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)

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

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.

Study Overview

• Status: Completed
• Conditions: Prevention of CMV Infection or Disease
• Intervention / Treatment: Drug: Letermovir; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 570
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Letermovir; Letermovir 240 mg / 480 mg tablets, or 240 mg / 480 mg intravenous solution in 250 mL to be infused over 60 minutes.; Other Names: MK-8228
Placebo Comparator: 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.	Drug: Placebo; Placebo tablets, or intravenous solution in 250 mL to be infused over 60 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinically-significant CMV Infection 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.	Up to Week 24 post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at 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.	Up to Week 24 post-transplant
Percentage of Participants With Clinically-significant CMV Infection 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.	Up to Week 14 post-transplant
Percentage of Participants With CMV End-organ Disease 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.	Up to Week 24 post-transplant
Percentage of Participants With CMV End-organ Disease 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.	Up to Week 14 post-transplant
Percentage of Participants With Pre-emptive Therapy for CMV Viremia 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.	Up to Week 14 post-transplant
Percentage of Participants With Pre-emptive Therapy for CMV Viremia 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.	Up to Week 24 post-transplant
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)	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.	Up to Week 24 post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant	An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.	Up to Week 48 post-transplant
Percentage of Participants Discontinued From Study Medication Due to an Adverse Event	An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.	Up to Week 14 post-transplant

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2014
• Primary Completion (Actual): August 8, 2016
• Study Completion (Actual): November 21, 2016

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 12, 2014
• First Posted (Estimate): May 14, 2014

Study Record Updates

• Last Update Posted (Actual): September 11, 2019
• Last Update Submitted That Met QC Criteria: August 29, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Letermovir
• Other Study ID Numbers: 8228-001; 2013-003831-31 (EudraCT Number); 152923 (Registry Identifier: JAPIC-CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No