Letermovir Treatment in Pediatric Participants Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) (MK-8228-030)
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Letermovir Letermovir administered either orally or intravenously within 28 days post-transplant, once daily through week 14 (approximately 100 days). Dosing will vary based on age, weight, and whether participant takes cyclosporin A as a concomitant medication. |
Drug: Letermovir oral granules
Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.
Other Names:
Drug: Letermovir tablet
Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.
Other Names:
Drug: Letermovir intravenous
Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Area under the concentration-time curve of plasma letermovir for oral formulation [Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose]
Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir during intensive pharmacokinetics (PK), for participants receiving oral formulation.
- Maximal concentration of plasma letermovir for oral formulation [Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose]
Maximal concentration (Cmax) of plasma letermovir during intensive PK, for participants receiving oral formulation.
- Minimum concentration of plasma letermovir observed before next dose for oral formulation [Day 7: Pre-dose]
Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving oral formulation.
- Area under the concentration-time curve of plasma letermovir for intravenous formulation [After 5 consecutive days of administration of intravenous formulation: Pre-dose, 1, 2.5, 8, and 24 hours post-dose (up to 14 weeks)]
Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir, for participants receiving intravenous (IV) formulation.
- Concentration at the end of infusion of plasma letermovir for IV formulation [After 5 consecutive days of administration of IV formulation: 1 hour post-dose (up to 14 weeks)]
Concentration of plasma letermovir at the end of infusion (Ceoi), for participants receiving IV formulation.
- Minimum concentration of plasma letermovir observed before next dose for IV formulation [After 5 consecutive days of administration of IV formulation: Pre-dose (up to 14 weeks)]
Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving IV formulation.
- Minimum concentration of plasma letermovir observed before next dose during sparse PK for oral formulation [Pre-dose on Weeks 2, 4, 6, 8, 12, 14]
Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving oral formulation.
- Minimum concentration of plasma letermovir observed before next dose during sparse PK for IV formulation [Pre-dose on Weeks 2, 4, 6, 8, 12, 14]
Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving IV formulation.
Secondary Outcome Measures
- Participants with an adverse event [Up to Week 48 post-transplant (up to 52 weeks)]
Percentage of participants with one or more adverse event (AE).
- Participants who discontinued study medication [Up to Week 14 post-transplant (up to 18 weeks)]
Percentage of participants who discontinued study medication due to an AE.
- Participants with clinically significant CMV infection through Week 14 post-transplant [Up to Week 14 post-transplant (up to 18 weeks)]
Percentage of participants with clinically significant CMV infection (CS-CMVi) through Week 14 post-transplant
- Participants with clinically significant CMV infection through Week 24 post-transplant [Up to Week 24 post-transplant (up to 28 weeks)]
Percentage of participants with clinically significant CMV infection (CS-CMVi) through Week 24 post-transplant
- Score on a palatability scale for participants receiving oral granules. [On the first and eighth day of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks)]
Palatability was measured by a facial hedonic scale (FHS), a five point facial expression scale depicting various degrees of pleasure, where a score of 1 indicated disliked very much; ranging to a score of 5 which indicated liked very much.
Eligibility Criteria
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.
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Is the recipient of a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant).
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Has undetectable CMV DNA from a plasma or whole blood sample collected within 5 days prior to enrollment.
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Is within 28 days post-HSCT at the time of enrollment.
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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.
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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.
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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:
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Has received a previous allogeneic HSCT (Note: receipt of a previous autologous HSCT is acceptable).
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Has a history of CMV end-organ disease within 6 months prior to enrollment.
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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.
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Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations.
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Has severe hepatic insufficiency within 5 days prior to enrollment.
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Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis) OR b) has end-stage renal impairment.
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Has both moderate hepatic insufficiency and moderate-to-severe renal insufficiency.
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Has an uncontrolled infection on the day of enrollment.
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Requires mechanical ventilation or is hemodynamically unstable at the time of enrollment.
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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.
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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).
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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.
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Has received within 7 days prior to screening any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir; valacyclovir; famciclovir.
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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.
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Has received LET at any time prior to enrollment in this study.
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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.
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Has previously participated in this study or any other study involving LET.
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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.
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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.
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Is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study intervention.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Comprehensive Cancer Center ( Site 0251) | Duarte | California | United States | 91010 |
| 2 | Children's Hospital of Orange County ( Site 0241) | Orange | California | United States | 92868 |
| 3 | UCSF Benioff Children's Hospital San Francisco ( Site 0245) | San Francisco | California | United States | 94158 |
| 4 | University Of Chicago School Of Medicine ( Site 0253) | Chicago | Illinois | United States | 60637 |
| 5 | Boston Children's Hospital ( Site 0243) | Boston | Massachusetts | United States | 02115-5737 |
| 6 | Memorial Sloan Kettering Cancer Center ( Site 0254) | New York | New York | United States | 10065 |
| 7 | Duke University Health System ( Site 0252) | Durham | North Carolina | United States | 27705 |
| 8 | Cincinnati Children's Hospital Medical Center ( Site 0244) | Cincinnati | Ohio | United States | 45229 |
| 9 | Children's Hospital of Pittsburgh of UPMC ( Site 0258) | Pittsburgh | Pennsylvania | United States | 15224 |
| 10 | Children's Medical Center ( Site 0257) | Dallas | Texas | United States | 75235 |
| 11 | Seattle Childrens Hospital ( Site 0248) | Seattle | Washington | United States | 98105 |
| 12 | The Children s Hospital at Westmead ( Site 0185) | Westmead | New South Wales | Australia | 2145 |
| 13 | Lady Cilento Children s Hospital ( Site 0182) | South Brisbane | Queensland | Australia | 4101 |
| 14 | Royal Childrens Hospital Melbourne ( Site 0181) | Parkville | Victoria | Australia | 3052 |
| 15 | Instituto De Cancerologia S.A. ( Site 0213) | Medellin | Antioquia | Colombia | 050024 |
| 16 | Fundacion Valle del Lili ( Site 0212) | Cali | Valle Del Cauca | Colombia | 760032 |
| 17 | Centro Medico Imbanaco de Cali S.A ( Site 0211) | Cali | Valle Del Cauca | Colombia | 760042 |
| 18 | Hôpital Universitaire Necker Enfants Malades-, Unite d'Immunologie-Hematologie et Rhumatologie Pedi | Paris | France | 75015 | |
| 19 | Universitaetsklinikum Frankfurt ( Site 0112) | Frankfurt | Hessen | Germany | 60590 |
| 20 | Universitaetsklinikum Muenster ( Site 0114) | Muenster | Nordrhein-Westfalen | Germany | 48149 |
| 21 | Charite Universitaetsmedizin Berlin - Campus-Virchow-Klinikum ( Site 0113) | Berlin | Germany | 13353 | |
| 22 | Universitatsklinikum Hamburg-Eppendorf ( Site 0111) | Hamburg | Germany | 20246 | |
| 23 | Rambam Medical Center ( Site 0121) | Haifa | Israel | 3109601 | |
| 24 | Schneider Children's Medical Center ( Site 0122) | Petah Tikva | Israel | 4920235 | |
| 25 | Pediatric Hemato Oncology Safra Children's Hospital, Sheba Medical Center ( Site 0123) | Ramat Gan | Israel | 5265601 | |
| 26 | Saitama Children's Medical Center ( Site 0202) | Saitama | Japan | 330-8777 | |
| 27 | National Center for Child Health and Development ( Site 0201) | Tokyo | Japan | 157-8535 | |
| 28 | Instituto Nacional de Pediatria ( Site 0224) | Mexico City | Distrito Federal | Mexico | 04530 |
| 29 | Hospital Infantil de Mexico ( Site 0221) | Mexico City | Distrito Federal | Mexico | 06720 |
| 30 | Nuevo Hospital Civil Dr Juan I Menchaca ( Site 0223) | Guadalajara | Jalisco | Mexico | 44340 |
| 31 | Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 0222) | Monterrey | Nuevo Leon | Mexico | 66460 |
| 32 | Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckieg-Klinika Transplantacji Szpiku, Onkolog | Wrocław | Dolnoslaskie | Poland | 50-556 |
| 33 | Szpital Uniwersytecki nr 1 im. Dr. Antoniego Jurasza w Bydgoszczy ( Site 0141) | Bydgoszcz | Kujawsko-pomorskie | Poland | 85-094 |
| 34 | H. de la Santa Creu I Sant Pau ( Site 0155) | Barcelona | Spain | 08025 | |
| 35 | Hospital Universitari Vall d Hebron ( Site 0154) | Barcelona | Spain | 08035 | |
| 36 | Hospital Infantil Universitario Nino Jesus ( Site 0151) | Madrid | Spain | 28009 | |
| 37 | Hospital Universitario La Paz ( Site 0153) | Madrid | Spain | 28046 | |
| 38 | Acibadem Adana Hastanesi ( Site 0162) | Adana | Turkey | 01130 | |
| 39 | Akdeniz University Faculty of Medicine ( Site 0161) | Antalya | Turkey | 07070 | |
| 40 | Ege Univ.Tip Fakultesi Cocuk Has ( Site 0163) | Izmir | Turkey | 35040 |
Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 8228-030
- MK-8228-030
- 205242
- 2018-001326-25