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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)

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

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

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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

Resource links provided by the National Library of Medicine

Drug Information available for: Letermovir

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.




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03930615


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

Locations
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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
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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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    Key Record Dates
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
Cytomegalovirus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases