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

NCT02452047 | Completed Phase 3 Results

• 3 other identifiers: 7655A-0132015-000066-62163367
• Study Type: interventional
• Target: 50
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Bacterial Infections

Outcome Measures

Primary Outcomes (9)

• Percentage of Participants With Favorable Overall Response (FOR)

  The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen \[e.g., ≥10\^5 CFU/mL at study entry is reduced to \<10\^4 CFU/mL\]) at Early Follow-up (EFU).

  Up to Day 30 (up to 9 days after completing study treatment)

• Percentage of Participants With ≥1 Adverse Events (AEs)

  The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants With ≥1 Serious Adverse Events (SAEs)

  The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants With ≥1 Drug-Related AEs

  The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants With ≥1 Drug-Related SAEs

  The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs

  The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 21

• Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs

  The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 21

• Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group

  The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had \<4 participants and therefore no data are presented.

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants With ≥1 Events of Clinical Interest (ECI)

  The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

  Up to Day 35 (up to 14 days after completing study treatment)

Secondary Outcomes (9)

• Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity

  Up to Day 35 (up to 14 days after completing study treatment)

• Percentage of Participants With Favorable Clinical Response (FCR) at Day 28

  Day 28

• Percentage of Participants With All-cause Mortality Up to Day 28

  Up to Day 28

• Percentage of Participants With FCR on Therapy (OTX)

  OTX (Day 3)

• Percentage of Participants With FCR at End of Therapy (EOT)

  At EOT (up to Day 21)

Study Arms (3)

Group 1: Imipenem+Cilastatin/Relebactam

EXPERIMENTAL

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.

Drug: Imipenem+Cilastatin/Relebactam; Drug: Placebo to CMS

Group 2: Colistimethate sodium + Imipenem+Cilastatin

ACTIVE COMPARATOR

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.

Drug: Colistimethate sodium (CMS); Drug: Imipenem+Cilastatin

Group 3: Imipenem+Cilastatin/Relebactam

EXPERIMENTAL

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.

Drug: Imipenem+Cilastatin/Relebactam

Interventions

Imipenem+Cilastatin/Relebactam DRUG

Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours

Also known as: MK-7655A

Group 1: Imipenem+Cilastatin/Relebactam; Group 3: Imipenem+Cilastatin/Relebactam

Colistimethate sodium (CMS) DRUG

Colistimethate base activity 300 mg (\~720 mg CMS) IV infusion loading dose, followed by colistimethate base activity 75 mg to 150 mg (\~180 to 360 mg CMS), depending on renal function, once every 12 hours

Group 2: Colistimethate sodium + Imipenem+Cilastatin

Imipenem+Cilastatin DRUG

Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours

Group 2: Colistimethate sodium + Imipenem+Cilastatin

Placebo to CMS DRUG

Placebo to CMS IV infusion once every 12 hours

Group 1: Imipenem+Cilastatin/Relebactam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (3)

• 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.

  PMID: 32154325 DERIVED

• 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.

  PMID: 32094127 DERIVED

• 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.

  PMID: 31400759 DERIVED

MeSH Terms

Conditions

Bacterial Infections

Interventions

imipenem, cilastatin and relebactam; colistinmethanesulfonic acid; Cilastatin, Imipenem Drug Combination

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Imipenem; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2015
• First Posted: May 22, 2015
• Study Start: August 21, 2015
• Primary Completion: September 18, 2017
• Study Completion: September 18, 2017
• Last Updated: October 19, 2018
• Results First Posted: October 19, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will share