
facility: Research Site
city: Rostov-on-Don
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: St. Petersburg
country: Russian Federation
facility: Research Site
city: St.Petersburg
country: Russian Federation
facility: Research Site
city: Vsevolozhsk
country: Russian Federation
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Kragujevac
country: Serbia
facility: Research Site
city: Poprad
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Trnava
country: Slovakia
facility: Research Site
city: Zilina
country: Slovakia
facility: Research Site
city: Chiayi
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Diyarbakir
country: Turkey
facility: Research Site
city: Cherkasy
country: Ukraine
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Mykolaiv
country: Ukraine
facility: Research Site
city: Odesa
country: Ukraine
facility: Research Site
city: Odessa
country: Ukraine
facility: Research Site
city: Uzhhorod
country: Ukraine
facility: Research Site
city: Zaporizhzhya
country: Ukraine
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Paul Newell, MBBS, MRCP
role: STUDY_DIRECTOR
References:
citation: Cheng K, Newell P, Chow JW, Broadhurst H, Wilson D, Yates K, Wardman A. Safety Profile of Ceftazidime-Avibactam: Pooled Data from the Adult Phase II and Phase III Clinical Trial Programme. Drug Saf. 2020 Aug;43(8):751-766. doi: 10.1007/s40264-020-00934-3.
citation: Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.
citation: Nichols WW, Stone GG, Newell P, Broadhurst H, Wardman A, MacPherson M, Yates K, Riccobene T, Critchley IA, Das S. Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018 Oct 24;62(11):e02590-17. doi: 10.1128/AAC.02590-17. Print 2018 Nov.
citation: Stone GG, Newell P, Gasink LB, Broadhurst H, Wardman A, Yates K, Chen Z, Song J, Chow JW. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother. 2018 Sep 1;73(9):2519-2523. doi: 10.1093/jac/dky204.
citation: 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.