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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)

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ClinicalTrials.gov Identifier: NCT02137772
Recruitment Status : Completed
First Posted : May 14, 2014
Results First Posted : November 17, 2017
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE May 12, 2014
First Posted Date  ICMJE May 14, 2014
Results First Submitted Date  ICMJE October 16, 2017
Results First Posted Date  ICMJE November 17, 2017
Last Update Posted Date October 25, 2018
Actual Study Start Date  ICMJE June 6, 2014
Actual Primary Completion Date August 8, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2017)
Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 12, 2014)
Percentage of Participants with Clinically-Significant CMV Infection [ Time Frame: Up to 24 weeks after transplant ]
Change History Complete list of historical versions of study NCT02137772 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2017)
  • Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2014)
  • Time to Onset of Clinically-Significant CMV Infection [ Time Frame: Up to 24 weeks after transplant ]
  • Percentage of Participants with Clinically-Significant CMV Infection [ Time Frame: Up to 14 weeks after transplant ]
  • Percentage of Participants with CMV Disease [ Time Frame: Up to 14 weeks after transplant ]
  • Percentage of Participants with CMV Disease [ Time Frame: Up to 24 weeks after transplant ]
  • Percentage of Participants with Pre-emptive Therapy for CMV Viremia [ Time Frame: Up to 14 weeks after transplant ]
  • Percentage of Participants with Pre-emptive Therapy for CMV Viremia [ Time Frame: Up to 24 weeks after transplant ]
  • Time to Initiation of Pre-emptive Therapy for CMV Viremia [ Time Frame: Up to 24 weeks after transplant ]
Current Other Pre-specified Outcome Measures
 (submitted: October 16, 2017)
  • Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant [ Time Frame: 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.
  • Percentage of Participants Discontinued From Study Medication Due to an Adverse Event [ Time Frame: Up to Week 14 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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Prevention of CMV Infection or Disease
Intervention  ICMJE
  • 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 Name: MK-8228
  • Drug: Placebo
    Placebo tablets, or intravenous solution in 250 mL to be infused over 60 minutes.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Letermovir
  • 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.
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 7, 2016)
570
Original Estimated Enrollment  ICMJE
 (submitted: May 12, 2014)
540
Actual Study Completion Date  ICMJE November 21, 2016
Actual Primary Completion Date August 8, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Austria,   Belgium,   Brazil,   Canada,   Finland,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Lithuania,   New Zealand,   Peru,   Poland,   Romania,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02137772
Other Study ID Numbers  ICMJE 8228-001
2013-003831-31 ( EudraCT Number )
152923 ( Registry Identifier: JAPIC-CTI )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP