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)

Phase 3

Completed

• Conditions: Prevention of CMV Infection or Disease
• Interventions: Drug: Placebo; Drug: Letermovir

• Registration Number: NCT02137772
• Lead Sponsor: Merck Sharp & Dohme LLC

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-05-12
• Study First Submitted QC: 2014-05-12
• Study First Posted: 2014-05-14
• Study Start: 2014-06-06
• Primary Completion: 2016-08-08
• Study Completion: 2016-11-21
• Results First Submitted: 2017-10-16
• Results First Submitted QC: 2017-10-16
• Results First Posted: 2017-11-17
• Status Verified: 2019-08
• Last Update Submitted: 2019-08-29
• Last Update Posted: 2019-09-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 570

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.
Letermovir	Letermovir	Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 days post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant	Up to Week 24 post-transplant	Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed.

Secondary Outcome Measures

Name	Time	Method
Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)	Up to Week 24 post-transplant	Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically-significant CMV infection was defined from the day of transplantation to the day the participant developed clinically-significant CMV infection, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not develop clinically-significant CMV infection.
Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant	Up to Week 14 post-transplant	Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed.
Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant	Up to Week 24 post-transplant	CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed.
Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant	Up to Week 14 post-transplant	CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed.
Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant	Up to Week 14 post-transplant	Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed.
Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant	Up to Week 24 post-transplant	Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed.
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)	Up to Week 24 post-transplant	The need for anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The outcome was calculated from the day of transplantation to the start of anti-CMV pre-emptive therapy, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not initiate pre-emptive therapy.