Extension of Letermovir (LET) From Day 100 to Day 200 Post-transplant for the Prevention of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant (HSCT) Participants (MK-8228-040)

NCT03930615 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 8228-040MK-8228-0401947972018-001038-17
• Study Type: interventional
• Target: 220
• Locations: 6 countries
• Sites: 32

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of letermovir (LET) versus placebo when cytomegalovirus (CMV) prophylaxis was extended from 100 days to 200 days post-transplant in CMV seropositive participants who received an allogenic hematopoietic stem cell transplant (HSCT). It was hypothesized that LET is superior to placebo in the prevention of clinically-significant CMV infection when LET prophylaxis is extended from 100 to 200 days.

Conditions

Cytomegalovirus Infection

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Clinically Significant CMV Infection From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant

  Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV preemptive therapy (PET) with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the observed failure (OF) approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (\~100 days) through week 28 post-transplant. It was hypothesized that LET is superior to placebo in the prevention of clinically significant CMV infection when LET prophylaxis is extended from 100 to 200 days.

  From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Secondary Outcomes (12)

• Percentage of Participants Experiencing ≥1 Adverse Events (AEs) From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant

  From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

• Percentage of Participants Withdrawing From Study Drug Due to an AE From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant

  From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

• Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 38 Post-transplant

  From Week 14 post-transplant to Week 38 post-transplant (approximately 24 weeks)

• Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 48 Post-transplant

  From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

• Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 28 Post-transplant

  From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Study Arms (2)

Letermovir

EXPERIMENTAL

Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

Drug: Letermovir

Placebo

PLACEBO COMPARATOR

Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.

Drug: Placebo

Interventions

Letermovir DRUG

LET tablet or intravenous infusion at a total daily dose of 240 mg (when given with cyclosporin A) or 480 mg (when given alone).

Also known as: PREVYMIS™, MK-8228

Letermovir

Placebo DRUG

Placebo was administered as tablets matched to LET or as inactive (saline or dextrose) intravenous infusion.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• have documented positive CMV serostatus (CMV immunoglobulin G \[IgG\] seropositive) for recipient (R+) at the time of transplant
• has a history of allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant) within \~100 days prior to randomization
• has undetectable CMV deoxyribonucleic acid (DNA) or detectable/not quantifiable CMV DNA from a plasma sample collected within 14 days prior to randomization
• has received LET as primary prophylaxis that started within 28 days of HSCT and continued through Week 14 post-transplant (± 1 week) prior to randomization
• is at high risk of CMV disease, defined as meeting one or more of the following criteria:
• has a related donor with at least 1 mismatch at 1 of the specified 3 human leukocyte antigen (HLA) gene loci (HLA-A, B, or DR)
• has an unrelated donor with at least one mismatch at one of the specified four HLA gene loci (HLA-A, B, C, and DRB1)
• has a haploidentical donor
• has umbilical cord blood as the stem-cell source
• has ex-vivo T-cell-depleted grafts
• has received anti-thymocyte globulin
• has received alemtuzumab
• has graft versus host disease (GVHD) or other conditions, requiring the use of systemic prednisone (or equivalent) at a dose of ≥1 mg/kg of body weight per day within 6 weeks of randomization
• for female participants, is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP) or is a WOBCP who agrees to use acceptable contraception during the treatment period and for ≥28 days after the last dose of study drug.

You may not qualify if:

• has a history of CMV end-organ disease or preemptive treatment therapy for CMV after HSCT prior to randomization
• has a history of \>14 days total of LET interruption during the first 100 days post-transplant prior to randomization
• has suspected or known hypersensitivity to active or inactive ingredients of LET formulations
• has severe hepatic insufficiency defined as Child-Pugh Class C within 14 days prior to randomization.
• has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5× the upper limit of normal (ULN) within 14 days prior to randomization
• has end-stage renal impairment with a creatinine clearance less than 10 mL/min, as calculated by the Cockcroft-Gault equation using serum creatinine within 14 days prior to randomization
• has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency
• has an uncontrolled infection on the day of enrollment
• requires mechanical ventilation or is hemodynamically unstable at the time of enrollment
• has a documented positive result for a human immunodeficiency virus antibody (HIV-Ab) test at any time prior to screening, or for hepatitis C virus antibody (HCV-Ab) with detectable HCV ribonucleic acid (RNA), or hepatitis B surface antigen (HBsAg) within 6 months prior to screening.
• has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (eg, lymphomas)
• has received cidofovir or CMV immunoglobulin with 30 days prior to screening
• is currently participating or has participated in a study with an unapproved investigational compound, monoclonal antibody, or device within 28 days or 5× half-life of the investigational compound or monoclonal antibody, whichever is longer, of initial dosing in this study
• has previously participated in this study or any other study involving LET, or is currently participating in any study involving administration of a CMV vaccine or another CMV investigational agent, or is planning to participate in a study of a CMV vaccine or another CMV investigational agent during the course of this study
• is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 28 days after the last dose of study therapy

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (32)

City of Hope National Medical Center ( Site 0158)

Duarte, California, 91010, United States

Location

University of California Davis Medical Center ( Site 0156)

Sacramento, California, 95817, United States

Location

University of Miami, Sylvester Comprehensive Cancer Center ( Site 0160)

Miami, Florida, 33136, United States

Location

Indiana Blood and Marrow Transplantation ( Site 0175)

Indianapolis, Indiana, 46237, United States

Location

Brigham & Women's Hospital ( Site 0161)

Boston, Massachusetts, 02115, United States

Location

John Theurer Cancer Center at Hackensack University Med Ctr ( Site 0174)

Hackensack, New Jersey, 07601, United States

Location

Memorial Sloan Kettering Cancer Center ( Site 0164)

New York, New York, 10065, United States

Location

Duke University Medical Center ( Site 0169)

Durham, North Carolina, 27710, United States

Location

The University of Texas MD Anderson Cancer Center ( Site 0154)

Houston, Texas, 77030, United States

Location

Fred Hutchinson Cancer Research Center ( Site 0152)

Seattle, Washington, 98109, United States

Location

Centre Hospitalier Universitaire Dupuytren ( Site 0182)

Limoges, Haute-Vienne, 87042, France

Location

Hopital Saint Eloi ( Site 0031)

Montpellier, Herault, 34295, France

Location

Centre Hopitalier Lyon Sud ( Site 0039)

Pierre-Bénite, Rhone, 69495, France

Location

CHU Henri Mondor ( Site 0032)

Créteil, Val-de-Marne, 94110, France

Location

Institut Gustave Roussy ( Site 0038)

Villejuif, Val-de-Marne, 94805, France

Location

CHU Hopital Saint Antoine ( Site 0036)

Paris, 75012, France

Location

Universitaetsklinikum Heidelberg-Medizinische Klinik V ( Site 0042)

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Universitaetsklinik Koeln ( Site 0041)

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Universitaetsklinikum Muenster ( Site 0043)

Münster, North Rhine-Westphalia, 48149, Germany

Location

ASST Spedali Civili di Brescia ( Site 0052)

Brescia, Lombardy, 25123, Italy

Location

IRCCS Ospedale San Raffaele ( Site 0051)

Milan, 20132, Italy

Location

Fondazione PTV Policlinico Tor Vergata ( Site 0054)

Roma, 00133, Italy

Location

Policlinico Umberto I ( Site 0056)

Roma, 00161, Italy

Location

Policlinico Universitario Agostino Gemelli ( Site 0055)

Roma, 00168, Italy

Location

Jichi Medical University Hospital ( Site 0123)

Shimotsuke, Tochigi, 329-0498, Japan

Location

Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital ( Site 0121)

Hiroshima, 730-8619, Japan

Location

National Hospital Organization Kumamoto Medical Center ( Site 0122)

Kumamoto, 860-0008, Japan

Location

Queen Elizabeth University Hospital [Glasgow, UK] ( Site 0096)

Glasgow, Glasgow City, G51 4TF, United Kingdom

Location

1Kings College Hospital ( Site 0091)

London, London, City of, SE5 9RS, United Kingdom

Location

UCL Cancer Institute ( Site 0093)

London, London, City of, WC1E 6BT, United Kingdom

Location

Manchester Royal Infirmary ( Site 0097)

Manchester, M13 9WL, United Kingdom

Location

Freeman Hospital Newcastle upon Tyne Foundation NHS Trust ( Site 0092)

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (2)

• Russo D, Schmitt M, Pilorge S, Stelljes M, Kawakita T, Teal VL, Haber B, Bopp C, Dadwal SS, Badshah C. Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2024 Feb;11(2):e127-e135. doi: 10.1016/S2352-3026(23)00344-7. Epub 2023 Dec 21.

  PMID: 38142695 RESULT

• Dwabe S, Hsiao M, Ali A, Rodman J, Savitala-Damerla L, Nazaretyan S, Kimberly Schiff NP, Tam E, Ladha A, Woan K, Chaudhary P, Yaghmour G. Real world experience: Examining outcomes using letermovir for CMV prophylaxis in high-risk allogeneic hematopoietic stem cell patients in the setting of using T-cell depletion as GVHD prophylaxis. Transpl Immunol. 2023 Feb;76:101769. doi: 10.1016/j.trim.2022.101769. Epub 2022 Dec 2.

  PMID: 36464218 DERIVED

MeSH Terms

Conditions

Cytomegalovirus Infections

Interventions

letermovir

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2019
• First Posted: April 29, 2019
• Study Start: June 21, 2019
• Primary Completion: October 27, 2021
• Study Completion: March 16, 2022
• Last Updated: August 22, 2024
• Results First Posted: November 1, 2022

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

DE (3); FR (6); JP (3); GB (5); US (10); IT (5)