Clinical trial NCT03940586: Letermovir Treatment in Pediatric Participants Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) (MK-8228-030)
Official 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cytomegalovirus (CMV) Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-05-07
Enrollment: 65
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as Oral Formulation by Ages <2 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Maximal Concentration (Cmax) of Plasma Letermovir Taken as Oral Formulation by Ages 2 - <18 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Cmax of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Cmax of Plasma Letermovir Taken as Oral Formulation by Ages < 2 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Minimum Concentration of Plasma Letermovir Observed Before Next Dose (Ctrough) Taken as Oral Formulation by Ages 2 - <18 Years
timeFrame: Day 7: 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as Oral Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as Oral Formulation by Ages < 2 Years
timeFrame: Day 7: 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as Intravenous (IV) Formulation by Ages 12 - <18 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: AUC0-24 of Plasma Letermovir Taken as IV Formulation by Ages <2 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Concentration at the End of Infusion (Ceoi) of Plasma Letermovir Taken as IV Formulation by Ages 12 - <18 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ceoi of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ceoi of Plasma Letermovir Taken as IV Formulation by Ages s 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ceoi of Plasma Letermovir Taken as IV Formulation by Ages <2 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 12 - <18 Years
timeFrame: Day 7: 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years
timeFrame: Day 7: 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as IV Formulation by Ages 2 to <12 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken as IV Formulation by Ages <2 Years
timeFrame: Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken During Sparse PK for Oral Formulation
timeFrame: Day 7: 24 hours post-dose
measure: Ctrough of Plasma Letermovir Taken During Sparse PK as IV Formulation
timeFrame: Day 7: 24 hours post-dose
Secondary outcomes:
measure: Percentage of Participants With One or More Adverse Event (AE)
timeFrame: Up to Week 48 post-transplant (up to 52 weeks)
measure: Percentage of Participants Who Discontinued Study Medication Due to an AE.
timeFrame: Up to Week 14 post-transplant (up to 18 weeks)
measure: Percentage of Participants With Clinically Significant CMV Infection Through Week 14 Post-transplant
timeFrame: Up to Week 14 post-transplant (up to 18 weeks)
measure: Percentage of Participants With Clinically Significant CMV Infection Through Week 24 Post-transplant
timeFrame: Up to Week 24 post-transplant (up to 28 weeks)
measure: Number of Participants Receiving Oral Granules With Palatability Response, Based on Taste of Medication on the First Day of Administration of Oral Formulation
timeFrame: Day 1 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)
measure: Number of Participants Receiving Oral Granules With Palatability Response, Based on Taste of Medication on the Eighth Day of Administration of Oral Formulation
timeFrame: Day 8 of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center ( Site 0251)
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County ( Site 0241)
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital San Francisco ( Site 0245)
state: California
city: Chicago
country: United States
facility: University Of Chicago School Of Medicine ( Site 0253)
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital ( Site 0243)
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 0254)
state: New York
city: Durham
country: United States
facility: Duke University Health System ( Site 0252)
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center ( Site 0244)
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC ( Site 0258)
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center ( Site 0257)
state: Texas
city: Seattle
country: United States
facility: Seattle Childrens Hospital ( Site 0248)
state: Washington
city: Westmead
country: Australia
facility: The Children s Hospital at Westmead ( Site 0185)
state: New South Wales
city: South Brisbane
country: Australia
facility: Lady Cilento Children s Hospital ( Site 0182)
state: Queensland
city: Parkville
country: Australia
facility: Royal Childrens Hospital Melbourne ( Site 0181)
state: Victoria
city: Medellin
country: Colombia
facility: Instituto De Cancerologia S.A. ( Site 0213)
state: Antioquia
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0212)
state: Valle Del Cauca
city: Cali
country: Colombia
facility: Centro Medico Imbanaco de Cali S.A ( Site 0211)
state: Valle Del Cauca
city: Paris
country: France
facility: Hôpital Universitaire Necker Enfants Malades-, Unite d'Immunologie-Hematologie et Rhumatologie Pedi
city: Frankfurt
country: Germany
facility: Universitaetsklinikum Frankfurt ( Site 0112)
state: Hessen
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster ( Site 0114)
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin Berlin - Campus-Virchow-Klinikum ( Site 0113)
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg-Eppendorf ( Site 0111)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 0121)
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center ( Site 0122)
city: Ramat Gan
country: Israel
facility: Pediatric Hemato Oncology Safra Children's Hospital, Sheba Medical Center ( Site 0123)
city: Saitama
country: Japan
facility: Saitama Children's Medical Center ( Site 0202)
city: Tokyo
country: Japan
facility: National Center for Child Health and Development ( Site 0201)
city: Mexico City
country: Mexico
facility: Instituto Nacional de Pediatria ( Site 0224)
state: Distrito Federal
city: Mexico City
country: Mexico
facility: Hospital Infantil de Mexico ( Site 0221)
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Nuevo Hospital Civil Dr Juan I Menchaca ( Site 0223)
state: Jalisco
city: Monterrey
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 0222)
state: Nuevo Leon
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckieg-Klinika Transplantacji Szpiku, Onkolog
state: Dolnoslaskie
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 1 im. Dr. Antoniego Jurasza w Bydgoszczy ( Site 0141)
state: Kujawsko-pomorskie
city: Barcelona
country: Spain
facility: H. de la Santa Creu I Sant Pau ( Site 0155)
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron ( Site 0154)
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus ( Site 0151)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz ( Site 0153)
city: Adana
country: Turkey
facility: Acibadem Adana Hastanesi ( Site 0162)
city: Antalya
country: Turkey
facility: Akdeniz University Faculty of Medicine ( Site 0161)
city: Izmir
country: Turkey
facility: Ege Univ.Tip Fakultesi Cocuk Has ( Site 0163)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Groll AH, Schulte JH, Antmen AB, Fraser CJ, Teal VL, Haber B, Caro L, McCrea JB, Fancourt C, Patel M, Menzel K, Badshah C. Pharmacokinetics, Safety, and Efficacy of Letermovir for Cytomegalovirus Prophylaxis in Adolescent Hematopoietic Cell Transplantation Recipients. Pediatr Infect Dis J. 2024 Mar 1;43(3):203-208. doi: 10.1097/INF.0000000000004208. Epub 2024 Jan 19.