Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Imipenem
Imipenem+ Cilastatin · 3 trials · 4 indications
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.
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.
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.
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.
The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
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).
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.
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.
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.
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.
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.
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| Imipenem+Cilastatin/Relebactam | EXPERIMENTAL | Participants with cIAI or cUTI will receive imipenem+cilastatin/relebactam intravenous (IV) infusion once every 6 hours for 5 to 14 days |
| IMI/REL | EXPERIMENTAL | Imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered intravenously (IV) every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days. |
| PIP/TAZ | ACTIVE_COMPARATOR | Piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days. |
| 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. |
| 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. |
| 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. |
| Name | Type | Description |
|---|---|---|
| Imipenem+Cilastatin/Relebactam | DRUG | Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, 30-minute IV infusion once every 6 hours |
| Imipenem | DRUG | Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days |
| Relebactam | DRUG | Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days |
| Cilastatin | DRUG | Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days |
| Piperacillin | DRUG | Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days |
| Tazobactam | DRUG | Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days |
| Linezolid | DRUG | Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days |
| 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 |
| Imipenem+Cilastatin | DRUG | Imipenem+cilastatin 200 mg to 500 mg, depending on renal function, IV infusion once every 6 hours |
| Placebo to CMS | DRUG | Placebo to CMS IV infusion once every 12 hours |
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 caus...
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