Urinary Tract Infection SymptomaticPhase 2/3ZEUSNCT02753946
Safety and Efficacy of ZTI-01 (IV Fosfomycin) vs Piperacillin/Tazobactam for Treatment cUTI/AP Infections
A Phase 2/3 study testing ZTI-01 and Piperacillin-tazobactam in people with Urinary Tract Infection Symptomatic and Acute Pyelonephritis, run by Nabriva Therapeutics AG at 68 sites in 16 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urinary Tract Infection Symptomatic, Acute Pyelonephritis, Urinary Tract Infection Complicated
- What is being tested?
- ZTI-01 and Piperacillin-tazobactam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 465 participants
- Where
- 68 sitesin 16 countries
- Study dates
- Apr 2016to 30 May 2017
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A signed informed consent form (ICF);
- Male or female, at least 18 years of age;
- Diagnosis requires hospitalization and treatment with intravenous (IV) antibiotics;
- 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
- Pretreatment baseline urine culture specimen
- Expectation that any implanted urinary instrumentation will be removed or replaced not longer than 24 hours, after randomization;
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- Expectation that patient will survive anticipated duration of the study;
- Patient requires initial hospitalization to manage the cUTI or AP;
- Women of childbearing potential have had a negative pregnancy test before randomization and be willing to consistently use a highly effective method of contraception
- Male study participants will be required to use condoms with a spermicide throughout study
Who cannot join
- 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
- Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
- Gross hematuria requiring intervention;
- Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period;
- Creatinine clearance <20 mL/min using the Cockcroft-Gault formula;
- Non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization;
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- Signs of severe sepsis as defined per protocol;
- Pregnant or breastfeeding women;
- Known seizure disorder requiring current treatment with anti-seizure medication which would prohibit the patient from complying with the protocol;
- Cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation with 30 days of randomization;
- Significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
- ALT/AST >5 × ULN or total bilirubin >3 × ULN at Screening;
- 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);
- Requirement for additional systemic antibiotic therapy (other than study drug) or antifungal therapy for vaginal candidiasis;
- Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the study;
- Known history of HIV virus infection and known recent CD4 count <200/mm3;
- Presence of significant immunodeficiency or an immunocompromised condition and long-term use of systemic corticosteroids;
- Presence of neutropenia;
- Presence of thrombocytopenia;
- A QT interval corrected using Fridericia's formula >480 msec;
- History of significant hypersensitivity or allergic reaction to fosfomycin, any contraindication to the use of piperacillin/tazobactam;
- Participation in a clinical study involving investigational medication or investigational device within the last 30 days prior to randomization;
- Inability, in the judgment of the Investigator, to tolerate the salt load required for study drug administration;
- Unable or unwilling, in the judgment of the Investigator, to comply with the protocol;
- Any patients previously randomized in this study.
Trial locations and contacts
68 sites in 16 countries.
68 sites in 16 countries
Russia11 sites
Study site
Krasnoyarsk
Study site
Moscow
Study site
Moscow, Zelenograd
Study site
Nizhny Novgorod
Study site
Novosibirsk
Study site
Penza
Study site
Rostov-on-Don
Study site
Saint Petersburg
Study site
Saratov
Study site
Smolensk
Study site
Vsevolozhsk
Poland7 sites
Study site
Bielsko-Biala
Study site
Krakow
Study site
Lodz
Study site
Piaseczno
Study site
Tychy
Study site
Wroclaw
Study site
Zamość
United States6 sites
Study site
Augusta, Georgia
Study site
Boylston, Massachusetts
Study site
Butte, Montana
Study site
Columbus, Georgia
Study site
Pensacola, Florida
Study site
St Louis, Missouri
Hungary6 sites
Study site
Budapest
Study site
Miskolc
Study site
Nagykanizsa
Study site
Pécs
Study site
Szekszárd
Study site
Szentes
Ukraine6 sites
Study site
Chernihiv
Study site
Dnipropetrovsk
Study site
Kharkiv
Study site
Kyiv
Study site
Odesa
Study site
Zaporizhzhya
Belarus5 sites
Study site
Brest
Study site
Grodno
Study site
Homyel
Study site
Minsk
Study site
Vitebsk
About this study
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
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).
Read the 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.
- Conditions
- Urinary Tract Infection Symptomatic, Acute Pyelonephritis, Urinary Tract Infection Complicated
- Being tested
- ZTI-01, Piperacillin-tazobactam
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZTI-01Drug
Also called disodium fosfomycin
6g ZTI-01 intravenous infusion TID q8 hours
Piperacillin-tazobactamDrug
Also called piperacillin-tazobactam combination product
4.5g piperacillin-tazobactam intravenous infusion TID q8 hours
| Study group | Role | What they receive |
|---|---|---|
| ZTI-01 | Experimental | 6 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days) Receives: Drug: ZTI-01 |
| piperacillin tazobactam | Active comparator | 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) Receives: Drug: Piperacillin-tazobactam |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: TOC Visit (Day 19)
Secondary outcomes (2)
Number of Patients With a Response of Clinical Cure in Various Protocol Populations
mMITT
Measured: TOC Visit (Day 19)
Number of Patients With a Response of Microbiologic Eradication
mMITT
Measured: TOC Visit (Day 19)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Apr 2016 (estimated)
- Study startApr 2016
- Primary completion12 Jan 2017
- Study completion30 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Urinary Tract Infection SymptomaticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 465 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nabriva Therapeutics AG
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Medpace, Inc.
- Responsible party
- Sponsor
- Investigators
- Evelyn J Ellis-Grosse, PhD, Study chair, Zavante Therapeutics, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02753946
- Sponsor's protocol ID
- ZTI-01-200
- Other IDs
- 2015-003372-73, 2015
- Acronym
- ZEUS
- Status last verified
- Mar 2019
- First submitted
- 13 Apr 2016
- Last updated
- 7 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Individual IPD data will be shared in listings with FDA, IRB/ECs, Data Monitoring Committee
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.
PubMed 30861061
Study at a glance
From the registry record, last updated by the sponsor on 7 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02753946
- Acronym / sponsor ID
- ZEUS / ZTI-01-200
- Conditions
- Urinary Tract Infection Symptomatic, Acute Pyelonephritis, Urinary Tract Infection Complicated
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 465 participants (actual)
- Lead sponsor
- Nabriva Therapeutics AGIndustry (pharma, biotech, devices)
- Collaborators
- Medpace, Inc.
- Study start
- Apr 2016 (actual)
- Primary completion
- 12 Jan 2017 (actual)
- Study completion
- 30 May 2017 (actual)
- First posted
- 28 Apr 2016 (estimated)
- Results
- Posted 11 Dec 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ZTI-01 | Experimental | Drug: ZTI-016 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days) |
| piperacillin tazobactam | Active comparator | Drug: Piperacillin-tazobactam4.5 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- A signed informed consent form (ICF);
- Male or female, at least 18 years of age;
- Diagnosis requires hospitalization and treatment with intravenous (IV) antibiotics;
- 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
- Pretreatment baseline urine culture specimen
Key exclusion criteria (25 listed)
- 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
- Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
- Gross hematuria requiring intervention;
- Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period;
- Creatinine clearance <20 mL/min using the Cockcroft-Gault formula;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZTI-01Also: disodium fosfomycin6g ZTI-01 intravenous infusion TID q8 hours | Drug | ZTI-01 |
| Piperacillin-tazobactamAlso: piperacillin-tazobactam combination product4.5g piperacillin-tazobactam intravenous infusion TID q8 hours | Drug | piperacillin tazobactam |
Primary outcome
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
2 secondary outcomes
Number of Patients With a Response of Clinical Cure in Various Protocol Populations
Time frame: TOC Visit (Day 19)
Number of Patients With a Response of Microbiologic Eradication
Time frame: TOC Visit (Day 19)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 30861061Kaye 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.
- Individual participant dataSharing planned: Yes. Individual IPD data will be shared in listings with FDA, IRB/ECs, Data Monitoring Committee
Related trials for Urinary Tract Infection Symptomatic
Active, not recruitingObservational study
Bacteriuria and Indwelling Urinary Catheter.
Bacteriuria Asymptomatic, Urinary Tract Infections
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Evelyn J Ellis-Grosse, PhD study chair
Zavante Therapeutics, Inc.
68 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing ZTI-01 and Piperacillin-tazobactam in people with Urinary Tract Infection Symptomatic and Acute Pyelonephritis, run by Nabriva Therapeutics AG at 68 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 68 sites in Russia, Poland, United States, Hungary, Ukraine and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Dec 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With an Overall Success (time frame: TOC Visit (Day 19)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02753946, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Mar 2019.