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

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

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.

Study Overview

• Status: Completed
• Conditions: Complicated Urinary Tract Infections
• Intervention / Treatment: Drug: Sulopenem; Drug: Sulopenem-Etzadroxil/Probenecid; Drug: Ertapenem; Drug: Ciprofloxacin; Drug: Amoxicillin-clavulanate

• Study Type: Interventional
• Enrollment (Actual): 1395
• Phase: Phase 3

Contacts and Locations

Study Locations

• Estonia
  • Kohtla-Järve, Estonia, 31025
    • Medical facility
  • Tallinn, Estonia, 10617
    • Medical facility
  • Võru, Estonia, 65526
    • Medical facility
• Georgia
  • Tbilisi, Georgia, 00144
    • Medical facility
  • Tbilisi, Georgia, 00159
    • Medical facility
  • Tbilisi, Georgia, 00160
    • Medical facility
• Hungary
  • 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
    • Medical facility
• Latvia
  • Daugavpils, Latvia, LV5417
    • Medical facility
  • Liepāja, Latvia, LV3414
    • Medical facility
  • Riga, Latvia, LV1002
    • Medical facility
  • Riga, Latvia, LV1038
    • Medical facility
  • Valmiera, Latvia, LV4201
    • Medical facility
• United States
  • California
    • 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
      • Medical facility
  • Florida
    • Miami Lakes, Florida, United States, 33014
      • Medical facility
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Medical facility
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Medical facility
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Medical facility
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Medical facility
  • Montana
    • Butte, Montana, United States, 59701
      • Medical facility
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Medical facility
    • Columbus, Ohio, United States, 43214
      • Medical facility
  • Texas
    • Dallas, Texas, United States, 75246
      • Medical facility
    • Houston, Texas, United States, 77057
      • Medical facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Invanz; Drug: Ciprofloxacin; Antibiotic therapy for complicated UTI; Other Names: Cipro; Drug: Amoxicillin-clavulanate; Antibiotic therapy for complicated UTI; Other Names: Augmentin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Success	Clinical success 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)	Day 21 +/- 1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Microbiologic Success	Microbiologic success is defined as demonstrating <1000 CFU/mL of the baseline urpathogen by quantitative urine culture	Day 21 +/- 1 day

Collaborators and Investigators

• Sponsor: Iterum Therapeutics, International Limited

Publications and helpful links

General Publications

• Dunne MW, Aronin SI, Das AF, Akinapelli K, Breen J, Zelasky MT, Puttagunta S. Sulopenem For The Treatment of Complicated Urinary Tract Infection Including Pyelonephritis: A Phase 3 Randomized Trial. Clin Infect Dis. 2022 Sep 7:ciac704. doi: 10.1093/cid/ciac704. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2018
• Primary Completion (Actual): December 14, 2019
• Study Completion (Actual): December 14, 2019

Study Registration Dates

• First Submitted: November 20, 2017
• First Submitted That Met QC Criteria: November 25, 2017
• First Posted (Actual): November 30, 2017

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 3, 2020
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Urologic Diseases; Urinary Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Gout Suppressants; Cytochrome P-450 CYP1A2 Inhibitors; beta-Lactamase Inhibitors; Renal Agents; Uricosuric Agents; Ciprofloxacin; Amoxicillin; Ertapenem; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Lactams; Probenecid
• Other Study ID Numbers: IT001-302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No