ZEUS: Safety and Efficacy of ZTI-01 (IV Fosfomycin) vs Piperacillin/Tazobactam for Treatment cUTI/AP Infections

• Sponsor: Nabriva Therapeutics AG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02753946
• Collaborator: Medpace, Inc. (Industry)
• Enrollment: 465
• Locations: 69
• Arms: 2
• Actual Duration (Months): 13.9
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Urinary Tract Infection Symptomatic; Acute Pyelonephritis; Urinary Tract Infection Complicated	Drug: ZTI-01; Drug: Piperacillin-tazobactam	Phase 2/Phase 3

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

• Study Type: Interventional
• Actual Enrollment: 465 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Jan 12, 2017
• Actual Study Completion Date: May 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ZTI-01 6 g ZTI-01 (IV fosfomycin) intravenously administered every 8 hours (18g total daily dose for 7-14 calendar days)	Drug: ZTI-01; 6g ZTI-01 intravenous infusion TID q8 hours; Other Names: disodium fosfomycin
Active Comparator: 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)	Drug: Piperacillin-tazobactam; 4.5g piperacillin-tazobactam intravenous infusion TID q8 hours; Other Names: piperacillin-tazobactam combination product

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Number of Patients With a Response of Clinical Cure in Various Protocol Populations [TOC Visit (Day 19)]

   mMITT

2. Number of Patients With a Response of Microbiologic Eradication [TOC Visit (Day 19)]

   mMITT

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Pensacola	Florida	United States
2		Augusta	Georgia	United States
3		Columbus	Georgia	United States
4		Boylston	Massachusetts	United States
5		Saint Louis	Missouri	United States
6		Butte	Montana	United States
7		Brest		Belarus
8		Gomel		Belarus
9		Grodno		Belarus
10		Minsk		Belarus
11		Vitebsk		Belarus
12		Plovdiv		Bulgaria
13		Sofia		Bulgaria
14		Slavonski Brod		Croatia
15		Split		Croatia
16		Zagreb		Croatia
17		Brno		Czechia
18		Hradec Kralove		Czechia
19		Liberec		Czechia
20		Kohtla Jarve		Estonia
21		Tallinn		Estonia
22		Batumi		Georgia
23		Kutaisi		Georgia
24		Tbilisi		Georgia
25		Ambelokipoi		Greece
26		Athens		Greece
27		Thessaloníki		Greece
28		Budapest		Hungary
29		Miskolc		Hungary
30		Nagykanizsa		Hungary
31		Pecs		Hungary
32		Szekszard		Hungary
33		Szentes		Hungary
34		Riga		Latvia
35		Valmiera		Latvia
36		Kaunas		Lithuania
37		Klaipeda		Lithuania
38		Vilnius		Lithuania
39		Bielsko-Biala		Poland
40		Krakow		Poland
41		Lodz		Poland
42		Piaseczno		Poland
43		Tychy		Poland
44		Wrocław		Poland
45		Zamosc		Poland
46		Bucharest		Romania
47		Craiova		Romania
48		Oradea		Romania
49		Krasnoyarsk		Russian Federation
50		Moscow, Zelenograd		Russian Federation
51		Moscow		Russian Federation
52		Nizhny Novgorod		Russian Federation
53		Novosibirsk		Russian Federation
54		Penza		Russian Federation
55		Rostov-On-Don		Russian Federation
56		Saratov		Russian Federation
57		Smolensk		Russian Federation
58		St Petersburg		Russian Federation
59		St. Petersburg		Russian Federation
60		Vsevolozhsk		Russian Federation
61		Martin		Slovakia
62		Poprad		Slovakia
63		Zilina		Slovakia
64		Chernihiv		Ukraine
65		Dnipropetrovsk		Ukraine
66		Kharkiv		Ukraine
67		Kyiv		Ukraine
68		Odesa		Ukraine
69		Zaporizhzhia		Ukraine

Sponsors and Collaborators

• Nabriva Therapeutics AG
• Medpace, Inc.

Investigators

• Study Chair: Evelyn J Ellis-Grosse, PhD, Zavante Therapeutics, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nabriva Therapeutics AG
• ClinicalTrials.gov Identifier: NCT02753946
• Other Study ID Numbers: ZTI-01-200; 2015-003372-73
• First Posted: Apr 28, 2016
• Last Update Posted: Mar 7, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Tazobactam; Piperacillin; Fosfomycin; Piperacillin, Tazobactam Drug Combination

Study Results

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 Detail	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.

Arm/Group Title	ZTI-01	Piperacillin Tazobactam
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	233	231
COMPLETED	219	222
NOT COMPLETED	14	9

Baseline Characteristics

Arm/Group Title	ZTI-01	Piperacillin Tazobactam	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	233	232	465
Age, Customized (Count of Participants)
< 65 years of age	159 68.2%	155 66.8%	314 67.5%
65 to 75 years of age	52 22.3%	42 18.1%	94 20.2%
> 75 years of age	22 9.4%	35 15.1%	57 12.3%
Sex: Female, Male (Count of Participants)
Female	151 64.8%	146 62.9%	297 63.9%
Male	82 35.2%	86 37.1%	168 36.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	233 100%	232 100%	465 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	233 100%	232 100%	465 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Romania	6 2.6%	2 0.9%	8 1.7%
Hungary	4 1.7%	5 2.2%	9 1.9%
United States	1 0.4%	0 0%	1 0.2%
Czechia	7 3%	7 3%	14 3%
Ukraine	71 30.5%	73 31.5%	144 31%
Belarus	39 16.7%	31 13.4%	70 15.1%
Russia	39 16.7%	39 16.8%	78 16.8%
Latvia	13 5.6%	16 6.9%	29 6.2%
Poland	10 4.3%	12 5.2%	22 4.7%
Georgia	11 4.7%	14 6%	25 5.4%
Slovakia	8 3.4%	16 6.9%	24 5.2%
Bulgaria	6 2.6%	4 1.7%	10 2.2%
Lithuania	6 2.6%	7 3%	13 2.8%
Croatia	5 2.1%	3 1.3%	8 1.7%
Estonia	7 3%	3 1.3%	10 2.2%
BMI (kg/m^2) (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	25.81 (5.355)	26.44 (6.167)	26.12 (5.776)
Screening Creatinine Clearance Group (Count of Participants)
<20 mL/min	0 0%	0 0%	0 0%
> or = 20 to 30 mL/min	4 1.7%	1 0.4%	5 1.1%
>30 to 40 mL/min	12 5.2%	7 3%	19 4.1%
>40 to 50 mL/min	16 6.9%	19 8.2%	35 7.5%
> 50 mL/min	200 85.8%	205 88.4%	405 87.1%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With an Overall Success
Description	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)

Outcome Measure Data

Analysis Population Description

Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess overall success.

Arm/Group Title	ZTI-01	Piperacillin Tazobactam
Arm/Group Description	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	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
Measure Participants	184	178
Count of Participants [Participants]	119 51.1%	97 41.8%

2. Secondary Outcome

Title	Number of Patients With a Response of Clinical Cure in Various Protocol Populations
Description	mMITT
Time Frame	TOC Visit (Day 19)

Outcome Measure Data

Analysis Population Description

Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess clinical cure.

Arm/Group Title	ZTI-01	Piperacillin Tazobactam
Arm/Group Description	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	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
Measure Participants	184	178
Count of Participants [Participants]	167 71.7%	163 70.3%

3. Secondary Outcome

Title	Number of Patients With a Response of Microbiologic Eradication
Description	mMITT
Time Frame	TOC Visit (Day 19)

Outcome Measure Data

Analysis Population Description

Microbiologic Modified Intent-to-Treat (m-MITT) population was used to assess microbiologic eradication.

Arm/Group Title	ZTI-01	Piperacillin Tazobactam
Arm/Group Description	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	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
Measure Participants	184	178
Count of Participants [Participants]	121 51.9%	100 43.1%

Adverse Events

Arm/Group Title	ZTI-01		Piperacillin Tazobactam
Arm/Group Description	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		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
All Cause Mortality
	ZTI-01		Piperacillin Tazobactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/233 (0%)		0/231 (0%)
Serious Adverse Events
	ZTI-01		Piperacillin Tazobactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/233 (2.1%)		6/231 (2.6%)
Infections and infestations
Urinary Tract Infection	1/233 (0.4%)		1/231 (0.4%)
Acute Media Otitis	1/233 (0.4%)		0/231 (0%)
Prostatic Abscess	1/233 (0.4%)		0/231 (0%)
Renal Abscess	0/233 (0%)		1/231 (0.4%)
Septic Embolus	0/233 (0%)		1/231 (0.4%)
Pyelonephritis Acute	0/233 (0%)		1/231 (0.4%)
Metabolism and nutrition disorders
Hypokalemia	1/233 (0.4%)		0/231 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic Gastric Cancer	1/233 (0.4%)		0/231 (0%)
Renal and urinary disorders
Renal Impairment	0/233 (0%)		1/231 (0.4%)
Haematuria	0/233 (0%)		1/231 (0.4%)
Other (Not Including Serious) Adverse Events
	ZTI-01		Piperacillin Tazobactam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/233 (23.6%)		31/231 (13.4%)
Gastrointestinal disorders
Nausea	10/233 (4.3%)		3/231 (1.3%)
Diarrhea	9/233 (3.9%)		11/231 (4.8%)
Vomiting	9/233 (3.9%)		1/231 (0.4%)
General disorders
Infusion site phlebitis	2/233 (0.9%)		6/231 (2.6%)
Investigations
Alanine aminotransferase increased	20/233 (8.6%)		6/231 (2.6%)
Aspartate aminotransferase increased	17/233 (7.3%)		6/231 (2.6%)
Metabolism and nutrition disorders
Hypokalemia	14/233 (6%)		3/231 (1.3%)
Nervous system disorders
Headache	6/233 (2.6%)		5/231 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.