| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hospital-Acquired Bacterial Pneumonia / Ventilator-Associated Bacterial Pneumonia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hospital acquired bacterial pneumonia/ ventilator associated bacterial pneumonia |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004051 |
| E.1.2 | Term | Bacterial pneumonia, unspecified |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 the modified intention-to-treat (MITT) population. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate favorable clinical response (CR) rate associated with treatment with IMI/REL compared to treatment with PIP/TAZ in the following visits and analysis populations:
- At the early follow-up (EFU) visit in the MITT population
- At the EFU visit in the clinically evaluable (CE) population
- At the end of treatment (EOT) visit in the MITT population
- At the EOT visit in the CE population
2. To evaluate favorable microbiological response (MR) rate associated with treatment with IMI/REL compared to treatment with PIP/TAZ in the following visits and analysis populations:
- At the EFU visit in the microbiologically evaluable (ME) population
- At the EOT visit in the microbiologically modified intention-to-treat (mMITT) population
- At the EOT visit in the ME population
3. Objective: To evaluate the safety and tolerability profile of IMI/REL compared with PIP/TAZ. |
|
| 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. |
|
| E.3 | Principal inclusion criteria |
1. Require treatment with IV antibiotic therapy for HABP or VABP.
2. Fulfill the clinical and radiographic criteria described below, with onset of criteria occurring after more than 2 days (48 hours) of hospitalization or within 7 days after discharge from a hospital (for HABP) or at least 2 days (48 hours) after mechanical ventilation (for VABP):
(a) Participant has at least one of the following clinical features:
- New onset or worsening pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (eg, respiratory rate greater than 25 breaths per minute), expectorated sputum production, or requirement for mechanical ventilation
- Hypoxemia (eg, a partial pressure of oxygen less than 60 millimeters of mercury while the participant is breathing room air at standard atmosphere pressure, as determined by arterial blood gas [ABG] or worsening of the ratio of the partial pressure of oxygen to the fraction of inspired oxygen [PaO2/FiO2])
- Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure
- New onset of suctioned respiratory secretions
AND
(b) Participant has at least one of the following signs:
- Documented fever (body temperature ≥38 degrees Celsius)
- Hypothermia (body temperature ≤35 degrees Celsius)
- Total peripheral white blood cell (WBC) count ≥10,000 cells/cubic millimeter (mm3)
- Leukopenia with total WBC ≤4,000 cells/mm3
- Greater than 15 percent immature neutrophils (bands) noted on peripheral blood smear
AND
(c) Participant has a chest radiograph showing the presence of a new or progressive infiltrate(s) suggestive of pneumonia.
3. Have an adequate baseline (at or within 2 days [48 hours] of screening) lower respiratory tract specimen obtained for Gram stain and culture.
4. Have an infection known or thought to be, in the opinion of the investigator, caused by microorganisms susceptible to the IV study therapy.
5. 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 and long-term storage.
6. Be between 18 to 75 (inclusive) years of age on the day of signing informed consent.
7. A male participant must agree to use contraception as detailed in the protocol from the time of providing informed consent through completion of the study and refrain from donating sperm during this period.
8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance from the time of providing informed consent through completion of the study.
9. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However the participant may participate in the main study without participating in future biomedical research.
10. If a penicillin skin test is required by local clinical practice, the participant must have a negative skin test result for allergy to penicillin before receipt of first dose of IV study therapy. |
|
| 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 caused by Mycoplasma, Chlamydia, or Legionella, or 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. Including but not limited to:
(1) HIV (AIDS or CD4 <200 cell/mm³),
(2) Chemotherapy was performed within 6 weeks before randomization,
(3) Immunosuppressive therapy, including maintenance glucocorticoid therapy (>40mg/d prednisolone equivalent dose), (4) Neutrophilic granulocyte absolute count<500/mm³.
7. The participant is expected to die during the 7- to 14-day treatment period, despite adequate antibiotic therapy.
8. Has a concurrent condition or infection that, in the investigator’s judgment, would preclude evaluation of therapeutic response (eg, active tuberculosis, cystic fibrosis, granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary infection or endocarditis).
9. Has a history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to any of the following:
- any β-lactams (including PIP/TAZ, carbapenems, cephalosporins, or other β-lactam agents)
- β-lactamase inhibitors (eg, tazobactam, sulbactam, clavulanic acid, avibactam)
10. Has a history of a seizure disorder which has required ongoing treatment with anticonvulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years.
11. Is currently undergoing hemodialysis or peritoneal dialysis.
12. 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 participant’s participation for the full duration of the study, or pose additional risk in administering the study drugs to the participant.
13. A WOCBP who has a positive urine pregnancy test at screening. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; a WOCBP who has a positive serum pregnancy test will be excluded.
14. Has received effective antibacterial drug therapy with known coverage of pathogens that cause HABP/VABP for a continuous duration of more than 48 hours during the previous 72 hours.
15. Is anticipated to be treated with any of the following medications during the course of study therapy:
- valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in the 2 weeks prior to screening)
- serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), or monoamine oxidase inhibitors
- monoamine oxidase inhibitors (MAOIs) (or has used MAOIs during the 2 weeks prior to screening)
- meperidine
- buspirone
- concomitant systemic (IV or oral) antibacterial agents in addition to those designated in the study treatment groups
- concomitant systemic (IV or oral) antifungal or antiviral therapy for the index infection of HABP/VABP
- traditional Chinese medicine or herbal medicine
16. Is currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of the presentation or during the previous 90 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial.
17. Has previously participated in this study at any time.
18. Has an estimated or actual creatinine clearance of <15 mL/min at screening, based on the findings of local laboratory values. Creatinine clearance in mL/min may be calculated from serum creatinine concentration by the Cockcroft-Gault (C-G) equation provided in the Protocol.
19. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Favorable clinical response at end of treatment (EOT) visit
2.Favorable clinical response at early follow-up (EFU) visit
3.Favorable microbiological response at EFU visit.
4.Favorable microbiological response at EOT visit.
5.Adverse Events
6.Discontinuations due to adverse events
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.From treatment Day 7 up to Day 15
2.7-14 days post-EOT (up to Day 28)
3.7-14 days post-EOT (up to Day 28)
4.From treatment Day 7 up to Day 15
5.Up to Day 31
6.Up to Day 14
|
|
| 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 | No |
| 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 | No |
| 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 | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Brazil |
| China |
| France |
| Mexico |
| Philippines |
| Romania |
| Russian Federation |
| Ukraine |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
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