Urinary Tract Infection Symptomatic, Acute Pyelonephritis, Urinary Tract Infection Complicated
Conditions
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.
Interventions
DRUGZTI-01
6g ZTI-01 intravenous infusion TID q8 hours
4.5g piperacillin-tazobactam intravenous infusion TID q8 hours
Sponsors
Medpace, Inc.
Nabriva Therapeutics AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With an Overall Success | TOC Visit (Day 19) | Clinical cure (resolution or significant improvement in signs and symptoms) and microbiologic eradication (baseline pathogen) in m-MITT population |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Response of Clinical Cure in Various Protocol Populations | TOC Visit (Day 19) | mMITT |
| Number of Patients With a Response of Microbiologic Eradication | TOC Visit (Day 19) | mMITT |
Countries
Belarus, Bulgaria, Croatia, Czechia, Estonia, Georgia, Greece, Hungary, Latvia, Lithuania, Poland, Romania, Russia, Slovakia, Ukraine, United States
Participant flow
Recruitment details
Patients diagnosed with cUTI/AP based on signs and symtoms requiring 7 days hospitalization (or up to 14 days in case of bacteremia). No oral switch is allowed in the study. Confirmatory microbiology data only available after randomization.
Pre-assignment details
At least 30% of patients required a diagnosis of AP. Receipt of effective systemic antibiotic for \>24 hrs within 72-hr window before randomization exclusionary but receiving single dose of short-acting systemic antibiotic within 72 hrs of randomization permitted up to a max of 25% of the study enrollments.
Participants by arm
| Arm | Count |
|---|---|
| ZTI-01 6 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days)
ZTI-01: 6g ZTI-01 intravenous infusion TID q8 hours | 233 |
| 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)
Piperacillin-tazobactam: 4.5g piperacillin-tazobactam intravenous infusion TID q8 hours | 232 |
| Total | 465 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | ZTI-01 | Piperacillin Tazobactam | Total |
|---|---|---|---|
| Age, Customized 65 to 75 years of age | 52 Participants | 42 Participants | 94 Participants |
| Age, Customized < 65 years of age | 159 Participants | 155 Participants | 314 Participants |
| Age, Customized > 75 years of age | 22 Participants | 35 Participants | 57 Participants |
| BMI (kg/m^2) | 25.81 kg/m2 STANDARD_DEVIATION 5.355 | 26.44 kg/m2 STANDARD_DEVIATION 6.167 | 26.12 kg/m2 STANDARD_DEVIATION 5.776 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 233 Participants | 232 Participants | 465 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 233 Participants | 232 Participants | 465 Participants |
| Region of Enrollment Belarus | 39 Participants | 31 Participants | 70 Participants |
| Region of Enrollment Bulgaria | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment Croatia | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Czechia | 7 Participants | 7 Participants | 14 Participants |
| Region of Enrollment Estonia | 7 Participants | 3 Participants | 10 Participants |
| Region of Enrollment Georgia | 11 Participants | 14 Participants | 25 Participants |
| Region of Enrollment Hungary | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment Latvia | 13 Participants | 16 Participants | 29 Participants |
| Region of Enrollment Lithuania | 6 Participants | 7 Participants | 13 Participants |
| Region of Enrollment Poland | 10 Participants | 12 Participants | 22 Participants |
| Region of Enrollment Romania | 6 Participants | 2 Participants | 8 Participants |
| Region of Enrollment Russia | 39 Participants | 39 Participants | 78 Participants |
| Region of Enrollment Slovakia | 8 Participants | 16 Participants | 24 Participants |
| Region of Enrollment Ukraine | 71 Participants | 73 Participants | 144 Participants |
| Region of Enrollment United States | 1 Participants | 0 Participants | 1 Participants |
| Screening Creatinine Clearance Group <20 mL/min | 0 Participants | 0 Participants | 0 Participants |
| Screening Creatinine Clearance Group >30 to 40 mL/min | 12 Participants | 7 Participants | 19 Participants |
| Screening Creatinine Clearance Group >40 to 50 mL/min | 16 Participants | 19 Participants | 35 Participants |
| Screening Creatinine Clearance Group > 50 mL/min | 200 Participants | 205 Participants | 405 Participants |
| Screening Creatinine Clearance Group > or = 20 to 30 mL/min | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 151 Participants | 146 Participants | 297 Participants |
| Sex: Female, Male Male | 82 Participants | 86 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 233 | 0 / 231 |
| other Total, other adverse events | 55 / 233 | 31 / 231 |
| serious Total, serious adverse events | 5 / 233 | 6 / 231 |
Outcome results
Primary
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
Time frame: TOC Visit (Day 19)
Population: Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess overall success.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ZTI-01 | Number of Patients With an Overall Success | 119 Participants |
| Piperacillin Tazobactam | Number of Patients With an Overall Success | 97 Participants |
Secondary
Number of Patients With a Response of Clinical Cure in Various Protocol Populations
mMITT
Time frame: TOC Visit (Day 19)
Population: Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess clinical cure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ZTI-01 | Number of Patients With a Response of Clinical Cure in Various Protocol Populations | 167 Participants |
| Piperacillin Tazobactam | Number of Patients With a Response of Clinical Cure in Various Protocol Populations | 163 Participants |
Secondary
Number of Patients With a Response of Microbiologic Eradication
mMITT
Time frame: TOC Visit (Day 19)
Population: Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess microbiologic eradication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ZTI-01 | Number of Patients With a Response of Microbiologic Eradication | 121 Participants |
| Piperacillin Tazobactam | Number of Patients With a Response of Microbiologic Eradication | 100 Participants |