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

• Sponsor: Iterum Therapeutics, International Limited (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03357614
• Collaborator: (none)
• Enrollment: 1,395
• Locations: 32
• Arms: 2
• Actual Duration (Months): 14.9
• Patients Per Site: 43.6
• Patients Per Site Per Month: 2.9

Study Details

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
• 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: Sep 18, 2018
• Actual Primary Completion Date: Dec 14, 2019
• Actual Study Completion Date: Dec 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 Names: Invanz ; Drug: Ciprofloxacin; Antibiotic therapy for complicated UTI; Other Names: Cipro ; Drug: Amoxicillin-clavulanate; Antibiotic therapy for complicated UTI; Other Names: Augmentin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

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

4. Pyelonephritis with normal anatomy

5. Complicated UTI as defined by one or more of the following factors:

1. The presence of an indwelling catheter ii. >100 mL of residual urine after voiding

1. 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

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

2. Rigors, chills or fever/hypothermia

3. Flank pain or pelvic pain

4. Nausea or vomiting

5. Dysuria, urinary frequency or urinary urgency

6. Costovertebral angle tenderness on physical examination

7. A mid-stream urine specimen with:

8. a dipstick analysis positive for nitrite AND

9. 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)

1. Patients participating in any other clinical study that involved the administration of an investigational medication

2. Patient immunocompromised

3. Patients unlikely to comply with the protocol

4. Patients considered unlikely to survive the 4-week study period or has a rapidly progressive or terminal illness

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Facility	Bellflower	California	United States	90706
2	Medical Facility	Chula Vista	California	United States	91911
3	Medical Facility	La Mesa	California	United States	91942
4	Medical Facility	La Palma	California	United States	90623
5	Medical Facility	Torrance	California	United States	90502
6	Medical Facility	Miami Lakes	Florida	United States	33014
7	Medical Facility	Columbus	Georgia	United States	31904
8	Medical Facility	Idaho Falls	Idaho	United States	83404
9	Medical Facility	Boston	Massachusetts	United States	02111
10	Medical Facility	Royal Oak	Michigan	United States	48073
11	Medical Facility	Butte	Montana	United States	59701
12	Medical Facility	Columbus	Ohio	United States	43214
13	Medical Facility	Columbus	Ohio	United States	43215
14	Medical Facility	Dallas	Texas	United States	75246
15	Medical Facility	Houston	Texas	United States	77057
16	Medical Facility	Kohtla-Järve		Estonia	31025
17	Medical Facility	Tallinn		Estonia	10617
18	Medical Facility	Võru		Estonia	65526
19	Medical Facility	Tbilisi		Georgia	00144
20	Medical Facility	Tbilisi		Georgia	00159
21	Medical Facility	Tbilisi		Georgia	00160
22	Medical Facility	Baja		Hungary	6500
23	Medical Facility	Budapest		Hungary	01204
24	Medical Facility	Nagykanizsa		Hungary	8800
25	Medical Facility	Nyiregyhaza		Hungary	4400
26	Medical Facility	Szentes		Hungary	06600
27	Medical Facility	Tatabánya		Hungary	2800
28	Medical Facility	Daugavpils		Latvia	LV5417
29	Medical Facility	Liepāja		Latvia	LV3414
30	Medical Facility	Riga		Latvia	LV1002
31	Medical Facility	Riga		Latvia	LV1038
32	Medical Facility	Valmiera		Latvia	LV4201

Sponsors and Collaborators

• Iterum Therapeutics, International Limited

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 4, 2018
• Statistical Analysis Plan - Feb 11, 2020

More Information

Publications

None provided.

• Responsible Party: Iterum Therapeutics, International Limited
• ClinicalTrials.gov Identifier: NCT03357614
• Other Study ID Numbers: IT001-302
• First Posted: Nov 30, 2017
• Last Update Posted: Dec 29, 2020
• Last Verified: Nov 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: Urinary Tract Infections; Amoxicillin; Ciprofloxacin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Ertapenem; Lactams; Probenecid

Study Results

Participant Flow

Arm/Group Title	Sulopenem	Ertapenem
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	697	698
COMPLETED	672	670
NOT COMPLETED	25	28

Baseline Characteristics

Arm/Group Title	Sulopenem	Ertapenem	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	697	698	1395
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.8 (18.2)	59.3 (18.2)	58.5 (18.2)
Sex: Female, Male (Count of Participants)
Female	389 55.8%	380 54.4%	769 55.1%
Male	308 44.2%	318 45.6%	626 44.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 3.2%	20 2.9%	42 3%
Not Hispanic or Latino	672 96.4%	675 96.7%	1347 96.6%
Unknown or Not Reported	3 0.4%	3 0.4%	6 0.4%
Region of Enrollment (participants) [Number]
Latvia	31 4.4%	42 6%	73 5.2%
Hungary	70 10%	47 6.7%	117 8.4%
United States	30 4.3%	31 4.4%	61 4.4%
Georgia	81 11.6%	92 13.2%	173 12.4%
Estonia	16 2.3%	18 2.6%	34 2.4%
Bulgaria	150 21.5%	145 20.8%	295 21.1%
Czechia	8 1.1%	10 1.4%	18 1.3%
Poland	3 0.4%	3 0.4%	6 0.4%
Russia	180 25.8%	194 27.8%	374 26.8%
Serbia	1 0.1%	4 0.6%	5 0.4%
Slovakia	10 1.4%	8 1.1%	18 1.3%
Ukraine	109 15.6%	98 14%	207 14.8%
Croatia	8 1.1%	6 0.9%	14 1%
Diabetes (Count of Participants)
Count of Participants [Participants]	114 16.4%	114 16.3%	228 16.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Success
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sulopenem	Ertapenem
Arm/Group Description	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	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
Measure Participants	444	440
Count of Participants [Participants]	301 43.2%	325 46.6%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Sulopenem	Ertapenem
Arm/Group Description	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	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
Measure Participants	444	440
Count of Participants [Participants]	316 45.3%	343 49.1%

Adverse Events

Time Frame	From the time of informed consent through the final visit, an average of 28 days.
Arm/Group Title	Sulopenem		Ertapenem
Arm/Group Description	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		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
All Cause Mortality
	Sulopenem		Ertapenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/697 (0.3%)		0/698 (0%)
Serious Adverse Events
	Sulopenem		Ertapenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/697 (2%)		6/698 (0.9%)
Cardiac disorders
Cardiac failure	1/697 (0.1%)	1	0/698 (0%)	0
Cardiac failure congestive	1/697 (0.1%)	1	0/698 (0%)	0
Atrioventricular block complete	0/697 (0%)	0	1/698 (0.1%)	1
Infections and infestations
Abscess neck	0/697 (0%)	0	1/698 (0.1%)	1
Cystitis	0/697 (0%)	0	1/698 (0.1%)	1
Pneumonia	1/697 (0.1%)	1	0/698 (0%)	0
Pyelonephritis	0/697 (0%)	0	2/698 (0.3%)	2
Pyelonephritis acute	2/697 (0.3%)	2	0/698 (0%)	0
Pyelonephritis chronic	1/697 (0.1%)	1	1/698 (0.1%)	1
Urinary tract infection	5/697 (0.7%)	5	0/698 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma	1/697 (0.1%)	1	0/698 (0%)	0
Salivary gland neoplasm	1/697 (0.1%)	1	0/698 (0%)	0
Nervous system disorders
Seizure	0/697 (0%)	0	1/698 (0.1%)	1
Syncope	0/697 (0%)	0	1/698 (0.1%)	1
Renal and urinary disorders
Urinary retention	1/697 (0.1%)	1	1/698 (0.1%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary artery thrombosis	0/697 (0%)	0	1/698 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Sulopenem		Ertapenem
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/697 (0%)		0/698 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The PIs will provide Iterum opportunity to review proposed publication/other type of disclosure before it's submitted/otherwise disclosed. PI will provide manuscripts, abstracts, or full text of intended disclosure (poster, invited speaker presentation, etc) to Iterum at least 30 days before submitted for publication/otherwise disclosed. If any patent action is required to protect intellectual property rights, PI agrees to delay disclosure for a period not to exceed an additional 60 days.