Complicated Urinary Tract Infections
Conditions
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.
Interventions
DRUGSulopenem
Antibiotic therapy for complicated UTI
Antibiotic therapy for complicated UTI
DRUGErtapenem
Antibiotic therapy for complicated UTI
DRUGCiprofloxacin
Antibiotic therapy for complicated UTI
Antibiotic therapy for complicated UTI
Sponsors
Iterum Therapeutics, International Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Success | Day 21 +/- 1 day | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Microbiologic Success | Day 21 +/- 1 day | Microbiologic success is defined as demonstrating \<1000 CFU/mL of the baseline urpathogen by quantitative urine culture |
Countries
Estonia, Georgia, Hungary, Latvia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Sulopenem: Antibiotic therapy for complicated UTI
Sulopenem-Etzadroxil/Probenecid: Antibiotic therapy for complicated UTI | 697 |
| 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
Ertapenem: Antibiotic therapy for complicated UTI
Ciprofloxacin: Antibiotic therapy for complicated UTI
Amoxicillin-clavulanate: Antibiotic therapy for complicated UTI | 698 |
| Total | 1,395 |
Baseline characteristics
| Characteristic | Sulopenem | Ertapenem | Total |
|---|---|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 18.2 | 59.3 years STANDARD_DEVIATION 18.2 | 58.5 years STANDARD_DEVIATION 18.2 |
| Diabetes | 114 Participants | 114 Participants | 228 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 20 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 672 Participants | 675 Participants | 1347 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment Bulgaria | 150 participants | 145 participants | 295 participants |
| Region of Enrollment Croatia | 8 participants | 6 participants | 14 participants |
| Region of Enrollment Czechia | 8 participants | 10 participants | 18 participants |
| Region of Enrollment Estonia | 16 participants | 18 participants | 34 participants |
| Region of Enrollment Georgia | 81 participants | 92 participants | 173 participants |
| Region of Enrollment Hungary | 70 participants | 47 participants | 117 participants |
| Region of Enrollment Latvia | 31 participants | 42 participants | 73 participants |
| Region of Enrollment Poland | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Russia | 180 participants | 194 participants | 374 participants |
| Region of Enrollment Serbia | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Slovakia | 10 participants | 8 participants | 18 participants |
| Region of Enrollment Ukraine | 109 participants | 98 participants | 207 participants |
| Region of Enrollment United States | 30 participants | 31 participants | 61 participants |
| Sex: Female, Male Female | 389 Participants | 380 Participants | 769 Participants |
| Sex: Female, Male Male | 308 Participants | 318 Participants | 626 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 697 | 0 / 698 |
| other Total, other adverse events | 0 / 697 | 0 / 698 |
| serious Total, serious adverse events | 14 / 697 | 6 / 698 |
Outcome results
Primary
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)
Time frame: Day 21 +/- 1 day
Population: Analysis population is the microbiologic modified intent-to-treat population (all modified intent-to-treat patients with a positive study entry urine culture within 48 hours prior to first dose, defined as \>100,000 CFU/mL of a uropathogen and no more than 2 species of a uropathogen \>100,000 CFU/mL; if 1 of the uropathogens was also isolated from baseline blood culture, however, the patient was included in this population regardless of the baseline urine culture result).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sulopenem | Percentage of Participants With Overall Success | 301 Participants |
| Ertapenem | Percentage of Participants With Overall Success | 325 Participants |
Secondary
Percentage of Participants With Microbiologic Success
Microbiologic success is defined as demonstrating \<1000 CFU/mL of the baseline urpathogen by quantitative urine culture
Time frame: Day 21 +/- 1 day
Population: Analysis population is the microbiologic modified intent-to-treat population (all modified intent-to-treat patients with a positive study entry urine culture within 48 hours prior to first dose, defined as \>100,000 CFU/mL of a uropathogen and no more than 2 species of a uropathogen \>100,000 CFU/mL; if 1 of the uropathogens was also isolated from baseline blood culture, however, the patient was included in this population regardless of the baseline urine culture result).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sulopenem | Percentage of Participants With Microbiologic Success | 316 Participants |
| Ertapenem | Percentage of Participants With Microbiologic Success | 343 Participants |