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Safety and Efficacy of ZTI-01 (IV Fosfomycin) vs Piperacillin/Tazobactam for Treatment cUTI/AP Infections (ZEUS)

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ClinicalTrials.gov Identifier: NCT02753946
Recruitment Status : Completed
First Posted : April 28, 2016
Results First Posted : December 11, 2018
Last Update Posted : March 7, 2019
Sponsor:
Collaborator:
Medpace, Inc.
Information provided by (Responsible Party):
Nabriva Therapeutics AG

Study Description
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Brief Summary:
The purpose of the study is to demonstrate the safety and efficacy of ZTI-01 (IV fosfomycin) as non-inferior to piperacillin/tazobactam in overall success (clinical cure and microbiologic eradication) for the treatment of hospitalized patients with complicated urinary tract infections (cUTI) or acute pyelonephritis (AP).

Condition or disease Intervention/treatment Phase
Urinary Tract Infection Symptomatic Acute Pyelonephritis Urinary Tract Infection Complicated Drug: ZTI-01 Drug: Piperacillin-tazobactam Phase 2 Phase 3

Detailed Description:
This is a multi-center, randomized, double-blind, parallel-group study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of ZTI-01 (IV fosfomycin) compared to piperacillin/tazobactam in the treatment of hospitalized adults with cUTI or AP. Diagnosed and prescreened hospitalized patients will be randomized 1:1 to receive one of two intravenous treatments: 6 g ZTI-01 three times daily (18g total daily dose) or 4.5 g piperacillin/tazobactam three times daily (13.5g total daily dose) for 7 calendar days, with option to extend treatment up to 14 days in patients with positive blood culture at pretreatment. Patients will participate in the study for approximately 26 days. Urine cultures will be obtained and organisms quantified for qualified patients at baseline, during treatment, at end of treatment (EOT), at test of cure (TOC) and late follow up visits (LFU). Blood cultures will be obtained at baseline and repeated if positive throughout the study. Safety and efficacy evaluations will include vital signs, labs, physical exams, ECG and overall response as evaluated by the Investigator. Pharmacokinetic samples will be obtained (sparse sampling) for all patients.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 465 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized, Double-Blind, Comparative Study to Evaluate the Safety and Efficacy of ZTI-01 vs Piperacillin/Tazobactam in the Treatment of cUTI/AP Infection in Hospitalized Adults
Actual Study Start Date : April 2016
Actual Primary Completion Date : January 12, 2017
Actual Study Completion Date : May 30, 2017

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Arms and Interventions
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Arm Intervention/treatment
Experimental: ZTI-01
6 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days)
 Drug: ZTI-01
6g ZTI-01 intravenous infusion TID q8 hours
Other Name: disodium fosfomycin
Active Comparator: piperacillin tazobactam
4.5 g piperacillin/tazobactam (4 g piperacillin/0.5 g tazobactam) intravenously administered every 8 hours (13.5g total daily dose for 7-14 calendar days)
 Drug: Piperacillin-tazobactam
4.5g piperacillin-tazobactam intravenous infusion TID q8 hours
Other Name: piperacillin-tazobactam combination product


Outcome Measures
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Primary Outcome Measures :
  1. Number of Patients With an Overall Success [ Time Frame: TOC Visit (Day 19) ]
    Clinical cure (resolution or significant improvement in signs and symptoms) and microbiologic eradication (baseline pathogen) in m-MITT population


Secondary Outcome Measures :
  1. Number of Patients With a Response of Clinical Cure in Various Protocol Populations [ Time Frame: TOC Visit (Day 19) ]
    mMITT

  2. Number of Patients With a Response of Microbiologic Eradication [ Time Frame: TOC Visit (Day 19) ]
    mMITT


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. A signed informed consent form (ICF);
  2. Male or female, at least 18 years of age;
  3. Diagnosis requires hospitalization and treatment with intravenous (IV) antibiotics;
  4. Documented or suspected cUTI or AP including at least 2 protocol defined signs and symptoms and a urine specimen with evidence of pyuria plus at least one protocol defined associated risk
  5. Pretreatment baseline urine culture specimen
  6. Expectation that any implanted urinary instrumentation will be removed or replaced not longer than 24 hours, after randomization;
  7. Expectation that patient will survive anticipated duration of the study;
  8. Patient requires initial hospitalization to manage the cUTI or AP;
  9. Women of childbearing potential have had a negative pregnancy test before randomization and be willing to consistently use a highly effective method of contraception
  10. Male study participants will be required to use condoms with a spermicide throughout study

Exclusion Criteria:

  1. Presence of any of the following conditions: perinephric abscess, renal corticomedullary abscess, uncomplicated urinary tract infection, recent history of trauma to the pelvis or urinary tract, polycystic kidney disease, chronic vesicoureteral reflux, previous or planned renal transplantation; patients receiving dialysis/hemodialysis/CVVH, previous or planned cystectomy or ileal loop surgery; known or suspected infection; caused by pathogen resistant to study treatment antibiotics
  2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
  3. Gross hematuria requiring intervention;
  4. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period;
  5. Creatinine clearance <20 mL/min using the Cockcroft-Gault formula;
  6. Non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization;
  7. Signs of severe sepsis as defined per protocol;
  8. Pregnant or breastfeeding women;
  9. Known seizure disorder requiring current treatment with anti-seizure medication which would prohibit the patient from complying with the protocol;
  10. Cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation with 30 days of randomization;
  11. Significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
  12. ALT/AST >5 × ULN or total bilirubin >3 × ULN at Screening;
  13. Receipt of any potentially-effective systemic antibiotic with activity against Gram-negative uropathogens for more than 24 hours within the 72-hour window prior to randomization (exceptions defined in protocol);
  14. Requirement for additional systemic antibiotic therapy (other than study drug) or antifungal therapy for vaginal candidiasis;
  15. Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the study;
  16. Known history of HIV virus infection and known recent CD4 count <200/mm3;
  17. Presence of significant immunodeficiency or an immunocompromised condition and long-term use of systemic corticosteroids;
  18. Presence of neutropenia;
  19. Presence of thrombocytopenia;
  20. A QT interval corrected using Fridericia's formula >480 msec;
  21. History of significant hypersensitivity or allergic reaction to fosfomycin, any contraindication to the use of piperacillin/tazobactam;
  22. Participation in a clinical study involving investigational medication or investigational device within the last 30 days prior to randomization;
  23. Inability, in the judgment of the Investigator, to tolerate the salt load required for study drug administration;
  24. Unable or unwilling, in the judgment of the Investigator, to comply with the protocol;
  25. Any patients previously randomized in this study.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02753946


Locations
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Sponsors and Collaborators
Nabriva Therapeutics AG
Medpace, Inc.
Investigators
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Study Chair: Evelyn J Ellis-Grosse, PhD Zavante Therapeutics, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Nabriva Therapeutics AG
ClinicalTrials.gov Identifier: NCT02753946    
Other Study ID Numbers: ZTI-01-200
2015-003372-73 ( EudraCT Number )
First Posted: April 28, 2016    Key Record Dates
Results First Posted: December 11, 2018
Last Update Posted: March 7, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual IPD data will be shared in listings with FDA, IRB/ECs, Data Monitoring Committee
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: ongoing submissions to IND
Access Criteria: IND/NDA submission, CTA submissions
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Urinary Tract Infections
Pyelonephritis
Urologic Diseases
Nephritis, Interstitial
Nephritis
Kidney Diseases
Pyelitis
 Tazobactam
Piperacillin
Fosfomycin
Piperacillin, Tazobactam Drug Combination
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action