Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013) (RESTORE-IMI 1)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3

Conditions: Bacterial Infections

Treatments: Drug: Imipenem+Cilastatin/Relebactam; Drug: Colistimethate sodium (CMS); Drug: Imipenem+Cilastatin; Drug: Placebo to CMS

Study type: Interventional

Funder types: Industry

Identifiers

NCT02452047

163367 (Registry Identifier)

2015-000066-62 (EudraCT Number)

7655A-013

Details and patient eligibility

About

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).

Enrollment: 50 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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50 participants in 3 patient groups

Group 1: Imipenem+Cilastatin/Relebactam

Experimental group

Description:

Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations \>21 days may be approved by the Sponsor for participants requiring longer treatment duration.

Treatment:

Drug: Placebo to CMS

Drug: Imipenem+Cilastatin/Relebactam

Group 2: Colistimethate sodium + Imipenem+Cilastatin

Active Comparator group

Description:

Participants will be stratified by infection type (HABP/VABP, cIAI, and cUTI) and randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations \>21 days may be approved by the Sponsor for participants requiring longer treatment duration.

Treatment:

Drug: Colistimethate sodium (CMS)

Drug: Imipenem+Cilastatin

Group 3: Imipenem+Cilastatin/Relebactam

Experimental group

Description:

Participants with documented imipenem-resistant and colistin-resistant bacterial infections may be eligible to receive open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days for cIAI and cUTI or for 7 to 21 days for HABP or VABP. Treatment durations \>21 days may be approved by the Sponsor for participants requiring longer treatment duration.

Treatment:

Drug: Imipenem+Cilastatin/Relebactam