A clinical trial to evaluate the safety and efficacy of ZTI-01 versus Piperacillin/Tazobactam in hospitalized patients with complicated urinary tract infections.

Phase 1

• Conditions: Complicated Urinary Tract Infections, Including Acute Pyelonephritis; MedDRA version: 19.1Level: PTClassification code 10037597Term: Pyelonephritis acuteSystem Organ Class: 10021881 - Infections and infestations; MedDRA version: 19.1Level: HLTClassification code 10046577Term: Urinary tract infectionsSystem Organ Class: 10021881 - Infections and infestations; Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

• Registration Number: EUCTR2015-003372-73-PL
• Lead Sponsor: Zavante Therapeutics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-02-23
• Last Update Posted: 23 July 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 460

Inclusion Criteria

1. A signed informed consent form (ICF) or, in case of a lack of decision making capacity and as permitted by local law and institutional Standard Operating Procedures, consent on behalf of study subject by a legally authorized representative;
2. Male or female, at least 18 years of age;
3.Expectation, in the judgment of the Investigator, that the patient's cUTI or AP would require hospitalization and treatment with intravenous (IV) antibiotics;
4. Documented or suspected cUTI or AP as defined below:

cUTI:
• Signs or symptoms evidenced by at least 2 of the following:
?Chills, rigors, or warmth associated with fever:
Note: Fever must be observed and documented by a health care provider within 24 hours of screening (oral, tympanic, rectal or core temperature > 38°C [100.4°F]);
Nausea or vomiting within 24 hours of screening, as reported by the
patient;
?Dysuria, increased urinary frequency, or urinary urgency;
?Lower abdominal pain or pelvic pain;
•And urine specimen with evidence of pyuria:
?Positive leukocyte esterase on urinalysis; or
?White blood cell count = 10 cells/mm3 in unspun urine; or
?White blood cell count = 10 cells/high-power field (hpf) in urine sediment;
•And at least one of the following associated risks:
- Use of intermittent bladder catheterization or presence of an indwelling bladder catheter (Note: indwelling bladder catheters that have been in place for >24 hours prior to Screening must be removed or replaced prior to collection of the screening urine for urinalysis and culture, unless removal or replacement is considered unsafe or contraindicated);
- Current known functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a post-void residual urine volume of = 100 mL;
- Complete or partial obstructive uropathy (eg, nephrolithiasis, tumor, fibrosis, urethral stricture) that is expected to be medically or surgically treated during study drug therapy (prior to EOT);
- Azotemia, defined as blood urea nitrogen (BUN) >20 mg/dL, blood urea >42.8 mg/dL, or serum creatinine > 1.4 mg/dL, due to known prior intrinsic renal disease;
- Chronic urinary retention in men, for example, previously diagnosed benign prostatic hypertrophy;

Acute pyelonephritis:
• Signs or symptoms evidenced by at least 2 of the following:
Chills, rigors, or warmth associated with fever:
Note: Fever must be observed and documented by a health care provider within 24 hours of screening (oral, tympanic, rectal or core temperature >38°C [>100.4°F]);
Nausea or vomiting within 24 hours of screening, as reported by the patient;
Dysuria, increased urinary frequency, or urinary urgency;
Acute flank pain (onset within 7 days prior to randomization) or costovertebral angle tenderness on physical examination;
•And urine specimen with evidence of pyuria:
?Positive leukocyte esterase on urinalysis; or
?White blood cell count = 10 cells/mm3 in unspun urine; or
?White blood cell count = 10 cells/hpf in urine sediment;
5. Have a baseline urine culture specimen obtained within 48 hours prior
to randomization;
Note: Patients may be randomized into this study and start IV study drug therapy before the Investigator knows the results of the baseline urine culture.
6. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (eg, nephrostomy tubes, ureteric stents) will be surgically removed or replaced before or within 24 h after randomization, unless removal or replacem

Exclusion Criteria

1.Presence of any known or suspected disease or condition that, in the opinion of the investigator, may confound the assessment of efficacy, including but not limited to the following:
a.Perinephric abscess;
b.Renal corticomedullary abscess;
c.Uncomplicated urinary tract infection;
d.Any recent history of trauma to the pelvis or urinary tract;
e.Polycystic kidney disease;
f.Chronic vesicoureteral reflux;
g.Previous or planned renal transplantation;
h.Patients receiving dialysis, including hemodialysis, peritoneal dialysis or continuous veno-venous hemofiltration (CVVH);
i.Previous or planned cystectomy or ileal loop surgery;
j.Known or suspected infection that is caused by pathogen(s) that is resistant to either study drug (fosfomycin or a ß-lactam/ß-lactam inhibitor [BL/BLI] combination), including infection caused by fungi (eg, candiduria) or mycobacteria (eg, urogenital tuberculosis).
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 other than administration of study drug or removal or exchange of a urinary catheter;
4.Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required to relieve an obstruction or place a stent or nephrostomy prior to End of Treatment [EOT]);
5.Renal function at screening as estimated by creatinine clearance < 20 mL/min using the Cockcroft-Gault formula and serum creatinine value obtained from a local laboratory;
6.Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization;
7.Any signs of severe sepsis, including but not limited to the following:
a.Shock or profound hypotension defined as systolic blood pressure < 90 mmHg or a decrease of > 40 mmHg from baseline (if known) that is not responsive to fluid challenge;
b.Disseminated intravascular coagulation as evidenced by prothrombin time (PT) or partial thromboplastin time (PTT)2 × the upper limit of normal (ULN) or 50,000 platelets/mm3 at screening in patients in whom
severe sepsis is suspected;
8.Pregnant or breastfeeding women;
9.Known seizure disorder requiring current treatment with anti-seizure medication which, in the Investigator's opinion, would prohibit the patient from complying with the protocol. Patients with a history of epilepsy or who are on stable treatment (ie, no change in therapy within 30 days) with well controlled seizure disorder (ie, no recurrent episodes in past 30 days) may be considered for enrollment in the study;
10.Treatment within 30 days prior to randomization with any cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation;
11.Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy;
12.Aspartate aminotransferase or alanine aminotransferase > 5 × ULN (upper limit of normal) 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. However, patients may enroll
who:
a.Have received > 48 hours of prior antimicrobial therapy and, (1) in the Investigator's opinion, have failed that preceding antimicrobi

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective is to demonstrate that ZTI-01 is non-inferior to piperacillin/tazobactam in overall success (clinical cure and microbiologic eradication) in the microbiologic Modified Intent-to-Treat (m­MITT) Population at the TOC Visit.;Secondary Objective: - To compare the clinical cure rates in the two treatment groups in the Modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable- (CE) TOC, and Microbiologic Evaluable- (ME) TOC Populations at the TOC Visit,<br>- To compare the microbiological eradication rate in the m-MITT and ME­TOC Populations at the TOC Visit,<br><br>;Primary end point(s): The primary efficacy endpoint is the proportion of patients with an overall success (clinical cure and microbiologic eradication) in the microbiologic Modified Intent-to-Treat (m-MITT) Population at the TOC Visit.;Timepoint(s) of evaluation of this end point: Test-of-Cure Visit (Day 19)