Clinical trial NCT02452047: Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013)
Official title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects With Imipenem-Resistant Bacterial Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bacterial Infections
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-05-22
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (MK-7655A) versus colistimethate sodium+imipenem+cilastatin in the treatment of imipenem-resistant bacterial infections. Infections evaluated in the study will be hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), and complicated urinary tract infection (cUTI).


Eligibility criteria: Inclusion Criteria:

* Hospitalization that requires treatment with IV antibiotic therapy for a new, persistent or progressing bacterial infection involving at least 1 of 3 primary infection types (HABP, VABP, cIAI, or cUTI)
* Positive culture data from the primary infection-site specimen collected within 1 week of study entry. At least one of the suspected causative pathogens from the specimen meets all of the following: 1) identified as a Gram-negative bacterium, 2) culture-confirmed imipenem resistance (and colistin resistance for Group 3 only), 3) culture-confirmed susceptibility to imipenem/relebactam and to colistin (for Groups 1 and 2 only)
* Not of reproductive potential, or of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner by complying with one of the following: 1) practice abstinence, or 2) use of acceptable contraception during heterosexual activity

Exclusion Criteria:

* Concurrent infection (endocarditis, osteomyelitis, meningitis, prosthetic joint infection, disseminated fungal infection, or active pulmonary tuberculosis) that would interfere with evaluation of the response to the study antibiotics
* Received treatment with any form of systemic colistin for \>24 hours within 72 hours before initiation of study drug (for Groups 1 and 2 only)
* HABP or VABP caused by an obstructive process
* cUTI which 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 an indwelling urinary catheter which cannot be removed at study entry
* History of serious allergy, hypersensitivity, or any serious reaction to listed antibiotics (per-protocol)
* Female who is pregnant or is expecting to conceive (or a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed before completion of the study
* Anticipated treatment with any of the following during the study: valproic acid or divalproex sodium, or concomitant systemic (e.g. IV, oral or inhaled) antimicrobial agents with known Gram-negative bacterial coverage
* Currently undergoing hemodialysis or peritoneal dialysis
* Participated or anticipates participating in any other clinical study involving administration of investigational medication up to 30 days before screening or during the course of the trial

Primary outcomes:
measure: Percentage of Participants With Favorable Overall Response (FOR)
timeFrame: Up to Day 30 (up to 9 days after completing study treatment)
measure: Percentage of Participants With ≥1 Adverse Events (AEs)
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants With ≥1 Serious Adverse Events (SAEs)
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants With ≥1 Drug-Related AEs
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants With ≥1 Drug-Related SAEs
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs
timeFrame: Up to Day 21
measure: Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs
timeFrame: Up to Day 21
measure: Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants With ≥1 Events of Clinical Interest (ECI)
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
Secondary outcomes:
measure: Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity
timeFrame: Up to Day 35 (up to 14 days after completing study treatment)
measure: Percentage of Participants With Favorable Clinical Response (FCR) at Day 28
timeFrame: Day 28
measure: Percentage of Participants With All-cause Mortality Up to Day 28
timeFrame: Up to Day 28
measure: Percentage of Participants With FCR on Therapy (OTX)
timeFrame: OTX (Day 3)
measure: Percentage of Participants With FCR at End of Therapy (EOT)
timeFrame: At EOT (up to Day 21)
measure: Percentage of Participants With FCR at EFU
timeFrame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
measure: Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX
timeFrame: OTX (Day 3)
measure: Percentage of cUTI Participants With FMR at EOT
timeFrame: At EOT (up to Day 21)
measure: Percentage of cUTI Participants With FMR at EFU
timeFrame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Brown ML, Motsch J, Kaye KS, File TM, Boucher HW, Vendetti N, Aggrey A, Joeng HK, Tipping RW, Du J, DePestel DD, Butterton JR, Paschke A. Evaluation of Renal Safety Between Imipenem/Relebactam and Colistin Plus Imipenem in Patients With Imipenem-Nonsusceptible Bacterial Infections in the Randomized, Phase 3 RESTORE-IMI 1 Study. Open Forum Infect Dis. 2020 Feb 19;7(3):ofaa054. doi: 10.1093/ofid/ofaa054. eCollection 2020 Mar.
citation: Kaye KS, Boucher HW, Brown ML, Aggrey A, Khan I, Joeng HK, Tipping RW, Du J, Young K, Butterton JR, Paschke A. Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02203-19. doi: 10.1128/AAC.02203-19. Print 2020 Apr 21.
citation: Motsch J, Murta de Oliveira C, Stus V, Koksal I, Lyulko O, Boucher HW, Kaye KS, File TM, Brown ML, Khan I, Du J, Joeng HK, Tipping RW, Aggrey A, Young K, Kartsonis NA, Butterton JR, Paschke A. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020 Apr 15;70(9):1799-1808. doi: 10.1093/cid/ciz530.