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

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).

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

Conditions
-----------------
Bacterial Infections

Intervention / Treatment
-----------------
* Drug: Imipenem+Cilastatin/Relebactam
* Drug: Colistimethate sodium (CMS)
* Drug: Imipenem+Cilastatin
* Drug: Placebo to CMS


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Imipenem+Cilastatin/Relebactam<br>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<br>* Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours<br>* Other names: MK-7655A;Drug: Placebo to CMS<br>* Placebo to CMS IV infusion once every 12 hours<br>|
| Active Comparator: Group 2: Colistimethate sodium + Imipenem+Cilastatin<br>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)<br>* 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<br>Drug: Imipenem+Cilastatin<br>* Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours<br>|
| Experimental: Group 3: Imipenem+Cilastatin/Relebactam<br>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<br>* Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours<br>* Other names: MK-7655A;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity | 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). | Up to Day 35 (up to 14 days after completing study treatment) | 
| Percentage of Participants With Favorable Clinical Response (FCR) at 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. | Day 28 | 
| Percentage of Participants With All-cause Mortality Up to Day 28 | The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2. | Up to Day 28 | 
| Percentage of Participants With FCR on Therapy (OTX) | 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. | OTX (Day 3) | 
| Percentage of Participants With FCR at End of Therapy (EOT) | 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. | At EOT (up to Day 21) | 
| Percentage of Participants With FCR at EFU | 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. | EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]) | 
| Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX | 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. | OTX (Day 3) | 
| Percentage of cUTI Participants With FMR at EOT | 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. | At EOT (up to Day 21) | 
| Percentage of cUTI Participants With FMR at EFU | 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. | EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT]) |