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

• Register: EUCTR
• Last refreshed on: 13 March 2017
• Main ID: EUCTR2015-003372-73-LT
• Date of registration: 13/01/2016
• Prospective Registration: Yes
• Primary sponsor: Zavante Therapeutics, Inc.
• Public title: A clinical trial to evaluate the safety and efficacy of ZTI-01 versus Piperacillin/Tazobactam in hospitalized patients with complicated urinary tract infections.
• Scientific title: A Multi-center, Randomized, Double-blind, Comparative Study to Evaluate the Safety and Efficacy of ZTI-01 Versus Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, in Hospitalized Adults
• Date of first enrolment: 11/02/2016
• Target sample size: 460
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003372-73
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: Piperacillin/Tazobactam Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belarus, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, Greece, Hungary, Latvia, Lithuania, Poland, Romania, Russian Federation, Serbia, Slovakia, Ukraine, United States

Contacts

• Name: Vasiliki Iassonidou
• Affiliation: Medpace Germany GmbH

• Name: Vasiliki Iassonidou
• Affiliation: Medpace Germany GmbH

Key inclusion & exclusion criteria

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:
ocUTI:
• 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;
o 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 costo-vertebral 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 repl
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 antimic

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Complicated Urinary Tract Infections, Including Acute Pyelonephritis
MedDRA version: 19.1 Level: PT Classification code 10037597 Term: Pyelonephritis acute System Organ Class: 10021881 - Infections and infestations
MedDRA version: 19.1 Level: HLT Classification code 10046577 Term: Urinary tract infections System Organ Class: 10021881 - Infections and infestations

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Trade Name: Piperacillin/Tazobactam HEXAL
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: PIPERACILLIN
CAS Number: 59703-84-3
Other descriptive name: PIPERACILLIN SODIUM
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 4.0-
INN or Proposed INN: TAZOBACTAM
CAS Number: 89785-84-2
Other descriptive name: TAZOBACTAM SODIUM
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Fosfocina
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: FOSFOMYCIN
CAS Number: 26016-99-9
Current Sponsor code: ZTI-01
Other descriptive name: FOSFOMYCIN DISODIUM
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 4-

Trade Name: Piperacillin/Tazobactam-TEVA
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: PIPERACILLIN
CAS Number: 59703-84-3
Other descriptive name: PIPERACILLIN SODIUM
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 4.0-
INN or Proposed INN: TAZOBACTAM
CAS Number: 89785-84-2
Other descriptive name: TAZOBACTAM SODIUM
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 0.5-

Primary Outcome(s)

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.

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,
- To compare the microbiological eradication rate in the m-MITT and ME­TOC Populations at the TOC Visit,

Timepoint(s) of evaluation of this end point: Test-of-Cure Visit (Day 19)

Secondary Outcome(s)

Secondary end point(s): Proportion of patients with a response of clinical cure in the Modified Intent-to-Treat (MITT), m-MITT, Clinical Evaluable- (CE) TOC, and Microbiologic Evaluable- (ME) TOC Populations at the TOC Visit;
- Proportion of patients with a response of microbiologic eradication in the m-MITT and METOC Populations at the TOC Visit;
- Proportion of patients with a response of sustained clinical cure in the MITT, m-MITT, CELFU, and ME-LFU Populations at the LFU Visit.

The following additional efficacy analyses will be conducted to support the efficacy findings for the primary and secondary outcomes:
- Proportion of patients with a response of sustained microbiologic eradication in the m-MITT and ME­LFU Populations at the LFU Visit;
- Proportion of patients with a response of sustained clinical cure in the MITT, m-MITT, CE­LFU, and ME-LFU Populations at the LFU Visit.
- Proportion of patients with a response of clincial cure in the MITT and m-MITT at Day 5
- Per-pathogen microciologic eradication rate i nthe m_MITT and ME-TOC Populations at hte TOC Visit;
- All-cause mortality through the LFU Visit in the MITT Population;
- Summary (number and percentage of patients) of the assessment of clinical signs and symptoms of cUTI and AP at each time point throughout the study by treatment group in the MITT Population;
- Incidence of superinfection, new infection, and colonization by treatment group for the m­MITT Population;
- Descriptive statistics of the length of hospital stay by treatment group for the MITT Population.

Timepoint(s) of evaluation of this end point: Test-of-Cure (Day 19)
Late Follow-Up Visit (Day 26)

Secondary ID(s)

2015-003372-73-CZ

ZTI-01-200

Source(s) of Monetary Support

Zavante Therapeutics, Inc.