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)

NCT02137772 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: 8228-0012013-003831-31152923
• Study Type: interventional
• Target: 570
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Prevention of CMV Infection or Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• 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

• Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant

  Up to Week 14 post-transplant

• Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant

  Up to Week 24 post-transplant

• Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant

  Up to Week 14 post-transplant

• Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant

  Up to Week 14 post-transplant

Other Outcomes (2)

• Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant

  Up to Week 48 post-transplant

• Percentage of Participants Discontinued From Study Medication Due to an Adverse Event

  Up to Week 14 post-transplant

Study Arms (2)

Letermovir

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Letermovir DRUG

Letermovir 240 mg / 480 mg tablets, or 240 mg / 480 mg intravenous solution in 250 mL to be infused over 60 minutes.

Also known as: MK-8228

Letermovir

Placebo DRUG

Placebo tablets, or intravenous solution in 250 mL to be infused over 60 minutes.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (4)

• 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.

  PMID: 34674258 DERIVED

• 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.

  PMID: 33440077 DERIVED

• 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.

  PMID: 31179485 DERIVED

• 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.

  PMID: 29211658 DERIVED

MeSH Terms

Conditions

Disease

Interventions

letermovir

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2014
• First Posted: May 14, 2014
• Study Start: June 6, 2014
• Primary Completion: August 8, 2016
• Study Completion: November 21, 2016
• Last Updated: September 11, 2019
• Results First Posted: November 17, 2017

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will share