Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) in Japanese Participants With Complicated Intra-abdominal Infection or Complicated Urinary Tract Infection (MK-7655A-017)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03293485
• Collaborator: (none)
• Enrollment: 83
• Locations: 29
• Arm: 1
• Actual Duration (Months): 11.3
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (IMI/REL, MK-7655A) in Japanese participants with complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI).

Condition or Disease	Intervention/Treatment	Phase
Complicated Intra-abdominal Infection; Complicated Urinary Tract Infection	Drug: Imipenem+Cilastatin/Relebactam	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Non-randomized, Non-controlled, Open Label Clinical Trial to Study the Safety and Efficacy of Imipenem/Cilastatin/Relebactam (IMI/REL [MK-7655A]) in Japanese Subjects With Complicated Intra-Abdominal Infection (cIAI) or Complicated Urinary Tract Infection (cUTI)
• Actual Study Start Date: Oct 4, 2017
• Actual Primary Completion Date: Sep 14, 2018
• Actual Study Completion Date: Sep 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Imipenem+Cilastatin/Relebactam Participants with cIAI or cUTI will receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours for 5 to 14 days	Drug: Imipenem+Cilastatin/Relebactam; Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, 30-minute IV infusion once every 6 hours; Other Names: IMI/REL MK-7655A

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Experiencing ≥1 Adverse Events (AE) [Up to 28 days]

   The percentage of participants experiencing ≥1 AE was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.

2. Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) [Up to 14 days (End of Therapy Visit)]

   The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.

3. Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at End of Therapy Visit [Between Day 5 and Day 14 (End of Therapy Visit)]

   The percentage of participants with cIAI who display a favorable clinical response at End of Therapy visit was presented. Per protocol, a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because clinical response is primarily relevant to cIAI. Favorable clinical response is a rating of "cure" or "improved" as determined by the investigator at the End of Therapy Visit. "Cure" is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. "Improved" is defined as: All or most pretherapy signs and symptoms of the index infection(s) have improved or resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.

4. Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at End of Therapy Visit [Between Day 5 and Day 14 (End of Therapy Visit)]

   The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the End of Therapy visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the End of Therapy Visit showing eradication (e.g., ≥10^5 CFU/mL is reduced to <10^4 CFU/mL) of all uropathogens found at study entry.

Secondary Outcome Measures

1. Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at Test of Cure Visit [Between Day 10 and Day 23 (Test of Cure Visit)]

   The percentage of participants with cIAI who display a favorable Clinical Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because the clinical response evaluation is primarily relevant to cIAI. A favorable clinical response is a rating of "cure" as determined by the investigator at the Test of Cure Visit. "Cure" is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to "preinfection status") AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.

2. Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at Test of Cure Visit [Between Day 10 and Day 23 (Test of Cure Visit)]

   The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the Test of Cure visit still showing eradication (e.g., ≥10^5 CFU/mL is reduced to <10^4 CFU/mL) of all uropathogens found at study entry.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• requires hospitalization and treatment with IV antibiotic therapy for complicated intraabdominal infection (cIAI) or complicated urinary tract infection (cUTI). Per-protocol diagnostic criteria apply to the qualifying infection types.

• infection is known or thought to be caused by microorganisms susceptible to the IV study therapy

• baseline specimen for primary infection site culture obtained at operative procedure in Screening period or at Baseline for cIAI participants, and within 48 hours before initiation of IV study drug for cUTI participants

• female or male who is not of reproductive potential, or female or male who is of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner from the time of consent through completion of the study, by practicing abstinence from heterosexual activity or using acceptable contraception during heterosexual activity.

Exclusion Criteria:

• received any amount of effective antibiotic therapy after obtaining the culture for admission to the study and before administration of the first dose of IV study therapy

• received treatment with systemic effective antibiotics for >24 hours within the 72 hours before initiation of study therapy

• has a concurrent infection, including endocarditis, osteomyelitis, meningitis, or prosthetic joint infection, that would interfere with evaluation of response to IMI/REL

• has a cIAI or cUTI due to a confirmed fungal pathogen

• has a cUTI that meets any of the following: 1) complete obstruction of any portion of the urinary tract, 2) known ileal loop, 3) intractable vesico-ureteral reflux, 4) presence of indwelling urinary catheter which cannot be removed at study entry

• has a cIAI that meets any of the following: 1) infection that should be managed by Staged Abdominal Repair (STAR) or open abdomen therapy, 2) infection limited to the hollow viscus

• history of serious allergy, hypersensitivity, or any serious reaction to any carbapenem, cephalosporin, penicillin or other beta-lactam agent, or other beta-lactamase inhibitors

• female who is pregnant or is expecting to conceive, is breastfeeding, or plans to breastfeed before completion of the study

• history of a seizure disorder

• anticipates to be treated with valproic acid, concomitant IV or an oral antimicrobial considered effective to the index pathogen, in addition to the study treatment

• is receiving immunosuppressive therapy, including high-dose corticosteroids

• is undergoing hemodialysis or peritoneal dialysis

• participated in any other clinical study involving an investigational or experimental medication during the previous 30 days before Screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nagoya Ekisaikai Hospital ( Site 1724)	Nagoya	Aichi	Japan	454-8502
2	Toyota Memorial Hospital ( Site 1708)	Toyota	Aichi	Japan	471-8513
3	Medical Corporation Chiyukai Fukuoka Shin Mizumaki Hospital ( Site 1710)	Onga-gun	Fukuoka	Japan	807-0051
4	Shin Yukuhashi Hospital ( Site 1722)	Yukuhashi	Fukuoka	Japan	824-0026
5	National Hospital Organization Fukuyama Medical Center ( Site 1706)	Fukuyama	Hiroshima	Japan	720-8520
6	Fukuyama City Hospital ( Site 1721)	Fukuyama	Hiroshima	Japan	721-8511
7	KKR Sapporo Medical Center ( Site 1728)	Sapporo	Hokkaido	Japan	062-0931
8	Sano Hospital ( Site 1701)	Kobe	Hyogo	Japan	655-0031
9	National Hospital Organization Mito Medical Center ( Site 1729)	Higashiibaraki-gun	Ibaraki	Japan	311-3193
10	Medical Corporation Tokushukai Koga General Hospital ( Site 1712)	Koga	Ibaraki	Japan	306-0041
11	Ishikawa Prefectural Central Hospital ( Site 1707)	Kanazawa	Ishikawa	Japan	920-8530
12	National Hospital Organization Kanazawa Medical Center ( Site 1716)	Kanazawa	Ishikawa	Japan	920-8650
13	Kawahara Clinic ( Site 1719)	Aira	Kagoshima	Japan	899-5431
14	National Hospital Organization Yokohama Medical Center ( Site 1702)	Yokohama	Kanagawa	Japan	245-8575
15	National Hospital Organization Mie Chuo Medical Center ( Site 1727)	Tsu	Mie	Japan	514-1101
16	Japan Labour Health And Safety Organization Tohoku Rosai Hospital ( Site 1714)	Sendai	Miyagi	Japan	981-8563
17	National Hospital Organization Sendai Medical Center ( Site 1723)	Sendai	Miyagi	Japan	983-8520
18	Suwa Red Cross Hospital ( Site 1705)	Suwa	Nagano	Japan	392-8510
19	National Hospital Organization Nagasaki Medical Center ( Site 1718)	Omura	Nagasaki	Japan	856-8562
20	National Hospital Organization Osaka Minami Medical Center ( Site 1715)	Kawachinagano	Osaka	Japan	586-8521
21	National Hospital Organization Utsunomiya National Hospital ( Site 1711)	Utsunomiya	Tochigi	Japan	329-1193
22	National Hospital Organization Minami Wakayama Medical Center ( Site 1725)	Tanabe	Wakayama	Japan	646-8558
23	Yamanashi Prefectural Central Hospital ( Site 1703)	Kofu	Yamanashi	Japan	400-8506
24	Fukuiken Saiseikai Hospital ( Site 1704)	Fukui		Japan	918-8503
25	Medical Corporation Chiyukai Fukuoka Wajiro Hospital ( Site 1709)	Fukuoka		Japan	811-0213
26	Medical Corporation Shingenkai Kawahara Urological Clinic ( Site 1726)	Kagoshima		Japan	890-0073
27	Medical Corporation Seifukai Yagi Clinic ( Site 1720)	Kagoshima		Japan	891-0105
28	National Hospital Organization Kumamoto Medical Center ( Site 1713)	Kumamoto		Japan	860-0008
29	National Hospital Organization Oita Medical Center ( Site 1717)	Oita		Japan	870-0263

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 18, 2017

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03293485
• Other Study ID Numbers: 7655A-017; 173738
• First Posted: Sep 26, 2017
• Last Update Posted: Feb 12, 2021
• Last Verified: Jan 1, 2021

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

Study Results

Participant Flow

Arm/Group Title	cIAI/cUTI
Arm/Group Description	Participants with complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI) received intravenous imipenem+cilastatin+relebactam (IMI/REL) once every 6 hours for 5-14 days.
Period Title: Overall Study
STARTED	83
Treated	81
COMPLETED	78
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	cIAI/cUTI
Arm/Group Description	Participants with cIAI or cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Overall Participants	83
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.8 (18.2)
Sex: Female, Male (Count of Participants)
Female	45 54.2%
Male	38 45.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	83 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	83 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Infection Type (Count of Participants)
cIAI	39 47%
cUTI	44 53%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Experiencing ≥1 Adverse Events (AE)
Description	The percentage of participants experiencing ≥1 AE was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants who received ≥1 dose of intravenous imipenem+cilastatin+relebactam.

Arm/Group Title	cIAI/cUTI
Arm/Group Description	Participants with cIAI or cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	81
Number (95% Confidence Interval) [Percentage of Participants]	74.1 89.3%

2. Primary Outcome

Title	Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
Description	The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
Time Frame	Up to 14 days (End of Therapy Visit)

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants who received ≥1 dose of intravenous imipenem+cilastatin+relebactam.

Arm/Group Title	cIAI/cUTI
Arm/Group Description	Participants with cIAI or cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	81
Number (95% Confidence Interval) [Percentage of Participants]	4.9 5.9%

3. Primary Outcome

Title	Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at End of Therapy Visit
Description	The percentage of participants with cIAI who display a favorable clinical response at End of Therapy visit was presented. Per protocol, a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because clinical response is primarily relevant to cIAI. Favorable clinical response is a rating of "cure" or "improved" as determined by the investigator at the End of Therapy Visit. "Cure" is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. "Improved" is defined as: All or most pretherapy signs and symptoms of the index infection(s) have improved or resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.
Time Frame	Between Day 5 and Day 14 (End of Therapy Visit)

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants with cIAI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative enteric and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.

Arm/Group Title	cIAI
Arm/Group Description	Participants with cIAI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	28
Number (95% Confidence Interval) [Percentage of Participants]	85.7 103.3%

4. Primary Outcome

Title	Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at End of Therapy Visit
Description	The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the End of Therapy visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the End of Therapy Visit showing eradication (e.g., ≥10^5 CFU/mL is reduced to <10^4 CFU/mL) of all uropathogens found at study entry.
Time Frame	Between Day 5 and Day 14 (End of Therapy Visit)

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants with cUTI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.

Arm/Group Title	cUTI
Arm/Group Description	Participants with cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	39
Number (95% Confidence Interval) [Percentage of Participants]	100 120.5%

5. Secondary Outcome

Title	Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at Test of Cure Visit
Description	The percentage of participants with cIAI who display a favorable Clinical Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because the clinical response evaluation is primarily relevant to cIAI. A favorable clinical response is a rating of "cure" as determined by the investigator at the Test of Cure Visit. "Cure" is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to "preinfection status") AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.
Time Frame	Between Day 10 and Day 23 (Test of Cure Visit)

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants with cIAI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative enteric and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.

Arm/Group Title	cIAI
Arm/Group Description	Participants with cIAI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	28
Number (95% Confidence Interval) [Percentage of Participants]	82.1 98.9%

6. Secondary Outcome

Title	Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at Test of Cure Visit
Description	The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the Test of Cure visit still showing eradication (e.g., ≥10^5 CFU/mL is reduced to <10^4 CFU/mL) of all uropathogens found at study entry.
Time Frame	Between Day 10 and Day 23 (Test of Cure Visit)

Outcome Measure Data

Analysis Population Description

Per protocol, the population analyzed was all participants with cUTI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.

Arm/Group Title	cUTI
Arm/Group Description	Participants with cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
Measure Participants	39
Number (95% Confidence Interval) [Percentage of Participants]	59.0 71.1%

Adverse Events

Time Frame	Up to 28 days (up to 14 days after completion of intravenous study therapy)
Adverse Event Reporting Description	Adverse events were reported for all participants who received at least one dose of IV study therapy.
Arm/Group Title	cIAI/cUTI
Arm/Group Description	Participants with cIAI or cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days.
All Cause Mortality
	cIAI/cUTI
	Affected / at Risk (%)	# Events
Total	1/81 (1.2%)
Serious Adverse Events
	cIAI/cUTI
	Affected / at Risk (%)	# Events
Total	9/81 (11.1%)
Eye disorders
Rhegmatogenous retinal detachment	1/81 (1.2%)	1
Gastrointestinal disorders
Large intestine perforation	1/81 (1.2%)	1
Pancreatitis acute	1/81 (1.2%)	1
Hepatobiliary disorders
Cholecystitis acute	1/81 (1.2%)	1
Infections and infestations
Abdominal abscess	2/81 (2.5%)	2
Pelvic abscess	1/81 (1.2%)	1
Peritonitis	1/81 (1.2%)	1
Injury, poisoning and procedural complications
Postoperative ileus	1/81 (1.2%)	1
Renal and urinary disorders
Acute kidney injury	1/81 (1.2%)	1
Renal haematoma	1/81 (1.2%)	1
Other (Not Including Serious) Adverse Events
	cIAI/cUTI
	Affected / at Risk (%)	# Events
Total	18/81 (22.2%)
Gastrointestinal disorders
Diarrhoea	7/81 (8.6%)	7
Nausea	7/81 (8.6%)	9
Infections and infestations
Nasopharyngitis	5/81 (6.2%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Subsequent to the multicenter publication (or after public disclosure of the results at www.clinicaltrials.gov if multicenter manuscript is not planned), an investigator and colleagues may publish their data independently. Sponsor must have opportunity to review proposed abstracts, manuscripts or presentations 45 days prior to submission for publication/presentation. Confidential information must be deleted prior to submission; this confidentiality does not include efficacy and safety results.