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

NCT01595438 | Completed Phase 3 Results

• 2 other identifiers: D4280C000022011-005721-43
• Study Type: interventional
• Target: 598
• Locations: 22 countries
• Sites: 80

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

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

Outcome Measures

Primary Outcomes (3)

• 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)).

  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)).

  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.

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

Secondary Outcomes (60)

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

  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)

  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)

  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)

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

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

  At LFU visit. LFU visit is 45 to 52 days from Randomization.

Study Arms (2)

Ceftazidime - Avibactam ( CAZ-AVI)

EXPERIMENTAL

IV treatment

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)

Doripenem

ACTIVE COMPARATOR

IV treatment

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)

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

Ceftazidime - Avibactam ( CAZ-AVI)

Doripenem DRUG

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

Doripenem

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

Ceftazidime - Avibactam ( CAZ-AVI); Doripenem

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

Ceftazidime - Avibactam ( CAZ-AVI); Doripenem

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Pfizer: lead
• Forest Laboratories: collaborator

Study Sites (80)

Research Site

Sylmar, California, United States

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Royal Oak, Michigan, United States

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Lima, Ohio, United States

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Corrientes, Argentina

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Córdoba, Argentina

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Mendoza, Argentina

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Santa Fe, Argentina

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Belo Horizonte, Brazil

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Campinas/SP, Brazil

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Salvador, Brazil

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São José Do Rio Preto - SP, Brazil

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São Paulo, Brazil

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Vila Clementino, Brazil

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Pleven, Bulgaria

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Rousse, Bulgaria

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Sofia, Bulgaria

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Zagreb, Croatia

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Kyjov, Czechia

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Opava, Czechia

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Jena, Germany

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Wuppertal, Germany

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Athens, Greece

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Budapest, Hungary

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Nagykanizsa, Hungary

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Nyíregyháza, Hungary

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Zalaegerszeg, Hungary

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Jerusalem, Israel

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Petah Tikva, Israel

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Safed, Israel

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Fukuoka, Japan

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Koshigaya-shi, Japan

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Kyoto, Japan

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Nagoya, Japan

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Nara, Japan

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Ōita, Japan

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Sendai, Japan

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Sunto-gun, Japan

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Tokushima, Japan

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Ueda-shi, Japan

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Utsunomiya, Japan

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Guadalajara, Jalisco, Mexico

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Inowrocław, Poland

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Krakow, Poland

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Warsaw, Poland

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Lisbon, Portugal

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Brasov, Romania

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Bucharest, Romania

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Cluj-Napoca, Romania

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Craiova, Romania

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Iași, Romania

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Arkhangelsk, Russia

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Krasnodar, Russia

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Moscow, Russia

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Novosibirsk, Russia

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Penza, Russia

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Rostov-on-Don, Russia

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Saint Petersburg, Russia

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Saratov, Russia

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Vsevolozhsk, Russia

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Belgrade, Serbia

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Kragujevac, Serbia

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Poprad, Slovakia

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Prešov, Slovakia

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Trnava, Slovakia

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Žilina, Slovakia

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Busan, South Korea

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Seoul, South Korea

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Wŏnju, South Korea

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Chiayi City, Taiwan

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Taipei, Taiwan

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Diyarbakır, Turkey (Türkiye)

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Cherkasy, Ukraine

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Dnipropetrovsk, Ukraine

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Kharkiv, Ukraine

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Kyiv, Ukraine

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Lviv, Ukraine

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Mykolaiv, Ukraine

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Odesa, Ukraine

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Uzhhorod, Ukraine

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Zaporizhzhya, Ukraine

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Related Publications (5)

• 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.

  PMID: 32602065 DERIVED

• 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.

  PMID: 30221827 DERIVED

• 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.

  PMID: 30061279 DERIVED

• 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.

  PMID: 29912399 DERIVED

• 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.

  PMID: 27313268 DERIVED

MeSH Terms

Interventions

avibactam, ceftazidime drug combination; Doripenem; Ciprofloxacin; Sulfamethoxazole; Trimethoprim

Intervention Hierarchy (Ancestors)

Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Benzenesulfonamides; Sulfonamides; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Gayan Makumburage
• Organization: AstraZeneca/ PPD

gayan.makumburage@ppdi.com

9105588682

Study Officials

• Paul Newell, MBBS, MRCP

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2012
• First Posted: May 10, 2012
• Study Start: October 1, 2012
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: September 6, 2017
• Results First Posted: March 9, 2016

Record last verified: 2017-08

Locations

GR (1); SE (2); RU (9); IL (3); CZ (2); BU (3); CR (1); HU (4); BR (6); RO (5); SL (4); KR (3); TW (2); PL (3); TU (1); UA (9); ME (1); JP (11); DE (2); AR (4); PT (1); US (3)