Evaluation of Safety and Efficacy of Intravenous Sulbactam-ETX2514 in the Treatment of Hospitalized Adults With Complicated Urinary Tract Infections

• Sponsor: Entasis Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03445195
• Collaborator: (none)
• Enrollment: 80
• Locations: 4
• Arms: 2
• Actual Duration (Months): 3.9
• Patients Per Site: 20
• Patients Per Site Per Month: 5.1

Study Details

Study Description

Brief Summary

This study is a double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of IV ETX2514SUL in patients with complicated urinary tract infections (cUTIs) who are otherwise relatively healthy.

Condition or Disease	Intervention/Treatment	Phase
Complicated Urinary Tract Infection; Acute Pyelonephritis	Drug: Sulbactam-ETX2514; Drug: Placebo; Drug: Imipenem-cilastatin	Phase 2

Detailed Description

This study is a double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of IV ETX2514SUL in patients with cUTIs who are otherwise relatively healthy. Patients with Acute Pyelonephritis may also be enrolled. Approximately 80 patients will be randomized to receive either 1 g ETX2514/1 g sulbactam IV or matching placebo every 6 hours (q6h). All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This study is a double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of IV ETX2514SUL in patients with cUTIs.This study is a double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of IV ETX2514SUL in patients with cUTIs.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Intravenous Sulbactam-ETX2514 in the Treatment of Hospitalized Adults With Complicated Urinary Tract Infections, Including Acute Pyelonephritis
• Actual Study Start Date: Jan 17, 2018
• Actual Primary Completion Date: May 17, 2018
• Actual Study Completion Date: May 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Drug: Sulbactam-ETX2514; The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h.; Other Names: ETX2514SUL ; Drug: Imipenem-cilastatin; All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
Placebo Comparator: Placebo + Imipenem/Cilastatin	Drug: Placebo; Matching 1g IV solution.; Drug: Imipenem-cilastatin; All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Overall Success [From baseline through day 21]

   The primary efficacy endpoint for this study was the proportion of patients with an overall success (clinical cure and micro-biologic eradication) for the m-MITT (Micro-biologically Modified Intent-to-Treat) Population at the TOC Visit.

Secondary Outcome Measures

1. Clinical Cure [Baseline to day 21]

   Proportion of patients with a response of clinical cure for the MITT(modified intent to treat), m-MITT (microbiologically modified intent to treat), CE(clinically evaluable), and ME(microbiologically evaluable) populations at the TOC(test of cure) visit.

2. Microbiologic Eradication [Baseline to day 21]

   Proportion of patients with a response of microbiologic eradication for the m-MITT(microbiologically modified intent to treat) and ME(microbiologically evaluable) populations at the TOC visit

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A signed informed consent form (ICF). If a study patient is unable to provide informed consent due to their medical condition, the patient's legally authorized representative may consent on behalf of the study patient as permitted by local law and institutional Standard Operating Procedures.

• Male or female, 18 to 90 years of age, inclusive.

• Expectation, in the judgment of the Investigator, that the patient's cUTI would require initial hospitalization and treatment with IV antibiotics.

• Documented or suspected cUTI or Acute pyelonephritis (AP).

Exclusion Criteria:

• Gross hematuria requiring intervention other than administration of study drug or removal or exchange of a urinary catheter.

• Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization that would interfere with evaluation of response to the study antibiotics.

• Patient requires continuing treatment with probenecid, methotrexate, ganciclovir, valproic acid, or divalproex sodium during the study.

• Receipt of a single dose of a long-acting, potentially-effective systemic antibiotic with activity against Gram-negative uropathogens for more than 24 hours within the 72-hour window prior to randomization.

• Requirement at time of randomization for any reason for additional systemic antimicrobial therapy (including antibacterial, antimycobacterial, or antifungal therapy) other than study drug, with the exception of a single oral dose of any antifungal treatment for vaginal candidiasis.

• Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the patient's participation in the study [from randomization through the Late Follow-up (LFU) Visit].

• Any patients previously randomized in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universeity Multiprofile Hospital for Active Teatment	Sofia		Bulgaria	1431
2	University Multiprofile Hospital for Active Teatment-Clinic of Nephrology	Sofia		Bulgaria	1431
3	Multiprofile Hospital for Active Teatment (MHAT) and Emergency Medicine - Pirogov	Sofia		Bulgaria	1606
4	Multiprofile Hospital for Active Teatment (MHAT) and Emergency Medicine - Doverie	Sofia		Bulgaria	1632

Sponsors and Collaborators

• Entasis Therapeutics

Investigators

• Study Chair: Anibal Calmaggi, MD, Medpace, Inc.

Study Documents (Full-Text)

• Study Protocol - Aug 1, 2017
• Statistical Analysis Plan - Apr 26, 2018

More Information

Publications

None provided.

• Responsible Party: Entasis Therapeutics
• ClinicalTrials.gov Identifier: NCT03445195
• Other Study ID Numbers: CS2514-2017-0003
• First Posted: Feb 26, 2018
• Last Update Posted: Jan 22, 2020
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Imipenem; Sulbactam; Cilastatin, Imipenem Drug Combination; Cilastatin

Study Results

Participant Flow

Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Placebo + Imipenem/Cilastatin
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
Period Title: Overall Study
STARTED	53	27
COMPLETED	51	27
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Placebo + Imipenem/Cilastatin	Total
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Total of all reporting groups
Overall Participants	53	27	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.4 (17.55)	54.9 (15.92)	52.6 (17.00)
Sex: Female, Male (Count of Participants)
Female	27 50.9%	11 40.7%	38 47.5%
Male	26 49.1%	16 59.3%	42 52.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.9%	0 0%	1 1.3%
Not Hispanic or Latino	52 98.1%	27 100%	79 98.8%
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	53 100%	27 100%	80 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
BMI (Body Mass Index) (Kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg/m^2]	28.09 (6.661)	28.63 (5.856)	28.27 (6.368)
Height (Centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters]	172.6 (8.81)	173.1 (8.44)	172.8 (8.63)
Weight (Kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms]	83.79 (20.644)	85.76 (17.929)	84.45 (19.677)
Screening Creatinine Clearance (Milliliters per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Milliliters per minute]	94.3 (23.76)	91.7 (18.19)	93.4 (21.96)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Overall Success
Description	The primary efficacy endpoint for this study was the proportion of patients with an overall success (clinical cure and micro-biologic eradication) for the m-MITT (Micro-biologically Modified Intent-to-Treat) Population at the TOC Visit.
Time Frame	From baseline through day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Placebo + Imipenem/Cilastatin
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
Measure Participants	47	21
Count of Participants [Participants]	36 67.9%	17 63%

2. Secondary Outcome

Title	Clinical Cure
Description	Proportion of patients with a response of clinical cure for the MITT(modified intent to treat), m-MITT (microbiologically modified intent to treat), CE(clinically evaluable), and ME(microbiologically evaluable) populations at the TOC(test of cure) visit.
Time Frame	Baseline to day 21

Outcome Measure Data

Analysis Population Description

The number analyzed for each population is different as the efficacy outcome is for the proportion of subjects with a clinical cure for each group.

Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Placebo + Imipenem/Cilastatin
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
Measure Participants	53	27
MITT population	52 98.1%	27 100%
m-MITT population	46 86.8%	21 77.8%
CE population	52 98.1%	27 100%
ME population	45 84.9%	21 77.8%

3. Secondary Outcome

Title	Microbiologic Eradication
Description	Proportion of patients with a response of microbiologic eradication for the m-MITT(microbiologically modified intent to treat) and ME(microbiologically evaluable) populations at the TOC visit
Time Frame	Baseline to day 21

Outcome Measure Data

Analysis Population Description

The analysis population differs for each group because the efficacy endpoint is for specific populations.

Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin	Placebo + Imipenem/Cilastatin
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.	Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
Measure Participants	53	27
m-MITT population	37 69.8%	17 63%
ME population	36 67.9%	17 63%

Adverse Events

Time Frame	48 hours to day 1, day 1, day 2, day 3, day 4, day 5, day 6,Day 7 to 14/ EOT + 1 day, 7 days post-EOT +/- 1 day(TOC), 7 days post-TOC +/- 2 days (LFU)
Arm/Group Title	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin		Placebo + Imipenem/Cilastatin
Arm/Group Description	Sulbactam-ETX2514: The ETX2514SUL regimen of 1 g ETX2514/1 g sulbactam infused over 3 hours q6h. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.		Placebo: Matching 1g IV solution. Imipenem-cilastatin: All patients will receive background therapy with 500 mg IV imipenem/cilastatin q6h.
All Cause Mortality
	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin		Placebo + Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/27 (0%)
Serious Adverse Events
	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin		Placebo + Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Sulbactam-ETX2514 (ETX2514SUL) + Imipenem/Cilastatin		Placebo + Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/53 (15.1%)		3/27 (11.1%)
Nervous system disorders
Headache	5/53 (9.4%)	5	2/27 (7.4%)	2
Vascular disorders
Phlebitis	3/53 (5.7%)	3	1/27 (3.7%)	1

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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.