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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)

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ClinicalTrials.gov Identifier: NCT02452047
Recruitment Status : Completed
First Posted : May 22, 2015
Results First Posted : October 19, 2018
Last Update Posted : October 19, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE May 20, 2015
First Posted Date  ICMJE May 22, 2015
Results First Submitted Date  ICMJE July 24, 2018
Results First Posted Date  ICMJE October 19, 2018
Last Update Posted Date October 19, 2018
Actual Study Start Date  ICMJE August 21, 2015
Actual Primary Completion Date September 18, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2018)
  • 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).
  • 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 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 ≥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 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 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.
  • 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 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 20, 2015)
  • Percentage of Participants with a Favorable Overall Response [ Time Frame: Up to Day 28 ]
  • Percentage of Participants with One or More Tier 1 Adverse Event [ Time Frame: Up to Day 35 ]
  • Percentage of Participants with One or More Tier 2 Adverse Event [ Time Frame: Up to Day 35 ]
  • Percentage of Participants with One or More Tier 3 Adverse Event [ Time Frame: Up to Day 35 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2018)
  • Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity [ Time Frame: Up to Day 35 (up to 14 days after completing study treatment) ]
    Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (<1.2 mg/dL) was defined as "doubling of serum creatinine to >1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)".
  • Percentage of Participants With Favorable Clinical Response (FCR) at Day 28 [ Time Frame: Day 28 ]
    The percentage of participants with FCR at Day 28 was determined for Groups 1 and 2. FCR at Day 28 was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
  • Percentage of Participants With All-cause Mortality Up to Day 28 [ Time Frame: Up to Day 28 ]
    The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.
  • Percentage of Participants With FCR on Therapy (OTX) [ Time Frame: OTX (Day 3) ]
    The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
  • Percentage of Participants With FCR at End of Therapy (EOT) [ Time Frame: At EOT (up to Day 21) ]
    The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.
  • Percentage of Participants With FCR at EFU [ Time Frame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]) ]
    The percentage of participants with FCR at EFU was determined for Groups 1 and 2. FCR at EFU was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".
  • Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX [ Time Frame: OTX (Day 3) ]
    The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10^5 colony forming units [CFU]/mL at baseline was reduced to <10^4 CFU/mL at OTX) of the uropathogen".
  • Percentage of cUTI Participants With FMR at EOT [ Time Frame: At EOT (up to Day 21) ]
    The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10^5 CFU/mL at baseline was reduced to <10^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EOT) of the uropathogen".
  • Percentage of cUTI Participants With FMR at EFU [ Time Frame: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]) ]
    The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EFU) of the uropathogen".
Original Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2015)
  • Percentage of Participants with Favorable Clinical Response [ Time Frame: Up to Day 28 ]
  • Percentage of Participants with All-cause Mortality [ Time Frame: Up to Day 28 ]
  • Percentage of Participants with Treatment-emergent Nephrotoxicity [ Time Frame: Day 35 ]
  • Percentage of Participants with Favorable Clinical Response [ Time Frame: Day 3 (On Therapy) ]
  • Percentage of Participants with Favorable Clinical Response [ Time Frame: Up to Day 21 (End of Therapy) ]
  • Percentage of Participants with Favorable Clinical Response [ Time Frame: Up to Day 30 (5 to 9 Days after End of Therapy) ]
  • Percentage of Participants with Favorable Microbiological Response [ Time Frame: Day 3 (On Therapy) ]
  • Percentage of Participants with Favorable Microbiological Response [ Time Frame: Up to Day 21 (End of Therapy) ]
  • Percentage of Participants with Favorable Microbiological Response [ Time Frame: Up to Day 30 (5 to 9 Days after End of Therapy) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013)
Official Title  ICMJE 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
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Bacterial Infections
Intervention  ICMJE
  • Drug: Imipenem+Cilastatin/Relebactam
    Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours
    Other Name: MK-7655A
  • Drug: Colistimethate sodium (CMS)
    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
  • Drug: Imipenem+Cilastatin
    Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours
  • Drug: Placebo to CMS
    Placebo to CMS IV infusion once every 12 hours
Study Arms  ICMJE
  • Experimental: 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.
    Interventions:
    • Drug: Imipenem+Cilastatin/Relebactam
    • Drug: Placebo to CMS
  • Active Comparator: 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.
    Interventions:
    • Drug: Colistimethate sodium (CMS)
    • Drug: Imipenem+Cilastatin
  • Experimental: 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: Drug: Imipenem+Cilastatin/Relebactam
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 27, 2017)
50
Original Estimated Enrollment  ICMJE
 (submitted: May 20, 2015)
64
Actual Study Completion Date  ICMJE September 18, 2017
Actual Primary Completion Date September 18, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Brazil,   Colombia,   Estonia,   Germany,   Greece,   Italy,   Japan,   Korea, Republic of,   Latvia,   Lithuania,   Mexico,   Peru,   Romania,   South Africa,   Turkey,   Ukraine,   United States
 
Administrative Information
NCT Number  ICMJE NCT02452047
Other Study ID Numbers  ICMJE 7655A-013
2015-000066-62 ( EudraCT Number )
163367 ( Registry Identifier: JAPIC-CTI )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP