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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)

Primary Purpose

Prevention of CMV Infection or Disease

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Letermovir
Placebo
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Prevention of CMV Infection or Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Letermovir

    Placebo

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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.
    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.
    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.
    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.
    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.
    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.
    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.

    Full Information

    First Posted
    May 12, 2014
    Last Updated
    August 29, 2019
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02137772
    Brief Title
    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

    2. Study Status

    Record Verification Date
    August 2019
    Overall Recruitment Status
    Completed
    Study Start Date
    June 6, 2014 (Actual)
    Primary Completion Date
    August 8, 2016 (Actual)
    Study Completion Date
    November 21, 2016 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Prevention of CMV Infection or Disease

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    570 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Letermovir
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Letermovir
    Other Intervention Name(s)
    MK-8228
    Intervention Description
    Letermovir 240 mg / 480 mg tablets, or 240 mg / 480 mg intravenous solution in 250 mL to be infused over 60 minutes.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Placebo tablets, or intravenous solution in 250 mL to be infused over 60 minutes.
    Primary Outcome Measure Information:
    Title
    Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant
    Description
    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.
    Time Frame
    Up to Week 24 post-transplant
    Secondary Outcome Measure Information:
    Title
    Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)
    Description
    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.
    Time Frame
    Up to Week 24 post-transplant
    Title
    Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant
    Description
    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.
    Time Frame
    Up to Week 14 post-transplant
    Title
    Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant
    Description
    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.
    Time Frame
    Up to Week 24 post-transplant
    Title
    Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant
    Description
    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.
    Time Frame
    Up to Week 14 post-transplant
    Title
    Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant
    Description
    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 Frame
    Up to Week 14 post-transplant
    Title
    Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant
    Description
    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 Frame
    Up to Week 24 post-transplant
    Title
    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)
    Description
    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.
    Time Frame
    Up to Week 24 post-transplant
    Other Pre-specified Outcome Measures:
    Title
    Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant
    Description
    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.
    Time Frame
    Up to Week 48 post-transplant
    Title
    Percentage of Participants Discontinued From Study Medication Due to an Adverse Event
    Description
    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.
    Time Frame
    Up to Week 14 post-transplant

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    34674258
    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.
    Results Reference
    derived
    PubMed Identifier
    33440077
    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.
    Results Reference
    derived
    PubMed Identifier
    31179485
    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.
    Results Reference
    derived
    PubMed Identifier
    29211658
    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.
    Results Reference
    derived

    Learn more about this trial

    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)

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