E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment for hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
To determine the incidence rate of all-cause mortality through Day 28 post-randomization associated with treatment with IMI/REL compared to treatment with PIP/TAZ in subjects diagnosed with HABP/VABP in the modified intention-to-treat (MITT) population.
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of IMI/REL versus PIP/TAZ with respect to clinical response at the early follow-up (EFU) visit 7 to 14 days after the end of therapy (EOT) for subjects diagnosed with HABP/VABP in the MITT population.
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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 |
A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects with Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia (Future Biomedical Research).
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 |
1. be ≥ 18 years of age on the day of signing informed consent.
2. require treatment with IV antibiotic therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP).
3. fulfill the clinical and radiographic criteria (detailed in the protocol) with onset of criteria occurring after more than 48 hours of hospitalization or within 7 days after discharge from a hospital (for HABP) or at least 48 hours after mechanical ventilation (for VABP): Refer to protocol for defining clinical features.
4. have a baseline (at or within 48 hours of screening) lower respiratory tract specimen obtained for Gram stain and culture.
5. have an infection known or thought to be, in the opinion of the investigator, caused by microorganisms susceptible to the IV study therapy.
6. agree to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided to the Central Microbiology Reference Laboratory for study-related microbiological testing, long-term storage, and other future testing.
7. understand (or have a legal representative that understands) the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agree to participate by giving written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
8. if male or female of childbearing potential, use appropriate contraception (refer to protocol for contraception guidance details). |
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E.4 | Principal exclusion criteria |
1.has a baseline lower respiratory tract specimen Gram stain that shows the presence of gram-positive cocci only.
2. has confirmed or suspected community-acquired bacterial pneumonia (CABP).
3. has confirmed or suspected pneumonia of viral, fungal, or parasitic etiology.
4. has HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction.
5. has a carcinoid tumor or carcinoid syndrome.
6. has active immunosuppression, defined as either receiving immunosuppressive medications or having a medical condition associated with immunodeficiency.
7. is expected to survive < 72 hours.
8. has a concurrent condition or infection that, in the investigator’s judgment, would preclude evaluation of therapeutic response (e.g. active tuberculosis, cystic fibrosis, granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary infection or endocarditis).
9. has received effective antibacterial drug therapy for the index infection of HABP/VABP for a continuous duration of more than 24 hours during the previous 72 hours.
10. a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to any of the following: any penicillin or β-lactamase inhibitors.
11. is a female who is pregnant or is expecting to conceive (or is a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed prior to completion of the study.
12. has a history of a seizure disorder which has required ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years.
13. is anticipated to be treated with any of the following medications during the course of study therapy: refer to protocol for list on concomitant meds
14. has an estimated or actual creatinine clearance of < 15 mL/min at screening, based on the findings of local laboratory values.
15. is currently undergoing hemodialysis or peritoneal dialysis.
16. has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that, in the opinion of the investigator, might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or pose additional risk in administering the study drugs to the subject.
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E.5 End points |
E.5.1 | Primary end point(s) |
Survival/All-cause Mortality: Survival status (i.e., whether the subject is alive or dead) through Day 28 post-randomization and EFU visits will be evaluated for all subjects in support of the primary and key secondary objectives, respectively. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Survival/All-cause Mortality: Day 28. |
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E.5.2 | Secondary end point(s) |
Clinical response will be assessed for all subjects based on evaluation by the investigator at the OTX1, OTX2, OTX3 (if applicable), EOT, EFU, and Day 28 post-randomization visits. Microbiological response will be evaluated separately for each lower respiratory tract pathogen isolated in the baseline culture (i.e., by-pathogen). The by-pathogen response rating determined by the investigator will be assessed based on local laboratory results. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Clinical response: OTX1, OTX2, OTX3 (if applicable), EOT, EFU, and Day 28 post-randomization visits.
2. Microbiological response: EOT & EFU.
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Bulgaria |
Canada |
Colombia |
Croatia |
Czech Republic |
Estonia |
France |
Georgia |
Germany |
Guatemala |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lithuania |
Mexico |
Norway |
Peru |
Philippines |
Portugal |
Romania |
Russian Federation |
Serbia |
Spain |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |