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

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

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).

Study Overview

• Status: Completed
• Conditions: Acute Pyelonephritis; Urinary Tract Infection Complicated; Urinary Tract Infection Symptomatic
• Intervention / Treatment: Drug: ZTI-01; Drug: Piperacillin-tazobactam

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 Type: Interventional
• Enrollment (Actual): 465
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Brest, Belarus
  • Gomel, Belarus
  • Grodno, Belarus
  • Minsk, Belarus
  • Vitebsk, Belarus
• Bulgaria
  • Plovdiv, Bulgaria
  • Sofia, Bulgaria
• Croatia
  • Slavonski Brod, Croatia
  • Split, Croatia
  • Zagreb, Croatia
• Czechia
  • Brno, Czechia
  • Hradec Kralove, Czechia
  • Liberec, Czechia
• Estonia
  • Kohtla Jarve, Estonia
  • Tallinn, Estonia
• Georgia
  • Batumi, Georgia
  • Kutaisi, Georgia
  • Tbilisi, Georgia
• Greece
  • Ambelokipoi, Greece
  • Athens, Greece
  • Thessaloníki, Greece
• Hungary
  • Budapest, Hungary
  • Miskolc, Hungary
  • Nagykanizsa, Hungary
  • Pecs, Hungary
  • Szekszard, Hungary
  • Szentes, Hungary
• Latvia
  • Riga, Latvia
  • Valmiera, Latvia
• Lithuania
  • Kaunas, Lithuania
  • Klaipeda, Lithuania
  • Vilnius, Lithuania
• Poland
  • Bielsko-Biala, Poland
  • Krakow, Poland
  • Lodz, Poland
  • Piaseczno, Poland
  • Tychy, Poland
  • Wrocław, Poland
  • Zamosc, Poland
• Romania
  • Bucharest, Romania
  • Craiova, Romania
  • Oradea, Romania
• Russian Federation
  • Krasnoyarsk, Russian Federation
  • Moscow, Russian Federation
  • Moscow, Zelenograd, Russian Federation
  • Nizhny Novgorod, Russian Federation
  • Novosibirsk, Russian Federation
  • Penza, Russian Federation
  • Rostov-On-Don, Russian Federation
  • Saratov, Russian Federation
  • Smolensk, Russian Federation
  • St Petersburg, Russian Federation
  • St. Petersburg, Russian Federation
  • Vsevolozhsk, Russian Federation
• Slovakia
  • Martin, Slovakia
  • Poprad, Slovakia
  • Zilina, Slovakia
• Ukraine
  • Chernihiv, Ukraine
  • Dnipropetrovsk, Ukraine
  • Kharkiv, Ukraine
  • Kyiv, Ukraine
  • Odesa, Ukraine
  • Zaporizhzhia, Ukraine
• United States
  • Florida
    • Pensacola, Florida, United States
  • Georgia
    • Augusta, Georgia, United States
    • Columbus, Georgia, United States
  • Massachusetts
    • Boylston, Massachusetts, United States
  • Missouri
    • Saint Louis, Missouri, United States
  • Montana
    • Butte, Montana, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: piperacillin-tazobactam combination product

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With an Overall Success	Clinical cure (resolution or significant improvement in signs and symptoms) and microbiologic eradication (baseline pathogen) in m-MITT population	TOC Visit (Day 19)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With a Response of Clinical Cure in Various Protocol Populations	mMITT	TOC Visit (Day 19)
Number of Patients With a Response of Microbiologic Eradication	mMITT	TOC Visit (Day 19)

Collaborators and Investigators

• Sponsor: Nabriva Therapeutics AG
• Collaborators: Medpace, Inc.
• Investigators: Study Chair: Evelyn J Ellis-Grosse, PhD, Zavante Therapeutics, Inc.

Publications and helpful links

General Publications

• Kaye KS, Rice LB, Dane AL, Stus V, Sagan O, Fedosiuk E, Das AF, Skarinsky D, Eckburg PB, Ellis-Grosse EJ. Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial. Clin Infect Dis. 2019 Nov 27;69(12):2045-2056. doi: 10.1093/cid/ciz181.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): January 12, 2017
• Study Completion (Actual): May 30, 2017

Study Registration Dates

• First Submitted: April 13, 2016
• First Submitted That Met QC Criteria: April 27, 2016
• First Posted (Estimate): April 28, 2016

Study Record Updates

• Last Update Posted (Actual): March 7, 2019
• Last Update Submitted That Met QC Criteria: March 5, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Nephritis; Nephritis, Interstitial; Pyelitis; Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Piperacillin; Fosfomycin; Tazobactam; Piperacillin, Tazobactam Drug Combination
• Other Study ID Numbers: ZTI-01-200; 2015-003372-73 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual IPD data will be shared in listings with FDA, IRB/ECs, Data Monitoring Committee
• IPD Sharing Time Frame: ongoing submissions to IND
• IPD Sharing Access Criteria: IND/NDA submission, CTA submissions
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code