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Completed

NCT Number: NCT03940586

Letermovir Treatment in Pediatric Participants Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) (MK-8228-030)

The primary objective of this study is to evaluate the pharmacokinetics (PK) of letermovir (LET) in pediatric participants. Participants will be enrolled in the following 3 age groups: Age Group 1: From 12 to <18 years of age (adolescents); Age Group 2: From 2 to <12 years of age (children); and Age Group 3: From birth to <2 years of age (neonates, infants and toddlers). All participants will receive open label LET for 14 weeks (~100 days) post-transplant, with doses based on body weight and age.

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Key information

Conditions

Cytomegalovirus (CMV) Infection Cytomegalovirus Infections DNA Virus Infections Herpesviridae Infections Infections Virus Diseases

Age range

Up to 17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

The Children s Hospital at Westmead ( Site 0185), Westmead, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • All participants 12 to <18 years old must have documented positive CMV serostatus (CMV IgG seropositive) for the recipient (R+) within 90 days prior to enrollment. Participants from birth to <12 years old must have documented positive CMV serostatus (CMV IgG seropositive) for the recipient (R+) within 90 days prior to enrollment and/or the donor (D+); the donor serostatus should be documented within 1 year prior to enrollment.
  • Is the recipient of a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant).
  • Has undetectable CMV DNA from a plasma or whole blood sample collected within 5 days prior to enrollment.
  • Is within 28 days post-HSCT at the time of enrollment.
  • Females are not pregnant, not breastfeeding,and is not a woman of childbearing potential (WOCBP); or is a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 28 days after the last dose of study intervention.
  • Participants from 2 to <18 years of age must not be on concomitant Cyclosporin A (CsA), and must be able to take LET tablets or the oral granules (either by mouth or via G tube/NG tube), provided the participant does not have a condition that may interfere with the absorption of oral medication (e.g. vomiting, diarrhea, or a malabsorptive condition) from the day of enrollment until the intensive PK sampling is completed in these participants.
  • For participants 2 <12 years old their weight should be at least 10 kg; for participants from birth to <2 years old their weight should be at least 2.5 kg and less than or equal to 15 kg at the time of enrollment.

Exclusion criteria

  • Has received a previous allogeneic HSCT (Note: receipt of a previous autologous HSCT is acceptable).
  • Has a history of CMV end-organ disease within 6 months prior to enrollment.
  • Has evidence of CMV viremia at any time from either signing of the ICF or the HSCT procedure, whichever is earlier, until the time of enrollment.
  • Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations.
  • Has severe hepatic insufficiency within 5 days prior to enrollment.
  • Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis) OR b) has end-stage renal impairment.
  • 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 (HIVAb) test at any time prior to enrollment, or for hepatitis C virus antibody (HCV-Ab) with detectable HCV RNA, or hepatitis B surface antigen (HBsAg) within 90 days prior to enrollment.
  • Has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (e.g. lymphomas).
  • Has a preexisting cardiac condition a) for which the patient is currently being treated or b) which required hospitalization within the last 6 months or c) that may be expected to recur during the course of the trial.
  • Has received within 7 days prior to screening any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir; valacyclovir; famciclovir.
  • Has received within 30 days prior to screening of any of the following: cidofovir; CMV immunoglobulin; any investigational CMV antiviral agent/biologic therapy; Rifampin and other strong inducers (such as phenytoin, carbamazepine, St John's wort (Hypericum perforatum), rifabutin and phenobarbital) and moderate inducers such as nafcillin, thioridazine, modafinil and bosentan.
  • Has received LET at any time prior to enrollment in this study.
  • Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing in this study.
  • Has previously participated in this study or any other study involving LET.
  • Has previously participated 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 intervention.
  • Is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study intervention.
  • 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.

Treatment and study plan

Letermovir oral granules

Drug

Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

Other names: MK-8228, AIC246, AIC001

Letermovir tablet

Drug

Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

Other names: MK-8228, AIC246, AIC001

Letermovir intravenous

Drug

Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

Other names: MK-8228, AIC246, AIC001

Primary outcomes

  1. Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Plasma Letermovir Taken as Oral Formulation by Ages 2 - <18 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  2. AUC0-24 of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged <2 and >12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  3. AUC0-24 of Plasma Letermovir Taken as Oral Formulation by Ages <2 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the AUC0-24 of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged 2 - <18 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2.

  4. Maximal Concentration (Cmax) of Plasma Letermovir Taken as Oral Formulation by Ages 2 - <18 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  5. Cmax of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged <2 and >12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  6. Cmax of Plasma Letermovir Taken as Oral Formulation by Ages < 2 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Cmax of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged 2 - <18 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2

  7. Minimum Concentration of Plasma Letermovir Observed Before Next Dose (Ctrough) Taken as Oral Formulation by Ages 2 - <18 Years

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 - <18 years in order to determine the Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  8. Ctrough of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged <2 and >12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  9. Ctrough of Plasma Letermovir Taken as Oral Formulation by Ages < 2 Years

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged 2 - <18 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2.

  10. AUC0-24 of Plasma Letermovir Taken as Intravenous (IV) Formulation by Ages 12 - <18 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  11. AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years and > 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  12. AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2.

  13. AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages <2 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the AUC0-24 of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2.

  14. Concentration at the End of Infusion (Ceoi) of Plasma Letermovir Taken as IV Formulation by Ages 12 - <18 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model .Participants aged < 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  15. Ceoi of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model. Participants aged < 2 years and > 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  16. Ceoi of Plasma Letermovir Taken as IV Formulation by Ages s 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. A measure of dispersion is not determined when N <2.

  17. Ceoi of Plasma Letermovir Taken as IV Formulation by Ages <2 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ceoi of plasma letermovir for participants receiving IV formulation. As samples were collected outside the collection window Ceoi for these samples were predicted by using a log linear model. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. A measure of dispersion is not determined when N <2.

  18. Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 12 - <18 Years

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 12 - <18 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  19. Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged 2 to <12 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged < 2 years and > 12 years were not presented as their data analysis resulted in a different measure type and method of dispersion.

  20. Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure of dispersion is not determined when N <2.

  21. Ctrough of Plasma Letermovir Taken as IV Formulation by Ages <2 Years

    Time frame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose

    Blood was collected on treatment Day 7 from participants aged <2 years in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant. Participants aged > 2 years were not presented as their data analysis resulted in a different measure type and method of dispersion. The measure type is Geometric Mean, and a measure of dispersion is not determined when N <2.

  22. Ctrough of Plasma Letermovir Taken During Sparse PK for Oral Formulation

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 in order to determine the Ctrough of plasma letermovir during sparse PK for participants receiving oral formulation. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant.

  23. Ctrough of Plasma Letermovir Taken During Sparse PK as IV Formulation

    Time frame: Day 7: 24 hours post-dose

    Blood was collected on treatment Day 7 in order to determine the Ctrough of plasma letermovir for participants receiving IV formulation during sparse PK. Individual values were natural log transformed and evaluated separately with a linear mixed effects model containing a fixed effect for treatment and a random effect for participant.

Secondary outcomes

  1. Percentage of Participants With One or More Adverse Event (AE)

    Time frame: Up to Week 48 post-transplant (up to 52 weeks)

    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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The 95% confidence interval (CI) is based on the exact binomial method proposed by Clopper and Pearson.

  2. Percentage of Participants Who Discontinued Study Medication Due to an AE.

    Time frame: Up to Week 14 post-transplant (up to 18 weeks)

    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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The 95% CI is based on the exact binomial method proposed by Clopper and Pearson.

  3. Percentage of Participants With Clinically Significant CMV Infection Through Week 14 Post-transplant

    Time frame: Up to Week 14 post-transplant (up to 18 weeks)

    Clinically significant cytomegalovirus (CMV) infection is defined as CMV end organ disease (proven or probable) or initiation of pre-emptive therapy (PET) based on documented CMV viremia and the clinical condition of the participant. The 95% confidence interval (CI) was based on the exact binomial method proposed by Clopper and Pearson. Missing values: were handled by the Non-Completer=Failure (NC=F) approach. where failure was defined as all participants who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through week 14 post-transplant visit window.

  4. Percentage of Participants With Clinically Significant CMV Infection Through Week 24 Post-transplant

    Time frame: Up to Week 24 post-transplant (up to 28 weeks)

    Clinically significant CMV infection is defined as CMV end organ disease (proven or probable) or initiation of PET based on documented CMV viremia and the clinical condition of the participant. The 95% confidence interval (CI) was based on the exact binomial method proposed by Clopper and Pearson. Missing values: were handled by the Non-Completer=Failure (NC=F) approach. where failure was defined as all participants who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through week 24 post-transplant visit window.

  5. Number of Participants Receiving Oral Granules With Palatability Response, Based on Taste of Medication on the First Day of Administration of Oral Formulation

    Time frame: Day 1 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)

    Palatability was measured by response to a questionnaire on the taste of medication , with responses from very good, good, neither good nor bad, bad or very bad.

  6. Number of Participants Receiving Oral Granules With Palatability Response, Based on Taste of Medication on the Eighth Day of Administration of Oral Formulation

    Time frame: Day 8 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)

    Palatability was measured by response to a questionnaire on the taste of medication , with responses from very good, good, neither good nor bad, bad or very bad.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study title

A Phase 2b Open-label, Single-arm Study to Evaluate Pharmacokinetics, Efficacy, Safety and Tolerability of Letermovir in Pediatric Participants From Birth to Less Than 18 Years of Age at Risk of Developing CMV Infection and/or Disease Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

Important dates

Study start
2019
Primary completion
2023
Study completion
2023
First posted
May 7, 2019
Registry last updated
Aug 22, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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