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
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 50
- Primary Endpoint
- Percentage of Participants With ≥1 Drug-Related SAEs
Study Overview
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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Group 1: Imipenem+Cilastatin/Relebactam
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.
Intervention: Imipenem+Cilastatin/Relebactam (Drug)
Group 1: Imipenem+Cilastatin/Relebactam
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.
Intervention: Placebo to CMS (Drug)
Group 2: Colistimethate sodium + Imipenem+Cilastatin
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.
Intervention: Colistimethate sodium (CMS) (Drug)
Group 2: Colistimethate sodium + Imipenem+Cilastatin
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.
Intervention: Imipenem+Cilastatin (Drug)
Group 3: Imipenem+Cilastatin/Relebactam
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.
Intervention: Imipenem+Cilastatin/Relebactam (Drug)
Outcomes
Primary Outcomes
Percentage of Participants With ≥1 Drug-Related SAEs
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs
Time Frame: Up to Day 21
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.
Percentage of Participants With ≥1 Serious Adverse Events (SAEs)
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Percentage of Participants With ≥1 Drug-Related AEs
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Percentage of Participants With Favorable Overall Response (FOR)
Time Frame: Up to Day 30 (up to 9 days after completing study treatment)
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).
Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Percentage of Participants With ≥1 Adverse Events (AEs)
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs
Time Frame: Up to Day 21
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.
Percentage of Participants With ≥1 Events of Clinical Interest (ECI)
Time Frame: Up to Day 35 (up to 14 days after completing study treatment)
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.
Secondary Outcomes
- 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 cUTI Participants With FMR at EOT(At EOT (up to Day 21))
- Percentage of Participants With FCR at End of Therapy (EOT)(At EOT (up to Day 21))
- Percentage of Participants With FCR at EFU(EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]))
- Percentage of cUTI Participants With FMR at EFU(EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]))
- 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 cUTI Participants With Favorable Microbiological Response (FMR) at OTX(OTX (Day 3))