Clinical trial NCT02753946: Safety and Efficacy of ZTI-01 (IV Fosfomycin) vs Piperacillin/Tazobactam for Treatment cUTI/AP Infections
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Urinary Tract Infection Symptomatic
Acute Pyelonephritis
Urinary Tract Infection Complicated
Lead sponsor: Nabriva Therapeutics AG
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2016-04-28
Enrollment: 465
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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.

Primary outcomes:
measure: Number of Patients With an Overall Success
timeFrame: TOC Visit (Day 19)
Secondary outcomes:
measure: Number of Patients With a Response of Clinical Cure in Various Protocol Populations
timeFrame: TOC Visit (Day 19)
measure: Number of Patients With a Response of Microbiologic Eradication
timeFrame: TOC Visit (Day 19)
Other outcomes:
Locations:
city: Pensacola
country: United States
state: Florida
city: Augusta
country: United States
state: Georgia
city: Columbus
country: United States
state: Georgia
city: Boylston
country: United States
state: Massachusetts
city: Saint Louis
country: United States
state: Missouri
city: Butte
country: United States
state: Montana
city: Brest
country: Belarus
city: Gomel
country: Belarus
city: Grodno
country: Belarus
city: Minsk
country: Belarus
city: Vitebsk
country: Belarus
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Slavonski Brod
country: Croatia
city: Split
country: Croatia
city: Zagreb
country: Croatia
city: Brno
country: Czechia
city: Hradec Kralove
country: Czechia
city: Liberec
country: Czechia
city: Kohtla Jarve
country: Estonia
city: Tallinn
country: Estonia
city: Batumi
country: Georgia
city: Kutaisi
country: Georgia
city: Tbilisi
country: Georgia
city: Ambelokipoi
country: Greece
city: Athens
country: Greece
city: Thessaloníki
country: Greece
city: Budapest
country: Hungary
city: Miskolc
country: Hungary
city: Nagykanizsa
country: Hungary
city: Pecs
country: Hungary
city: Szekszard
country: Hungary
city: Szentes
country: Hungary
city: Riga
country: Latvia
city: Valmiera
country: Latvia
city: Kaunas
country: Lithuania
city: Klaipeda
country: Lithuania
city: Vilnius
country: Lithuania
city: Bielsko-Biala
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Piaseczno
country: Poland
city: Tychy
country: Poland
city: Wrocław
country: Poland
city: Zamosc
country: Poland
city: Bucharest
country: Romania
city: Craiova
country: Romania
city: Oradea
country: Romania
city: Krasnoyarsk
country: Russian Federation
city: Moscow, Zelenograd
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Penza
country: Russian Federation
city: Rostov-On-Don
country: Russian Federation
city: Saratov
country: Russian Federation
city: Smolensk
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Vsevolozhsk
country: Russian Federation
city: Martin
country: Slovakia
city: Poprad
country: Slovakia
city: Zilina
country: Slovakia
city: Chernihiv
country: Ukraine
city: Dnipropetrovsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kyiv
country: Ukraine
city: Odesa
country: Ukraine
city: Zaporizhzhia
country: Ukraine
Study officials:
affiliation: Zavante Therapeutics, Inc.
name: Evelyn J Ellis-Grosse, PhD
role: STUDY_CHAIR
References:
citation: 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.