Sulopenem Followed by Sulopenem-etzadroxil/Probenecid vs Ertapenem Followed by Cipro for Complicated UTI in Adults

• ClinicalTrials.gov Identifier: NCT03357614
• Recruitment Status: Completed
• First Posted: November 30, 2017
• Last Update Posted: January 2, 2020
• Sponsor: Iterum Therapeutics, International Limited
• Information provided by (Responsible Party): Iterum Therapeutics, International Limited

Study Description

Brief Summary:

This is a prospective, phase 3, randomized, multicenter, double-blind, double-dummy study to compare the efficacy and safety of sulopenem followed by sulopenem-etzadroxil/probenecid versus ertapenem followed by ciprofloxacin for the treatment of complicated urinary tract infections (cUTI) in adults.

Condition or disease	Intervention/treatment	Phase
Complicated Urinary Tract Infections	Drug: Sulopenem; Drug: Sulopenem-Etzadroxil/Probenecid; Drug: Ertapenem; Drug: Ciprofloxacin; Drug: Amoxicillin-clavulanate	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1395 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prospective, Phase 3, Randomized, Multi-center, Double-blind, Double-dummy Study of Efficacy, Tolerability & Safety of Sulopenem Followed by Sulopenem-etzadroxil/Probenecid vs Ertapenem Followed by Cipro for Treatment of cUTI in Adults
• Actual Study Start Date: September 18, 2018
• Actual Primary Completion Date: December 14, 2019
• Actual Study Completion Date: December 14, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sulopenem; Sulopenem 1000 mg IV once daily for a minimum of 5 days, followed by sulopenem-etzadroxil/probenecid 500 mg PO twice daily to complete 7-10 total days of treatment	Drug: Sulopenem; Antibiotic therapy for complicated UTI; Drug: Sulopenem-Etzadroxil/Probenecid; Antibiotic therapy for complicated UTI
Active Comparator: Ertapenem; Ertapenem 1000 mg IV once daily for a minimum of 5 days, followed by ciprofloxacin 500 mg PO twice daily or amoxicillin-clavulanate 500 mg PO twice daily to complete 7-10 total days of treatment	Drug: Ertapenem; Antibiotic therapy for complicated UTI; Other Name: Invanz; Drug: Ciprofloxacin; Antibiotic therapy for complicated UTI; Other Name: Cipro; Drug: Amoxicillin-clavulanate; Antibiotic therapy for complicated UTI; Other Name: Augmentin

Outcome Measures

Primary Outcome Measures :

1. Overall response (combined clinical and microbiologic response) in the micro-MITT population [ Time Frame: Day 21 +/- 1 day ]
   Clinical response is defined as complete resolution of cUTI symptoms present at study entry and no new cUTI symptoms; microbiologic success is defined as eradication of the bacterial pathogen found at study entry (reduced to <1000 CFU/mL)

Secondary Outcome Measures :

1. Microbiologic response in each arm in the micro-MITT population [ Time Frame: Day 21 +/- 1 day ]
   Microbiologic response is defined as demonstrating <1000 CFU/mL of the baseline urpathogen by quantitative urine culture

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adults ≥18 years of age with more than 24 hours of urinary symptoms attributable to a UTI
2. Able to provide informed consent

3. Clinically documented pyelonephritis or complicated urinary tract infection:

   1. Pyelonephritis with normal anatomy
   2. Complicated UTI as defined by one or more of the following factors:

   i. The presence of an indwelling catheter ii. >100 mL of residual urine after voiding iii. Neurogenic bladder iv. Obstructive uropathy due to nephrolithiasis, tumor or fibrosis v. Azotemia due to intrinsic renal disease vi. Urinary retention in men possibly due to benign prostatic hypertrophy vii. Surgically modified or abnormal urinary tract anatomy

4. At least two of the following signs or symptoms:

   1. Rigors, chills or fever/hypothermia
   2. Flank pain or pelvic pain
   3. Nausea or vomiting
   4. Dysuria, urinary frequency or urinary urgency
   5. Costovertebral angle tenderness on physical examination

5. A mid-stream urine specimen with:

   1. a dipstick analysis positive for nitrite AND
   2. evidence of pyuria as defined by either: i. a dipstick analysis positive for leukocyte esterase AND/OR ii. at least 10 white blood cells per cubic millimeter on microscopic analysis of unspun urine AND/OR iii. White blood cell count ≥10 cells/high-powered field in urine sediment

Exclusion Criteria

1. Receipt of effective antibacterial drug therapy for complicated urinary tract infection (cUTI) for a continuous duration of more than 24 hours during the previous 72 hours. Patients who have objective documentation of clinical progression of cUTI while on antibacterial drug therapy, or patients who received antibacterial drugs for surgical prophylaxis and then develop cUTI, may be appropriate for enrollment.
2. Subjects with an organism isolated from the urine within the last year known to be resistant to ertapenem
3. Severe structural or functional urinary tract abnormality responsible for an intractable infection which in the opinion of the investigator would require > 10 days of therapy or post-treatment prophylaxis (eg. patients with chronic vesiculo-ureteral reflux).
4. Uncomplicated UTI
5. Patients with paraplegia/quadriplegia
6. Hypotension with systolic blood pressure < 90 mm Hg
7. Complicated UTI associated with complete obstruction, emphysematous pyelonephritis, known or suspected renal or perinephric abscess or expected to require surgical intervention (not placement of catheters) to achieve cure
8. Patients with a known history of myasthenia gravis
9. Patients who require concomitant administration of tizanidine or valproic acid
10. Patients with a history of allergy to carbapenems or quinolones or amoxicillin-clavulanate or other beta-lactams, or hypersensitivity to probenecid
11. Renal transplantation
12. Patients requiring dialysis
13. Acute or chronic prostatitis
14. High risk for cUTI caused by Pseudomonas sp. (eg,. history of prior UTI due to Pseudomonas species, recent steroid use, others)
15. Chronic indwelling catheters or stents
16. Ileal loops or vesico-urethral reflux
17. Recent trauma to the pelvis or urinary tract within the prior 30 days
18. History of seizures
19. Patients with a history of blood dyscrasias
20. Patients with a history of uric acid kidney stones
21. Patients with acute gouty attack
22. Patients on chronic methotrexate therapy
23. Females of child-bearing potential who are unable to take adequate contraceptive precautions, have a positive pregnancy test result within 24 hours of study entry, are otherwise known to be pregnant, or are currently breastfeeding an infant.
24. Male subjects must agree to use of an effective barrier method of contraception during the study and for 14 days post treatment

25. Patients known to have a history of liver or kidney disease or neutropenia as defined by the following baseline laboratory criteria:

    • Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) > 3 X Upper Limit of Normal
    • Total bilirubin > 2 X Upper Limit of Normal
    • Neutropenia (<1000 cells/mm3)
26. Patients participating in any other clinical study that involved the administration of an investigational medication
27. Patient immunocompromised
28. Patients unlikely to comply with the protocol
29. Patients considered unlikely to survive the 4-week study period or has a rapidly progressive or terminal illness

Contacts and Locations

Locations

United States, California

Medical Facility

Bellflower, California, United States, 90706

Medical Facility

Chula Vista, California, United States, 91911

Medical Facility

La Mesa, California, United States, 91942

Medical Facility

La Palma, California, United States, 90623

Medical Facility

Torrance, California, United States, 90502

United States, Florida

Medical Facility

Miami Lakes, Florida, United States, 33014

United States, Georgia

Medical Facility

Columbus, Georgia, United States, 31904

United States, Idaho

Medical Facility

Idaho Falls, Idaho, United States, 83404

United States, Massachusetts

Medical Facility

Boston, Massachusetts, United States, 02111

United States, Michigan

Medical Facility

Royal Oak, Michigan, United States, 48073

United States, Montana

Medical Facility

Butte, Montana, United States, 59701

United States, Ohio

Medical Facility

Columbus, Ohio, United States, 43214

Medical Facility

Columbus, Ohio, United States, 43215

United States, Texas

Medical Facility

Dallas, Texas, United States, 75246

Medical Facility

Houston, Texas, United States, 77057

Estonia

Medical Facility

Kohtla-Järve, Estonia, 31025

Medical Facility

Tallinn, Estonia, 10617

Medical Facility

Võru, Estonia, 65526

Georgia

Medical Facility

Tbilisi, Georgia, 00144

Medical Facility

Tbilisi, Georgia, 00159

Medical Facility

Tbilisi, Georgia, 00160

Hungary

Medical Facility

Baja, Hungary, 6500

Medical Facility

Budapest, Hungary, 01204

Medical Facility

Nagykanizsa, Hungary, 8800

Medical Facility

Nyiregyhaza, Hungary, 4400

Medical Facility

Szentes, Hungary, 06600

Medical Facility

Tatabánya, Hungary, 2800

Latvia

Medical Facility

Daugavpils, Latvia, LV5417

Medical Facility

Liepāja, Latvia, LV3414

Medical Facility

Riga, Latvia, LV1002

Medical Facility

Riga, Latvia, LV1038

Medical Facility

Valmiera, Latvia, LV4201

Sponsors and Collaborators

Iterum Therapeutics, International Limited

More Information

• Responsible Party: Iterum Therapeutics, International Limited
• ClinicalTrials.gov Identifier: NCT03357614
• Other Study ID Numbers: IT001-302
• First Posted: November 30, 2017
• Last Update Posted: January 2, 2020
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Urinary Tract Infections; Infection; Urologic Diseases; Amoxicillin; Ciprofloxacin; Clavulanic Acid; Clavulanic Acids; Ertapenem; Amoxicillin-Potassium Clavulanate Combination; Lactams; Probenecid; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; beta-Lactamase Inhibitors; Uricosuric Agents; Gout Suppressants; Antirheumatic Agents; Renal Agents