| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| imipenem-resistant bacterial infections, including hospital-associated or ventilator acquired pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI) or complicated urinary tract infection (cUTI). |
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| E.1.1.1 | Medical condition in easily understood language |
| antibiotic-resistant bacterial infections of the lungs, abdomen or urinary tract. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071097 |
| E.1.2 | Term | Beta-lactam antibiotic resistance |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
(1) To estimate the proportion of subjects with favorable overall response to IMI/MK-7655 (Treatment Group 1 only) and to CMS + IMI (Treatment Group 2).
The overall response will be estimated based on the following: (a) survival (based upon all-cause mortality) through Day 28 post-randomization in subjects with HABP/VABP, (b) clinical response at Day 28 post-randomization for subjects with cIAI and (c) the composite clinical and microbiological response at the early follow-up visit, EFU (Day 5 to 9 following completion of therapy) for subjects with cUTI.
(2) To evaluate the safety and tolerability profile of IMI/MK-7655 (Treatment Group 1 only). |
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| E.2.2 | Secondary objectives of the trial |
| (1) To estimate the proportion of subjects with a favorable clinical response to IMI/MK-7655 (Treatment Group 1 only) and CMS + IMI (Treatment Group 2) at Day 28 post-randomization; (2) To estimate the incidence of all-cause mortality through Day 28 post-randomization in Treatment Group 1 (IMI/MK-7655) and in Treatment Group 2 (CMS + IMI); (3) To estimate the proportion of subjects who experience treatment-emergent nephrotoxicity in Treatment Group 1 (IMI/MK-7655) and in Treatment Group 2 (CMS + IMI). Other secondary objective include evaluation of clinical response at various other timepoints during the trial, including on-therapy and post-therapy visits as well as evaluation of microbiological response in subjects with cUTI. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
| Inclusion criteria for the blinded treatment groups (Treatment Groups 1 and 2) are similar to those for the open-label treatment group (Group 3) with the exceptions as noted. Subjects must be adults (>18 yrs) who require hospitalization and IV treatment for a serious bacterial infection with at least one of 3 eligible primary infection sites (HABP/VABP, cIAI and/or cUTI) and who have a culture collected from the primary infection-site within 1 week of study entry showing that at least one of the suspected causative pathogen(s) from that specimen is Gram-negative, imipenem-resistant, imipenem/MK-7655 susceptible, and colistin susceptible (subjects in treatment group 3 must have colistin-resistant rather than colistin-susceptible pathogens). Subjects must also, if of reproductive potential, agree to avoid becoming pregnant or impregnating a partner from the time of consent through completion of the study |
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| E.4 | Principal exclusion criteria |
Exclusion criteria for the blinded treatment groups (Treatment Groups 1 and 2) are similar to those for the open-label treatment group (Group 3) with the exceptions as noted. The subject must be excluded from the trial if the subject has an APACHE II score >30 at screening;has an infection in which any of the causative pathogens are IMI-R Acinetobacter spp., suspected Class B metallo-beta-lactamase-producing bacteria (including NDM-1, IMP or VIM-containing strains, has a concurrent infection that would interfere with evaluation of response to the study antibiotics such asendocarditis, osteomyelitis, meningitis, prosthetic joint infection, active pulmonary tuberculosis or a disseminated fungal infection. A subject is also excluded if he/she has received treatment with any form of systemic colistin for > 24 hours within the 72 hours immediately prior to initiation of study therapy (Group 1 and 2 only, has HABP/VABP caused by an obstructive process, has cUTI with complete obstruction of any portion of the urinary tract, known ileal loop,intractable vesico-ureteral reflux or presence of indwelling urinary catheter which cannot be removed at study entry. Pregnant females as well as subjects with hypersensitivity to any of the study drug, subjects with seizure disorder, with an estimated or actual creatinine clearance of less than 15 mL/min at screening or is undergoing hemodialysis or peritoneal dialysis will be excluded.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint of the study is overall response. As the efficacy in clinical studies is typically measured differently for different infection types, overall response will be estimated based on the following: (a) all-cause mortality through Day 28 post-randomization in subjects with HABP/VABP, (b) clinical response at Day 28 post-randomization for subjects with cIAI and (c) the composite clinical and microbiological response at EFU (Day 5 to 9 following completion of therapy) for subjects with cUTI. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timing is dependent on the subject’s primary infection site. For HABP/VABP and cIAI, it is Day 28 post-randomization and for cUTI it is 5 to 9 days following completion of study therapy. |
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| E.5.2 | Secondary end point(s) |
There are two key secondary measurements for efficacy in this study:
• Clinical response at 28 days following initiation of IV study therapy (through Day 28 post-randomization)
• All-cause mortality within 28 days after initiation of study therapy (through Day 28 post-randomization)
Additional secondary endpoints include the following:
• Clinical response at various other timepoints during the trial, including at Day 3 of study therapy (OTX), End of study therapy (EOT) and EFU.
•Microbiological response in subjects with cUTI will be evaluated at OTX, EOT and at EFU.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Both key secondary endpoints will be evaluated 28 days following randomization. Evaluation of other secondary endpoints is varied and included on Day 3 of study therapy, at the end of study therapy and 5 to 9 days following the end of study therapy. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The trial includes both double-blind and open-label treatment groups. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Brazil |
| Colombia |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| South Africa |
| Turkey |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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