Clinical trial NCT02137772: Letermovir (MK-8228) Versus Placebo in the Prevention of Clinically-Significant Cytomegalovirus (CMV) Infection in Adult, CMV-Seropositive Allogeneic Hematopoietic Stem Cell Transplant Recipients (MK-8228-001)
Official title: A Phase III Randomized, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-8228 (Letermovir) for the Prevention of Clinically Significant Human Cytomegalovirus (CMV) Infection in Adult, CMV-Seropositive Allogeneic Hematopoietic Stem Cell Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prevention of CMV Infection or Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-05-14
Enrollment: 570
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The study evaluated the efficacy and safety of letermovir (MK-8228) for the prevention of clinically-significant CMV infection in adult, CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT). The hypothesis being tested was that MK-8228 is superior to placebo in the prevention of clinically-significant CMV infection through Week 24 post-transplant.


Eligibility criteria: Inclusion Criteria:

* Has documented seropositivity for CMV within 1 year before hematopoietic stem cell transplant (HSCT)
* Receiving first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant)
* Female or male participant who is not of reproductive potential, or, if of reproductive potential, agrees to true abstinence or to use (or have their partner use) 2 acceptable methods of birth control from the time of consent through 90 days after the last dose of study drug
* Able to read, understand, and complete questionnaires and diaries

Exclusion Criteria:

* Received a previous allogeneic HSCT (previous autologous HSCT is acceptable)
* History of CMV end-organ disease within 6 months before randomization
* Has evidence of CMV viremia (if tested) at any time from either signing of the Informed Consent Form or the HSCT procedure, whichever is earlier, until the time of randomization.
* Received the following within 7 days before screening or plans to receive during the study: ganciclovir, valganciclovir, foscarnet, acyclovir, valacyclovir, or famciclovir
* Received the following within 30 days before screening or plan to receive during the study: cidofovir, CMV hyper-immune globulin, any investigational CMV antiviral agent or biological therapy
* Has suspected or known hypersensitivity to ingredients of MK-8228 (letermovir) formulations
* Has severe hepatic insufficiency within 5 days before randomization
* Has end-stage renal impairment
* Has an uncontrolled infection on the day of randomization
* Requires mechanical ventilation or is hemodynamically unstable at the time of randomization
* Has documented positive results for human immunodeficiency virus (HIV) antibody, hepatitis C virus (HCV) antibody with detectable HCV ribonucleic acid, or hepatitis B surface antigen (HBsAg) within 90 days before randomization
* Has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (for example, lymphoma)
* Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of study drug
* Is expecting to donate eggs or sperm from the time of consent through 90 days after the last dose of study drug
* Has participated in a study with an unapproved investigational compound (monoclonal antibodies are excepted) or device within 28 days of the first dose of study drug
* Has previously participated in a MK-8228 (letermovir) study
* Has, is, or is planning (during the study) to participate in any study involving administration of a CMV vaccine or another CMV investigational agent
* Is a user of recreational or illicit drugs or has a recent history (\<=1 year) of drug or alcohol abuse or dependence

Primary outcomes:
measure: Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant
timeFrame: Up to Week 24 post-transplant
Secondary outcomes:
measure: Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)
timeFrame: Up to Week 24 post-transplant
measure: Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant
timeFrame: Up to Week 14 post-transplant
measure: Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant
timeFrame: Up to Week 24 post-transplant
measure: Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant
timeFrame: Up to Week 14 post-transplant
measure: Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant
timeFrame: Up to Week 14 post-transplant
measure: Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant
timeFrame: Up to Week 24 post-transplant
measure: Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)
timeFrame: Up to Week 24 post-transplant
Other outcomes:
measure: Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant
timeFrame: Up to Week 48 post-transplant
measure: Percentage of Participants Discontinued From Study Medication Due to an Adverse Event
timeFrame: Up to Week 14 post-transplant
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Prohn M, Cho CR, Viberg A, Dykstra K, Davis C, Sabato P, Stone J, Badshah C, Murata Y, Leavitt R, Fancourt C, Macha S. Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients. Clin Pharmacol Ther. 2022 Feb;111(2):485-495. doi: 10.1002/cpt.2456. Epub 2021 Nov 29.
citation: Prohn M, Viberg A, Zhang D, Dykstra K, Davis C, Macha S, Sabato P, de Alwis D, Iwamoto M, Fancourt C, Cho CR. Population pharmacokinetics of letermovir following oral and intravenous administration in healthy participants and allogeneic hematopoietic cell transplantation recipients. CPT Pharmacometrics Syst Pharmacol. 2021 Mar;10(3):255-267. doi: 10.1002/psp4.12593. Epub 2021 Mar 12.
citation: Ljungman P, Schmitt M, Marty FM, Maertens J, Chemaly RF, Kartsonis NA, Butterton JR, Wan H, Teal VL, Sarratt K, Murata Y, Leavitt RY, Badshah C. A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation. Clin Infect Dis. 2020 Apr 10;70(8):1525-1533. doi: 10.1093/cid/ciz490.
citation: Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.