Complicated Intra-abdominal Infection, Complicated Urinary Tract Infection
Conditions
Brief summary
The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (IMI/REL, MK-7655A) in Japanese participants with complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI).
Interventions
Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, 30-minute IV infusion once every 6 hours
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* requires hospitalization and treatment with IV antibiotic therapy for complicated intraabdominal infection (cIAI) or complicated urinary tract infection (cUTI). Per-protocol diagnostic criteria apply to the qualifying infection types. * infection is known or thought to be caused by microorganisms susceptible to the IV study therapy * baseline specimen for primary infection site culture obtained at operative procedure in Screening period or at Baseline for cIAI participants, and within 48 hours before initiation of IV study drug for cUTI participants * female or male who is not of reproductive potential, or female or male who is of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner from the time of consent through completion of the study, by practicing abstinence from heterosexual activity or using acceptable contraception during heterosexual activity.
Exclusion criteria
* received any amount of effective antibiotic therapy after obtaining the culture for admission to the study and before administration of the first dose of IV study therapy * received treatment with systemic effective antibiotics for \>24 hours within the 72 hours before initiation of study therapy * has a concurrent infection, including endocarditis, osteomyelitis, meningitis, or prosthetic joint infection, that would interfere with evaluation of response to IMI/REL * has a cIAI or cUTI due to a confirmed fungal pathogen * has a cUTI that 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 indwelling urinary catheter which cannot be removed at study entry * has a cIAI that meets any of the following: 1) infection that should be managed by Staged Abdominal Repair (STAR) or open abdomen therapy, 2) infection limited to the hollow viscus * history of serious allergy, hypersensitivity, or any serious reaction to any carbapenem, cephalosporin, penicillin or other beta-lactam agent, or other beta-lactamase inhibitors * female who is pregnant or is expecting to conceive, is breastfeeding, or plans to breastfeed before completion of the study * history of a seizure disorder * anticipates to be treated with valproic acid, concomitant IV or an oral antimicrobial considered effective to the index pathogen, in addition to the study treatment * is receiving immunosuppressive therapy, including high-dose corticosteroids * is undergoing hemodialysis or peritoneal dialysis * participated in any other clinical study involving an investigational or experimental medication during the previous 30 days before Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing ≥1 Adverse Events (AE) | Up to 28 days | The percentage of participants experiencing ≥1 AE was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined. |
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) | Up to 14 days (End of Therapy Visit) | The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined. |
| Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at End of Therapy Visit | Between Day 5 and Day 14 (End of Therapy Visit) | The percentage of participants with cIAI who display a favorable clinical response at End of Therapy visit was presented. Per protocol, a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because clinical response is primarily relevant to cIAI. Favorable clinical response is a rating of cure or improved as determined by the investigator at the End of Therapy Visit. Cure is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. Improved is defined as: All or most pretherapy signs and symptoms of the index infection(s) have improved or resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. |
| Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at End of Therapy Visit | Between Day 5 and Day 14 (End of Therapy Visit) | The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the End of Therapy visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the End of Therapy Visit showing eradication (e.g., ≥10\^5 CFU/mL is reduced to \<10\^4 CFU/mL) of all uropathogens found at study entry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at Test of Cure Visit | Between Day 10 and Day 23 (Test of Cure Visit) | The percentage of participants with cIAI who display a favorable Clinical Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because the clinical response evaluation is primarily relevant to cIAI. A favorable clinical response is a rating of cure as determined by the investigator at the Test of Cure Visit. Cure is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. |
| Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at Test of Cure Visit | Between Day 10 and Day 23 (Test of Cure Visit) | The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the Test of Cure visit still showing eradication (e.g., ≥10\^5 CFU/mL is reduced to \<10\^4 CFU/mL) of all uropathogens found at study entry. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| cIAI/cUTI Participants with cIAI or cUTI received intravenous imipenem+cilastatin+relebactam once every 6 hours for 5-14 days. | 83 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Screen Failure | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | cIAI/cUTI |
|---|---|
| Age, Continuous | 62.8 Years STANDARD_DEVIATION 18.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Infection Type cIAI | 39 Participants |
| Infection Type cUTI | 44 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 83 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 45 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 81 |
| other Total, other adverse events | 18 / 81 |
| serious Total, serious adverse events | 9 / 81 |
Outcome results
Primary
Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at End of Therapy Visit
The percentage of participants with cIAI who display a favorable clinical response at End of Therapy visit was presented. Per protocol, a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because clinical response is primarily relevant to cIAI. Favorable clinical response is a rating of cure or improved as determined by the investigator at the End of Therapy Visit. Cure is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed. Improved is defined as: All or most pretherapy signs and symptoms of the index infection(s) have improved or resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.
Time frame: Between Day 5 and Day 14 (End of Therapy Visit)
Population: Per protocol, the population analyzed was all participants with cIAI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative enteric and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at End of Therapy Visit | 85.7 Percentage of Participants |
Primary
Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at End of Therapy Visit
The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the End of Therapy visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the End of Therapy Visit showing eradication (e.g., ≥10\^5 CFU/mL is reduced to \<10\^4 CFU/mL) of all uropathogens found at study entry.
Time frame: Between Day 5 and Day 14 (End of Therapy Visit)
Population: Per protocol, the population analyzed was all participants with cUTI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at End of Therapy Visit | 100 Percentage of Participants |
Primary
Percentage of Participants Experiencing ≥1 Adverse Events (AE)
The percentage of participants experiencing ≥1 AE was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
Time frame: Up to 28 days
Population: Per protocol, the population analyzed was all participants who received ≥1 dose of intravenous imipenem+cilastatin+relebactam.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Participants Experiencing ≥1 Adverse Events (AE) | 74.1 Percentage of Participants |
Primary
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
Time frame: Up to 14 days (End of Therapy Visit)
Population: Per protocol, the population analyzed was all participants who received ≥1 dose of intravenous imipenem+cilastatin+relebactam.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) | 4.9 Percentage of Participants |
Secondary
Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at Test of Cure Visit
The percentage of participants with cIAI who display a favorable Clinical Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cIAI were evaluated because the clinical response evaluation is primarily relevant to cIAI. A favorable clinical response is a rating of cure as determined by the investigator at the Test of Cure Visit. Cure is defined as: all pretherapy signs and symptoms of the index infection(s) have resolved (or returned to preinfection status) AND no additional intravenous antibiotic therapy is required AND no unplanned surgical or percutaneous drainage procedures have been performed.
Time frame: Between Day 10 and Day 23 (Test of Cure Visit)
Population: Per protocol, the population analyzed was all participants with cIAI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative enteric and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Complicated Intra-Abdominal Infection (cIAI) Participants With Favorable Clinical Response at Test of Cure Visit | 82.1 Percentage of Participants |
Secondary
Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at Test of Cure Visit
The percentage of participants with cUTI who display a favorable Overall Microbiological Response at the Test of Cure visit was calculated. Per protocol, only a subset of the cIAI/cUTI study arm was analyzed: only participants with cUTI were evaluated because the microbiological response evaluation is primarily relevant to cUTI. A favorable Overall Microbiological Response is defined as a urine culture taken at the Test of Cure visit still showing eradication (e.g., ≥10\^5 CFU/mL is reduced to \<10\^4 CFU/mL) of all uropathogens found at study entry.
Time frame: Between Day 10 and Day 23 (Test of Cure Visit)
Population: Per protocol, the population analyzed was all participants with cUTI who received intravenous imipenem+cilastatin+relebactam ≥96 hours, whose pre-study infection-site culture grew ≥1 gram-negative and/or anaerobic pathogen, and who had no major deviations from the protocol that may substantially affect the results of the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| cIAI/cUTI | Percentage of Complicated Urinary Tract Infection (cUTI) Participants With Favorable Overall Microbiological Response at Test of Cure Visit | 59.0 Percentage of Participants |