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)

Cytomegalovirus Infection Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03930615
• Other study ID #: 8228-040
• Secondary ID: MK-8228-04019479
• Status: Completed
• Phase: Phase 3
• Start date: June 21, 2019
• Est. completion date: March 16, 2022

Study information

• Verified date: October 2022
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to evaluate the safety and efficacy of letermovir (LET) versus placebo when cytomegalovirus (CMV) prophylaxis was extended from 100 days to 200 days post-transplant in CMV seropositive participants who received an allogenic hematopoietic stem cell transplant (HSCT). It was 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: March 16, 2022
• Est. primary completion date: October 27, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ex-vivo 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 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

Related Conditions & MeSH terms

• Cytomegalovirus Infection
• Cytomegalovirus Infections
• Infections

Intervention

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).
• Placebo
Placebo was administered as tablets matched to LET or as inactive (saline or dextrose) intravenous infusion.

Locations

Country	Name	City	State
France	CHU Henri Mondor ( Site 0032)	Creteil	Val-de-Marne
France	Centre Hospitalier Universitaire Dupuytren ( Site 0182)	Limoges	Haute-Vienne
France	Hopital Saint Eloi ( Site 0031)	Montpellier	Herault
France	CHU Hopital Saint Antoine ( Site 0036)	Paris
France	Centre Hopitalier Lyon Sud ( Site 0039)	Pierre Benite	Rhone
France	Institut Gustave Roussy ( Site 0038)	Villejuif	Val-de-Marne
Germany	Universitaetsklinikum Heidelberg-Medizinische Klinik V ( Site 0042)	Heidelberg	Baden-Wurttemberg
Germany	Universitaetsklinik Koeln ( Site 0041)	Koeln	Nordrhein-Westfalen
Germany	Universitaetsklinikum Muenster ( Site 0043)	Muenster	Nordrhein-Westfalen
Italy	ASST Spedali Civili di Brescia ( Site 0052)	Brescia	Lombardia
Italy	IRCCS Ospedale San Raffaele ( Site 0051)	Milano
Italy	Fondazione PTV Policlinico Tor Vergata ( Site 0054)	Roma
Italy	Policlinico Umberto I ( Site 0056)	Roma
Italy	Policlinico Universitario Agostino Gemelli ( Site 0055)	Roma
Japan	Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital ( Site 0121)	Hiroshima
Japan	National Hospital Organization Kumamoto Medical Center ( Site 0122)	Kumamoto
Japan	Jichi Medical University Hospital ( Site 0123)	Shimotsuke	Tochigi
United Kingdom	Queen Elizabeth University Hospital [Glasgow, UK] ( Site 0096)	Glasgow	Glasgow City
United Kingdom	1Kings College Hospital ( Site 0091)	London	London, City Of
United Kingdom	UCL Cancer Institute ( Site 0093)	London	London, City Of
United Kingdom	Manchester Royal Infirmary ( Site 0097)	Manchester
United Kingdom	Freeman Hospital Newcastle upon Tyne Foundation NHS Trust ( Site 0092)	Newcastle upon Tyne
United States	Brigham & Women's Hospital ( Site 0161)	Boston	Massachusetts
United States	City of Hope National Medical Center ( Site 0158)	Duarte	California
United States	Duke University Medical Center ( Site 0169)	Durham	North Carolina
United States	John Theurer Cancer Center at Hackensack University Med Ctr ( Site 0174)	Hackensack	New Jersey
United States	The University of Texas MD Anderson Cancer Center ( Site 0154)	Houston	Texas
United States	Indiana Blood and Marrow Transplantation ( Site 0175)	Indianapolis	Indiana
United States	University of Miami, Sylvester Comprehensive Cancer Center ( Site 0160)	Miami	Florida
United States	Memorial Sloan Kettering Cancer Center ( Site 0164)	New York	New York
United States	University of California Davis Medical Center ( Site 0156)	Sacramento	California
United States	Fred Hutchinson Cancer Research Center ( Site 0152)	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Japan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Clinically Significant CMV Infection From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV preemptive therapy (PET) with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the observed failure (OF) approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 28 post-transplant. It was 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.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Percentage of Participants Experiencing =1 Adverse Events (AEs) From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant	An adverse event (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.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Percentage of Participants Withdrawing From Study Drug Due to an AE From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) 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.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 38 Post-transplant	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 38 post-transplant.	From Week 14 post-transplant to Week 38 post-transplant (approximately 24 weeks)
Secondary	Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 48 Post-transplant	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 48 post-transplant.	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
Secondary	Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 28 Post-transplant	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 48 Post-transplant	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data.	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
Secondary	Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 28 Post-transplant	The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 28 post-transplant.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 48 Post-transplant	The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 48 post-transplant.	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
Secondary	Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant	The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 28 was determined.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant	The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 48 was determined.	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
Secondary	Time to All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant	Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data.	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary	Time to All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant	Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data.	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)