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)

• ClinicalTrials.gov Identifier: NCT03930615
• Recruitment Status: Recruiting
• First Posted: April 29, 2019
• Last Update Posted: October 10, 2019
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Cytomegalovirus Infection	Drug: Letermovir; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 216 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Letermovir (LET) Prophylaxis When Extended From 100 Days to 200 Days Post-transplant in Cytomegalovirus (CMV) Seropositive Recipients (R+) of an Allogenic Hematopoietic Stem Cell Transplant (HSCT)
• Actual Study Start Date: June 21, 2019
• Estimated Primary Completion Date: June 11, 2022
• Estimated Study Completion Date: July 12, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Letermovir; 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; LET tablet or intravenous infusion at a total daily dose of 240 mg (when given with cyclosporin A) or 480 mg (when given alone).; Other Name: PREVYMIS™, MK-8228
Placebo Comparator: Placebo; Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.	Drug: Placebo; Placebo was administered as tablets matched to LET or as inactive (saline) intravenous infusion.

Outcome Measures

Primary Outcome Measures :

1. Percentage of participants with clinically-significant CMV infection from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant [ Time Frame: From Week 14 (~100 day post-transplant) to Week 28 (up to ~200 days post-transplant) ]
   The percentage of participants with clinically-significant CMV infection from Week 14 to Week 28 will be determined in each arm.

Secondary Outcome Measures :

1. Percentage of participants experiencing ≥1 adverse events (AEs) [ Time Frame: Up to 24 weeks (from Week 14 post-transplant to Week 38 post-transplant) ]
   An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
2. Percentage of participants withdrawing from study drug due to an adverse event (AE) [ Time Frame: Up to 14 weeks (from Week 14 post-transplant to Week 28 post-transplant) ]
   An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
3. Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 38 post-transplant [ Time Frame: Up to 24 weeks (from Week 14 post-transplant to Week 38 post-transplant) ]
   The percentage of participants with clinically-significant CMV infection from Week 14 to Week 38 will be determined in each arm.
4. Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 48 post-transplant [ Time Frame: Up to 34 weeks (from Week 14 post-transplant to Week 48 post-transplant) ]
   The percentage of participants with clinically-significant CMV infection from Week 14 to Week 48 will be determined in each arm.
5. Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 28 post-transplant [ Time Frame: Up to 14 weeks (from Week 14 post-transplant to Week 28 post-transplant) ]
   The time to onset of clinically-significant CMV infection from Week 14 to Week 28 will be determined in each arm.
6. Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 48 post-transplant [ Time Frame: Up to 34 weeks (from Week 14 post-transplant to Week 48 post-transplant) ]
   The time to onset of clinically-significant CMV infection from Week 14 to Week 48 will be determined in each arm.
7. Percentage of participants with pre-emptive therapy (PET) for CMV viremia from Week 14 post-transplant to Week 28 post-transplant [ Time Frame: Up to 14 weeks (from Week 14 post-transplant to Week 28 post-transplant) ]
   The percentage of participants with PET for CMV viremia from Week 14 to Week 28 will be determined in each arm.
8. Percentage of participants with pre-emptive therapy (PET) for CMV viremia from Week 14 post-transplant to Week 48 post-transplant [ Time Frame: Up to 34 weeks (from Week 14 post-transplant to Week 48 post-transplant) ]
   The percentage of participants with PET for CMV viremia from Week 14 to Week 48 will be determined in each arm.
9. Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 28 post-transplant [ Time Frame: Up to 14 weeks (from Week 14 post-transplant to Week 28 post-transplant) ]
   The percentage of participants with all-cause mortality from Week 14 to Week 28 will be determined.
10. Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 48 post-transplant [ Time Frame: Up to 34 weeks (from Week 14 post-transplant to Week 48 post-transplant) ]
    The percentage of participants with all-cause mortality from Week 14 to Week 48 will be determined.
11. Time to all-cause mortality from Week 14 post-transplant to Week 28 post-transplant [ Time Frame: Up to 14 weeks (from Week 14 post-transplant to Week 28 post-transplant) ]
    The time to all-cause mortality from Week 14 to Week 28 will be determined.
12. Time to all-cause mortality from Week 14 post-transplant to Week 48 post-transplant [ Time Frame: Up to 34 weeks (from Week 14 post-transplant to Week 48 post-transplant) ]
    The time to all-cause mortality from Week 14 to Week 48 will be determined.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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 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.

Exclusion Criteria:

• 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 any prohibited medications within 7 days prior to screening
• 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
• is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study therapy
• has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with participant treatment, assessment, or compliance with the protocol as assessed by the investigator
• has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or would be put at undue risk as judged by the investigator, such that it is not in the best interest of the participant to participate in this study

Contacts and Locations

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

Locations

United States, California

City of Hope National Medical Center ( Site 0158); Recruiting

Duarte, California, United States, 91010

Contact: Study Coordinator 626-256-4673

University of California Davis Medical Center ( Site 0156); Recruiting

Sacramento, California, United States, 95817

Contact: Study Coordinator 916-734-8033

United States, Florida

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

Miami, Florida, United States, 33136

Contact: Study Coordinator 305-243-7648

United States, Massachusetts

Brigham & Women's Hospital ( Site 0161); Recruiting

Boston, Massachusetts, United States, 02115

Contact: Study Coordinator 617-525-6778

United States, New Jersey

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

Hackensack, New Jersey, United States, 07601

Contact: Study Coordinator 551-996-8297

United States, New York

Memorial Sloan Kettering Cancer Center ( Site 0164); Recruiting

New York, New York, United States, 10065

Contact: Study Coordinator 212-639-8361

United States, Texas

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

Houston, Texas, United States, 77030

Contact: Study Coordinator 713-792-0007

United States, Washington

Fred Hutchinson Cancer Research Center ( Site 0152); Recruiting

Seattle, Washington, United States, 98109

Contact: Study Coordinator 206-667-6706

France

Centre Hopitalier Lyon Sud ( Site 0039); Recruiting

Pierre Benite, France, 69495

Contact: Study Coordinator +33478862236

Germany

Universitatsklinikum Heidelberg ( Site 0042); Recruiting

Heidelberg, Germany, 69120

Contact: Study Coordinator +496221565514

Universitaetsklinik Koeln ( Site 0041); Recruiting

Koeln, Germany, 50937

Contact: Study Coordinator +4922147886169

Universitaetsklinikum Muenster ( Site 0043); Recruiting

Muenster, Germany, 48149

Contact: Study Coordinator +492518352801

Italy

ASST Spedali Civili di Brescia ( Site 0052); Recruiting

Brescia, Italy, 25123

Contact: Study Coordinator +390303996812

Ospedale San Raffaele ( Site 0051); Recruiting

Milano, Italy, 20132

Contact: Study Coordinator +390226434289

Policlinico Umberto I ( Site 0056); Recruiting

Roma, Italy, 00161

Contact: Study Coordinator +390649974753

Policlinico Universitario Agostino Gemelli ( Site 0055); Recruiting

Roma, Italy, 00168

Contact: Study Coordinator +393355267999

Japan

Jichi Medical University Hospital ( Site 0123); Recruiting

Shimotsuke, Tochigi, Japan, 329-0498

Contact: Study Coordinator +81285442111

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

Hiroshima, Japan, 730-8619

Contact: Study Coordinator +81822413111

National Hospital Organization Kumamoto Medical Center ( Site 0122); Recruiting

Kumamoto, Japan, 860-0008

Contact: Study Coordinator +81963536501

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT03930615 History of Changes
• Other Study ID Numbers: 8228-040; 2018-001038-17 ( EudraCT Number ); MK-8228-040 ( Other Identifier: Merck Sharp & Dohme Corp. ); 194797 ( Registry Identifier: JAPIC-CTI )
• First Posted: April 29, 2019
• Last Update Posted: October 10, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infection; Cytomegalovirus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases