Clinical Trial Results:
Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients with Complicated Urinary Tract Infection
Summary
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EudraCT number |
2011-005707-32 |
Trial protocol |
ES GR LV BG PL |
Global end of trial date |
28 Jul 2015
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Results information
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Results version number |
v2(current) |
This version publication date |
17 Jul 2019
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First version publication date |
16 Jul 2016
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
7655-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01505634 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Merck Registration Number: MK-7655-003 | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme Corp.
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Jul 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Jul 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jul 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The purpose of this study is to evaluate the efficacy, safety and tolerability of adding 125 mg or 250 mg doses of MK-7655 (relebactam) to imipenem/cilastatin in adults 18 years or older with complicated urinary tract infection (cUTI). The primary hypothesis is that the relebactam + imipenem/cilastatin treatment regimen is non-inferior to imipenem/cilastatin with respect to the proportion of participants with a favorable microbiological response at completion of intravenous (IV) study therapy.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
16 May 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 54
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Country: Number of subjects enrolled |
Greece: 3
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Country: Number of subjects enrolled |
Latvia: 46
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Country: Number of subjects enrolled |
Peru: 21
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Country: Number of subjects enrolled |
Poland: 14
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Country: Number of subjects enrolled |
Romania: 63
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Country: Number of subjects enrolled |
Russian Federation: 6
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Country: Number of subjects enrolled |
Korea, Republic of: 5
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Country: Number of subjects enrolled |
Turkey: 27
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Country: Number of subjects enrolled |
Ukraine: 59
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Country: Number of subjects enrolled |
United States: 4
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Worldwide total number of subjects |
302
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EEA total number of subjects |
180
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
180
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From 65 to 84 years |
117
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85 years and over |
5
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants were enrolled with complicated urinary tract infection (cUTI) or acute pyelonephritis judged by the investigator to be serious (requiring hospitalization and intravenous (IV) antibiotic therapy); pyuria; and 1 positive urine culture within 48 hours of enrollment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Relebactam 250 mg with imipenem/cilastatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Relebactam 250 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Relebactam 250 mg IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
imipenem/cilastatin 500 mg
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Investigational medicinal product code |
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Other name |
PRIMAXIN®, TIENAM®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Relebactam 250 mg IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
Ciprofloxacin 500 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500 mg of Ciprofloxacin (as optional oral therapy following minimum duration of IV study drug) twice a day
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Arm title
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Relebactam 125 mg with imipenem/cilastatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
imipenem/cilastatin 500 mg
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Investigational medicinal product code |
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Other name |
PRIMAXIN®, TIENAM®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Relebactam 125 mg IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
Relebactam 125 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Relebactam 125 mg IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
Ciprofloxacin 500 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500 mg of Ciprofloxacin (as optional oral therapy following minimum duration of IV study drug) twice a day
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Arm title
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Placebo for relebactam with imipenem/cilastatin | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
imipenem/cilastatin 500 mg
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Investigational medicinal product code |
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Other name |
PRIMAXIN®, TIENAM®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Matching placebo for relebactam IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
Matching placebo for relebactam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Matching placebo for relebactam IV co-administered with imipenem/cilastatin 500 mg IV every 6 hours for a minimum of 96 hours
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Investigational medicinal product name |
Ciprofloxacin 500 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500 mg of Ciprofloxacin (as optional oral therapy following minimum duration of IV study drug) twice a day
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Baseline characteristics reporting groups
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Reporting group title |
Relebactam 250 mg with imipenem/cilastatin
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Reporting group description |
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Relebactam 125 mg with imipenem/cilastatin
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Reporting group description |
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo for relebactam with imipenem/cilastatin
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Reporting group description |
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Relebactam 250 mg with imipenem/cilastatin
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Reporting group description |
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||
Reporting group title |
Relebactam 125 mg with imipenem/cilastatin
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Reporting group description |
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||
Reporting group title |
Placebo for relebactam with imipenem/cilastatin
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Reporting group description |
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. |
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End point title |
Percentage of Participants with a Favorable Microbiological Response at Completion of IV Study Therapy | ||||||||||||||||
End point description |
Microbiological response (MR) was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as “favorable” if all pathogens isolated from a participant at baseline demonstrated a “favorable” response (eradication) at the time point evaluated. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
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End point type |
Primary
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End point timeframe |
At time of last dose of IV study medication (up to post-randomization day 14)
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Statistical analysis title |
Percent Difference (Diff) in Favorable MR | ||||||||||||||||
Statistical analysis description |
Non-inferiority for the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group was demonstrated if the lower bound of the 95% CI was not lower than the pre-specified non-inferiority margin of -15%.
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Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
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Number of subjects included in analysis |
142
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||
P-value |
= 0.005 | ||||||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-3.1
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-11.2 | ||||||||||||||||
upper limit |
3.2 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Favorable MR | ||||||||||||||||
Statistical analysis description |
Non-inferiority for the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group was demonstrated if the lower bound of the 95% CI was not lower than the pre-specified non-inferiority margin of -15%.
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Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
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Number of subjects included in analysis |
146
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-0.1
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-6.4 | ||||||||||||||||
upper limit |
5.9 |
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End point title |
Percentage of Participants with an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Value That Was ≥ 5X the Upper Limit of Normal (ULN) | ||||||||||||
End point description |
All randomized participants who received ≥1 dose of study treatment had AST and ALT levels measured up to 14 days following completion of all study medication. Participants who had 2 confirmed elevations of either AST or ALT that were 5X ULN or greater were recorded.
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End point type |
Primary
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End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
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Statistical analysis title |
Percent Diff in Number of ECI #1 | ||||||||||||
Statistical analysis description |
Event of Clinical Interest (ECI) #1 is a confirmed elevated AST or ALT ≥5X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group.
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Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
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Number of subjects included in analysis |
199
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.315 | ||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||
Parameter type |
Percent Difference | ||||||||||||
Point estimate |
1
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Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.7 | ||||||||||||
upper limit |
5.5 | ||||||||||||
Statistical analysis title |
Percent Diff in Number of ECI #1 | ||||||||||||
Statistical analysis description |
Event of Clinical Interest (ECI) #1 is a confirmed elevated AST or ALT ≥5X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group.
|
||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.315 | ||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||
Parameter type |
Percent Difference | ||||||||||||
Point estimate |
1
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.7 | ||||||||||||
upper limit |
5.5 |
|
|||||||||||||
End point title |
Percentage of Participants with Elevated AST or ALT Laboratory Values That Were ≥3X the ULN, as Well as Elevated Total Bilirubin ≥2X the ULN, and Alkaline Phosphatase Values <2X the ULN | ||||||||||||
End point description |
All randomized participants who received ≥1 dose of study treatment had AST, ALT, total bilirubin, and Alkaline Phosphatase (ALP) levels measured up to 14 days following completion of all study medication. Participants who had elevations of AST or ALT that were ≥3X ULN, total bilirubin measurements that were ≥2X ULN and, at the same time, an ALP measurement of < 2X ULN were recorded.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Percent Diff in Number of ECI #2 | ||||||||||||
Statistical analysis description |
Event of Clinical Interest (ECI) #2 is elevated AST or ALT ≥3X ULN, elevated total bilirubin ≥2X ULN, and with an ALP <2X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 250 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group.
|
||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [1] | ||||||||||||
P-value |
> 0.999 | ||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||
Parameter type |
Percent Difference | ||||||||||||
Point estimate |
0
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.7 | ||||||||||||
upper limit |
3.8 | ||||||||||||
Notes [1] - There were no participants who met the criteria for ECI #2. |
|||||||||||||
Statistical analysis title |
Percent Diff in Number of ECI #2 | ||||||||||||
Statistical analysis description |
Event of Clinical Interest (ECI) #2 is elevated AST or ALT ≥3X ULN, elevated total bilirubin ≥2X ULN, and with an ALP <2X ULN. Inferential testing for statistical significance with p-values and 95% confidence intervals was performed to provide a comparison between the relebactam 125 mg + imipenem/cilastatin group versus the Placebo for relebactam + imipenem/cilastatin group.
|
||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [2] | ||||||||||||
P-value |
> 0.999 | ||||||||||||
Method |
Miettinen and Nurminen Method | ||||||||||||
Parameter type |
Percent Difference | ||||||||||||
Point estimate |
0
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.7 | ||||||||||||
upper limit |
3.8 | ||||||||||||
Notes [2] - There were no participants who met the criteria for ECI #2. |
|
|||||||||||||||||
End point title |
Percentage of Participants with At Least 1 Adverse Event (AE) | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-1.7
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-14.3 | ||||||||||||||||
upper limit |
10.9 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-0.7
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-13.4 | ||||||||||||||||
upper limit |
12 |
|
|||||||||||||||||
End point title |
Percentage of Participants with Any Serious Adverse Event (SAE) | ||||||||||||||||
End point description |
SAEs were collected on all randomized participants who received ≥1 dose of study treatment. A SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of SAEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-5.8 | ||||||||||||||||
upper limit |
5.9 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of SAEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-2
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-7.6 | ||||||||||||||||
upper limit |
2.8 |
|
|||||||||||||||||
End point title |
Percentage of Participants with Any Drug-related AE | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of DR AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
1.1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-7.5 | ||||||||||||||||
upper limit |
9.8 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of DR AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
0.1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-8.4 | ||||||||||||||||
upper limit |
8.6 |
|
|||||||||||||||||
End point title |
Percentage of Participants with Drug-related Serious AEs | ||||||||||||||||
End point description |
Drug-related SAEs were collected on all randomized participants who received ≥1 dose of study treatment. A serious, drug-related AE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. The SAE was determined to be possibly, probably, or definitely related to the treatment by the investigator. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 42 days following completion of all study therapy (up to 56 days)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of DR SAEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.5 | ||||||||||||||||
upper limit |
4.6 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of DR SAEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-5.5 | ||||||||||||||||
upper limit |
2.8 |
|
|||||||||||||||||
End point title |
Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 14 days
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of Discons Due to AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.4 | ||||||||||||||||
upper limit |
6.8 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of Discons Due to AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
-1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-6.1 | ||||||||||||||||
upper limit |
3.7 |
|
|||||||||||||||||
End point title |
Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | ||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 14 days
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Percent Diff in Number of Discons Due to DR AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.6 | ||||||||||||||||
upper limit |
6.2 | ||||||||||||||||
Statistical analysis title |
Percent Diff in Number of Discons Due to DR AEs | ||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method
|
||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
other | ||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||
Point estimate |
0
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.5 | ||||||||||||||||
upper limit |
4.6 |
|
|||||||||||||||||||||||||||||||||||||
End point title |
Percentage of participants with specific AEs with incidence of ≥4 participants in one treatment group | ||||||||||||||||||||||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Analysis includes specific adverse events with an incidence of ≥4 participants in one treatment group or system organ class. The population analyzed was all randomized participants who received ≥1 dose of study treatment.
|
||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Up to 14 days following completion of all study medication (up to 28 days)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Diarrhoea | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
1.1
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-5.5 | ||||||||||||||||||||||||||||||||||||
upper limit |
7.8 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Diarrhoea | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-2
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-8.1 | ||||||||||||||||||||||||||||||||||||
upper limit |
3.6 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Nausea | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
0
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-6.4 | ||||||||||||||||||||||||||||||||||||
upper limit |
6.5 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Nausea | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
2.1
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-4.6 | ||||||||||||||||||||||||||||||||||||
upper limit |
9.2 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Bacteriuria | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-3
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-9 | ||||||||||||||||||||||||||||||||||||
upper limit |
1.9 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Bacteriuria | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-2
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-8.1 | ||||||||||||||||||||||||||||||||||||
upper limit |
3.6 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: WBC urine positive | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-3
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-9 | ||||||||||||||||||||||||||||||||||||
upper limit |
1.9 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: WBC urine positive | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-3
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-9 | ||||||||||||||||||||||||||||||||||||
upper limit |
1.9 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Headache | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 250 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
3.1
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-3.7 | ||||||||||||||||||||||||||||||||||||
upper limit |
10.4 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Percent Diff in Number of AEs: Headache | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Difference in percentage and 95% CI are based on unconditional and asymptotic Miettinen and Nurminen method.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
Relebactam 125 mg with imipenem/cilastatin v Placebo for relebactam with imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
199
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Percent Difference | ||||||||||||||||||||||||||||||||||||
Point estimate |
-1
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-7.2 | ||||||||||||||||||||||||||||||||||||
upper limit |
5.1 |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Microbiological Response at Completion of IV Study Therapy Who Have Imipenem-resistant, Gram-negative cUTI Infections | ||||||||||||||||
End point description |
Microbiological response was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for imipenem-resistant gram-negative or anaerobic infections at baseline. The overall microbiological response was determined as “favorable” if all pathogens isolated from a participant at baseline demonstrated a “favorable” response (eradication) at the time point evaluated. The analysis included all participants in the ME population with imipenem-resistant gram-negative infections at baseline.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At time of last dose of IV study medication (up to post-randomization day 14)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Microbiological Response at Early Follow-up | ||||||||||||||||
End point description |
Microbiological response was assessed based on results of bacterial cultures obtained up to 9 days following completion of all study medication (IV and oral) relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as “favorable” if all pathogens isolated from a participant at baseline demonstrated a “favorable” response (eradication) at the time point evaluated. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 9 days following completion of all IV and oral study medication (up to Day 23)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Clinical Response at Completion of IV Study Therapy | ||||||||||||||||
End point description |
Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At time of last dose of IV study medication (up to post-randomization day 14)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Clinical Response at Early Follow-up | ||||||||||||||||
End point description |
Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 9 days following completion of all IV and oral study medication (up to Day 23)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Clinical Response at Late Follow-up | ||||||||||||||||
End point description |
Clinical response was assessed as favorable (cured or improved) or unfavorable (failure) relative to baseline. Response determination was based on physical findings including fever (or history of fever), chills or rigors (accompanied by fever), flank pain, costovertebral angle tenderness, dysuria, urinary urgency, urinary frequency, suprapubic or pelvic pain, nausea, or vomiting. Clinical response was assessed in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 42 days following completion of all IV and oral study medication (up to Day 56)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants with a Favorable Microbiological Response at Late Follow-up | ||||||||||||||||
End point description |
Microbiological response was assessed based on results of bacterial cultures obtained up to 42 days following completion of all study medication (IV and oral) relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as “favorable” if all pathogens isolated from a participant at baseline demonstrated a “favorable” response at the time point evaluated. The analysis included all participants in the ME population with non-missing/non-indeterminate response.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 42 days following completion of all IV and oral study medication (up to Day 56)
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 42 days following completion of all study therapy for drug-related serious adverse events (up to 56 days); and up to 14 days following completion of all study therapy for all-cause serious and non-serious adverse events (up to 28 days).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
AEs were reported for the All Participants as Treated Population that included all randomized participants who received ≥ 1 dose of study treatment.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Relebactam 250 mg + imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo + imipenem/cilastatin
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Relebactam 125 mg + imipenem/cilastatin
|
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Reporting group description |
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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25 Oct 2012 |
Protocol Amendment 3 modified the initial inclusion criterion that allowed for inclusion of patients in the study with risk factors for infection with an antibacterial-resistant organism. Additional risk factors for inclusion of these patients were added in this amendment. |
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13 May 2014 |
Protocol Amendment 5 removed the inclusion criteria that allowed for participants in the study based on at least one of three risk factors for infection with an antibacterial-resistant organism. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |