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Submitted by: Gladys Joy Martinez 2016-02-22 00:00:00 Last Updated by: Gladys Joy Martinez 2020-07-10 10:02:31


Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014)

PHRR160226-001188

MK7655A-014, 7655A-014; CT.gov: NCT02493764

2015-CT0308

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

This study aims to compare treatment with imipenem/relebactam/cilastatin (IMI/REL) as a fixed-dose combination (FDC) with piperacillin/tazobactam (PIP/TAZ) FDC in participants with hospital-acquired and ventilator-associated bacterial pneumonia. The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the incidence rate of all-cause mortality.   Approximately 536 subjects will be randomized in a 1:1 ratio to one of two treatment arms of the study, Treatment Group 1 (IMI/REL) or Treatment Group 2 (PIP/TAZ). Both treatments will be provided as fixed-dose combinations, administered intravenously (IV) every six hours. After a maximum 48-hour screening period, randomized subjects in each treatment group will receive a minimum of 7 days to up to a maximum of 14 days of IV study therapy. Subjects with evidence of concurrent bacteremia or with P. aeruginosa infection should receive 14 days of IV study therapy. While on IV study therapy, study visits will be performed on Day 1 (randomization), Day 3 (on-therapy visit #1, OTX1), Day 6 (on-therapy visit #2, OTX2), Day 10 (on-therapy visit #3, OTX3, if applicable) and at the end of therapy (EOT). Following the completion of IV study therapy, all subjects will have a study visit 7 to 14 days following completion of therapy (at the early follow-up visit, EFU). In addition, a Day 28 post-randomization visit will be performed in all subjects (this visit may be performed on the same day as the EFU visit, depending on the duration of IV study therapy). All subjects will remain in the study for a total of up to 31 days.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2016-07-02 41 2019-12-02 2019-11-01

Completed

Institution Classification Region LTO #
Merck Sharp & Dohme (I.A.) LLC Private Business NCR CDRR-NCR-S-16
Institution Region
Merck Sharp & Dohme (I.A.) LLC NCR
Name E-Mail Institution and Institution Address
Priscila D. Perez priscila.d.perez@merck.com 26/F Philamlife Tower , 8767 Paseo de Roxas, Makati City, 1226 Philippines
Name E-Mail Institution and Institution Address
Priscila D. Perez priscila.d.perez@merck.com 26/F Philamlife Tower , 8767 Paseo de Roxas, Makati City, 1226 Philippines
Name Expertise Affiliation
Aileen David Wang, MD Internal Medicine - Pulmonary Philippine General Hospital
Arnold Germar, MD Internal Medicine - Pulmonary Veterans Memorial Medical Center
Joven Roque V. Gonong, MD Internal Medicine - Pulmonary Lung Center of the Philippines
Marie Grace Dawn T. Isidro, MD Internal Medicine - Pulmonary West Visayas State University Medical Center
Ronald Allan R. Payumo, MD Internal Medicine - Pulmonary Mary Johnston Hospital
Ronnie Z. Samoro, MD Internal Medicine - Pulmonary West Visayas State University Medical Center
Project Location Institutional Ethics Review Board
Philippine General Hospital Philippine General Hospital Ethics Review Board
Veterans Memorial Medical Center Veterans Memorial Medical Center Ethics Review Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
West Visayas State University Medical Center N/A
Mary Johnston Hospital Mary Johnston Hospital Ethics & Review Committee
West Visayas State University Medical Center N/A

Bacterial Pneumonia

Percentage of participants surviving at Day 28 [ Time Frame: Day 28 ]

Percentage of participants with a favorable clinical response at early follow up visit [ Time Frame: Up to 16 days after end of therapy (up to Day 30) ]

Completed

  • Argentina
  • Australia
  • Brazil
  • Bulgaria
  • Canada
  • Colombia
  • Croatia
  • Czech Republic
  • Estonia
  • France
  • Georgia
  • Germany
  • Guatemala
  • Italy
  • Japan
  • Latvia
  • Lithuania
  • Mexico
  • Norway
  • Peru
  • Philippines
  • Portugal
  • Romania
  • Russia
  • Serbia
  • South Korea
  • Spain
  • Turkey
  • Ukraine
  • United States

Clinical Trial

MK7655A-014, 7655A-014; CT.gov: NCT02493764

DTN 20150720160751 ; DTN 20151126155020 ; DTN 20160504123851 ; DTN 20180918083005

2016-01-26

0000-00-00

30

27

Global recruitment target was achieved earlier than expected and was closed on 6Mar2019.

02 Jul 2016

Inclusion Criteria: •Requires treatment with IV antibiotic therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) •Fulfills clinical and radiographic criteria, with onset of criteria occurring after more than 48 hour of hospitalization or within 7 days after discharge from a hospital (for HABP); or at least 48 hours after mechanical ventilation (for VABP) •Has an adequate baseline lower respiratory tract specimen obtained for Gram stain and culture •Has an infection known or thought to be caused by microorganisms susceptible to the IV study therapy •Agrees 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 •Is not of reproductive potential; or if of reproductive potential agrees to avoid impregnating a partner or avoid becoming pregnant, by practicing abstinence or using acceptable contraception Exclusion Criteria: •Has a baseline lower respiratory tract specimen Gram stain that shows the presence of Gram-positive cocci only •Has confirmed or suspected community-acquired bacterial pneumonia (CABP) •Has confirmed or suspected pneumonia of viral, fungal or parasitic origin •Has HABP/VABP caused by an obstructive process, including lung cancer or other known obstruction •Has a carcinoid tumor or carcinoid syndrome •Has active immunosuppression defined as either receiving immunosuppressive medications or having a medical condition associated with immunodeficiency •Is expected to survive for less than 72 hours •Has a concurrent condition or infection that would preclude evaluation of therapeutic response •Has received effective antibacterial drug therapy for the index infection of HABP/VABP for more than 24 hours continuously, during the previous 72 hours •Has a history of serious allergy, hypersensitivity or a serious reaction to any penicillin or beta-lactamase inhibitors •Female is pregnant, expecting to conceive, is breastfeeding or plans to breastfeed •Has a history of seizure disorder requiring ongoing prior treatment with anti-convulsive therapy within the last 3 years •Anticipates treatment with the following: valproic acid or divalproex sodium, serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin receptor antagonists, meperidine, buspirone, concomitant systemic antibacterial agents, antifungal or antiviral therapy for the index infection of HABP/VABP •Is currently undergoing hemodialysis or peritoneal dialysis •Is currently participating in, has participated in during the previous 30 days, or anticipates to participate in any other clinical study involving the administration of experimental medication •Has previously participated in this study

Interventional

• Drug: Imipenem 500 mg as part of a FDC • Drug: Relebactam 250 mg as part of a FDC • Drug: Cilastatin 500 mg as part of a FDC • Drug: Piperacillin 4000 mg as part of a FDC • Drug: Tazobactam 500 mg as part of a FDC • Drug: Linezolid 600 mg administered open-label

• Drug: ImipenemImipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days• Drug: RelebactamRelebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days• Drug: CilastatinCilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days• Drug: PiperacillinPiperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days• Drug: TazobactamTazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days• Drug: LinezolidLinezolid 600 mg administered open-label by IV every 12 hours for up to 14 daysExperimental: IMI/RELImipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered intravenously (IV) every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.Interventions:◦ Drug: Imipenem◦ Drug: Relebactam◦ Drug: Cilastatin◦ Drug: Linezolid• Active Comparator: PIP/TAZPiperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.Interventions:◦ Drug: Piperacillin◦ Drug: Tazobactam◦ Drug: Linezolid

Date Amendment Classification Reason
2016-06-08 Amendments related to the protocol Primary reasons for this amendment include: 1. Section 5.1.3: a. Exceptions under Exclusion Criterion #9 were added. This change was made to provide clarification for what defines effective antibacterial treatment versus a treatment failure. B. Added monoamine oxidase inhibitors (MAOIs) to the list of prohibited medications in Exclusion #13. MAOIs were inadvertently omitted as a class of prohibited medications in the protocol. The prohibition of MAOIs had been included in the informed consent form, but the protocol is now being updated to reflect this as well. 2. Section 7.1.1.5.1: Added the corresponding text per the update to Exclusion Criterion #9 above. This is in support of the added exceptions to Exclusion Criterion #9 above. Additional Changes for this amendment: 1. Section 5.1.2: Added language to the “NOTE” under Inclusion Criterion #4 regarding lower respiratory tract specimens and adequacy of the Gram stain. Updated for clarity. 2. Section 5.5: Added guidance on timing for prohibited concomitant medications. Updated for clarity regarding medications prohibited due to a drug interaction with linezolid. 3. Section 6.0: Updated footnotes f, g, h, j, n, q, s, and t. Each footnote was updated for clarity. Added footnote w. “Register completion of EOT, EFU, and Day 28 visits in IVRS.” Included for clarity. 4. Section 7.1.2.4, 7.1.2.5: Added language on timing of assessment at randomization (Visit 2). Updated for clarity." 5. Section 7.1.2.6: Added clarification on definition of serious adverse events considered by the investigator to be “possibly, probably, or definitely related” related to study drug. Updated for clarity. 6. Section 7.1.3.2.1: Added language regarding lower respiratory tract specimens and adequacy of the Gram stain as per Inclusion Criterion #4. Updated for clarity. 7. Section 7.1.3.2.3: Added language for consistency regarding Microbiology Central Laboratory. Updated for clarity. 8. Section 7.1.3.3. Added language on timing of PK sampling at the post- randomization visits on Day 3 and Day 6. Added language to allow flexibility of PK sampling on Day 3 and Day 6. 9. Section 7.1.5.2: Added clarification regarding OTX3 and EOT visits for subjects that end treatment on Day 10. Updated for clarity. 10. Section 8.1: Changed “clinical response” to “favorable clinical response.” Updated for clarity. 11. Section 8.2: Changed wording to “Modeling and Simulation (M&S) Analysis” and corrected some grammatical errors in this section. 12. Section 8.6.1: Updated the reference number in footnote 1 of Table 13. Corrected typographical error. 13. Section 8.6.2: Changed wording to “Membership in Tier 2 requires … at least one treatment group exhibit the event.” The same change was made in Table 14. Changed wording to “In addition, summary statistics for the difference between treatment groups will also be provided."" Modified as the Tier 3 safety parameter summary does not need to provide p-value. 14. Section 8.6.3: Updated the language regarding the use of “descriptive” statistics. Updated for clarity. 15. Section 8.10: Clarified that subgroup analysis will be based on “Pneumonia type at baseline (non-ventilated HABP, ventilated HABP/VABP).” Updated for clarity. 16. Section 9.1: Added optional template text regarding locally sourced products in the study. This text was inadvertently deleted during authoring. It is relevant to the study and should be included. 17. Appendix 12.5: Corrected several typographical errors as follows: A. Acute Physiology Score: • Serum HCO3 - High abnormal range +4:≧ 52; • Respiratory rate - Low abnormal range +4:≦ 5; • Oxygenation FiO2 ≧ 0.5; • Serum Potassium - High abnormal range +1: 5.5-5.9 B. Age Points:Age: • ≦44 • ≧75 18. Appendix 12.6: Corrected several typographical errors as follows: Temperature (oC): ≥39.0 or ≤36.5. White Blood Cell (WBC) Count (X 109/L): <4,000 or >11,000
2018-11-20 Amendments related to the protocol Primary reasons for amendment 04 include: 1. Sections 4.2.3.1.1.3 Microbiological Response, and 8.6.1 Statistical Methods for Efficacy Analyses: Added a fifth Indeterminate response option: e) No specimen taken because subject is deemed clinically cured or improved. Added/edited associated footnotes b and c linking this new indeterminate response category to “Presumed Eradication” in Tables 5 and 6 Definitions of Microbiological Response at the End-of-Therapy (EOT) and Early Follow-up (EFU) Visits, respectively, and added text description of this option for the efficacy analyses. This update is in alignment with the way the data are already being collected in the study. Rationale: This change was made to provide an additional option of indeterminate microbiological response so that a “presumed eradication” outcome may be derived based on patients who are clinically cured or improved and from whom a respiratory specimen could not be obtained. The outcome of “presumed eradication” will be considered a favorable overall microbiological response in the efficacy analyses. Additional Changes for amendment 04: 1. Sections 2.1, 5.4, 7.1.1.7, 8.1: The randomization requirement was modified to allow for “approximately” 50% of subjects with ventilated HABP or VABP. Rationale: This change was made to allow flexibility in the number and proportion of ventilated HABP or VABP subjects randomized. 2. Section 5.1.3: Added list of acceptable Gram stain patterns to clarify what constitutes an exclusionary pattern. Added a note clarifying that the use of seizure prophylaxis among patients with no active or prior history of seizure disorder is acceptable for the specified uses, considering Exclusion #12. Rationale: These clarifications were added to better define these exclusion criteria. 3. Section 5.5: Clarified that medications specifically prohibited in the protocol are not allowed during IV study therapy, rather than during the whole study. Rationale: This text was updated to align with current Merck standard protocol template. 4. Sections 6.0, 7.1.3.3: Clarified the timing of PK sampling to post-“start of” Dose 3. Rationale: This text was added to clarify PK sample collection timing relative to the start of infusion. 5. Section 7.1.3.2.2: Removed the acceptable sputum sample criterion for post-baseline specimens of “greater than 25 neutrophils on low power microscopy review of the Gram stain”. Rationale: This text was removed; it had been included in error in the previous protocol version. 8. Section 12.6: Upper limit of Temperature parameter corrected to ≤36.0. Rationale: This edit was made to correct the typographical error in the previous protocol versions.

Randomized

Double Blind

Double Blind (Participant, Investigator)

Parallel

Treatment

Phase III

Utilization Utilization Info
Publication
Oral Presentation
Drug Literature
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For updates, please refer to ClinicalTrials.gov data:
https://www.clinicaltrials.gov/ct2/show/record/NCT02493764?cond=NCT02493764&rank=1&view=record

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