| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cytomegalovirus (CMV) infection in pediatric allogeneic HSCT recipients |
|
| E.1.1.1 | Medical condition in easily understood language |
| CMV (Human cytomegalovirus) infection and disease sometimes develops in HSCT (hematopoietic stem cell transplant) recipients. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011831 |
| E.1.2 | Term | Cytomegalovirus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate letermovir PK in pediatric participants grouped by age. |
|
| E.2.2 | Secondary objectives of the trial |
A) To evaluate the safety and tolerability of treatment with letermovir through Week 48 post-transplant based on the proportion of participants with adverse events.
B) To evaluate the efficacy of letermovir in prevention of clinically significant CMV infection through Week 14 (~100 days) post-transplant and through Week 24 (~6 months) post-transplant.
C) To evaluate the palatability and acceptability of treatment with letermovir oral granules.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. All Age Group 1 participants must have documented positive CMV
serostatus (CMV IgG seropositive) for the recipient (R+) within 90 days
prior to enrollment. Participants in Age Group 2 and 3 must have
documented positive CMV serostatus (CMV IgG seropositive) for the
recipient (R+) within 90 days prior to enrollment and/or for the donor
(D+); the donor serostatus should be documented within 1 year prior to
enrollment.
3. Have undetectable CMV DNA from a plasma or whole blood sample collected within 5 days prior to enrollment.
4. Be within 28 days post-HSCT at the time of enrollment.
5. Participant is aged from birth to <18 years of age at the time of signing the informed consent/assent.
6. A female participant is eligible to participate if she is not pregnant (Appendix 5), not breastfeeding, and at least 1 of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in the protocol.
OR
b. A WOCBP who agrees to follow the contraceptive guidance in the protocol during the treatment period and for at least 28 days after the last dose of study intervention.
7. The participant (or legally acceptable representative) has provided
documented informed consent/assent for the study. The participant or
legally acceptable representative may also provide consent/assent for
FBR. However, the participant may participate in the study without
participating in FBR.
8. Study participants in Panel A of Age Groups 1 and 2 must not be on
concomitant CsA and must be able to take (as assessed by the
investigator) 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 (eg, vomiting,
diarrhea, or a malabsorptive condition) from the day of enrollment until
the intensive PK sampling is completed in these panels (Day 7 Visit).
9. For Age Group 2, the participant's weight should be at least 10 kg; and
for Age Group 3, the participant's weight should be at least 2.5 kg and
less than or equal to 15 kg at the time of enrollment. |
|
| E.4 | Principal exclusion criteria |
1. Received a previous allogeneic HSCT (Receipt of a previous autologous HSCT acceptable).
2. History of CMV end-organ disease within 6 months prior to enrollment.
3. Evidence of CMV viremia at any time from either signing of ICF or HSCT procedure, whichever is earlier, until time of enrollment.
4. Suspected or known hypersensitivity to active or inactive ingredients of LET formulations.
5. Severe hepatic insufficiency (defined as Child-Pugh Class C) within 5 days prior to enrollment.
6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 x the upper limit of normal (ULN) or serum total bilirubin >2.5 x ULN within 5 days prior to enrollment.
7. Is a) on renal replacement therapy (eg, hemodialysis, peritoneal
dialysis)
OR
b) has end-stage renal impairment with a creatinine clearance ≤10
mL/min, as calculated by the Cockcroft-Gault equation (for participants
≥12 years of age) or ≤10 mL/min/1.73 m2 by the modified Schwartz
equation (for participants <12
8. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency.
9. Uncontrolled infection on the day of enrollment.
10. Requires mechanical ventilation or is hemodynamically unstable at the time of enrollment.
11. Has a documented positive result for a 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.
12. Active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (eg, lymphomas).
13. 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. Examples of preexisting cardiac conditions that would preclude enrollment include atrial fibrillation and atrial flutter.
14. Received within 7 days prior to enrollment any of the following -
ganciclovir, valganciclovir, foscarnet, acyclovir (at doses greater than
those recommended for HSV/VZV prophylaxis), valacyclovir (at doses
greater than those recommended for HSV/VZV prophylaxis), famciclovir
15. Received within 30 days prior to enrollment 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.
16. Received letermovir at any time prior to enrollment in this study.
17. 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. Participants previously treated with a monoclonal antibody will be eligible to participate after a 28-day washout period.
18. Previously participated in this study or any other study involving LET.
19. 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.
20. 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.
21. Is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study intervention.
22. 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.
23. History or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or would be put at undue risk as judged by the investigator, such that it is not in the best interest of the participant to participate in this study.
24. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir during intensive PK, for participants receiving oral formulation.
2. Maximal concentration (Cmax) of plasma letermovir during intensive PK, for participants receiving oral formulation.
3. Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving oral formulation.
4. Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir, for participants receiving intravenous (IV) formulation.
5. Concentration of plasma letermovir at the end of infusion (Ceoi), for participants receiving IV formulation.
6. Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving IV formulation.
7. Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving oral formulation.
8. Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving IV formulation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Day 7: Pre-dose, 1, 2. 5, 8, and 24 hours post-dose
2. Day 7: Pre-dose, 1, 2. 5, 8, and 24 hours post-dose
3. Day 7: Pre-dose
4. Weeks 2-14, after 5 consecutive days of administration of IV formulation: Pre-dose, 1, 2. 5, 8, and 24 hours post-dose
5. Weeks 2-14, after 5 consecutive days of administration of IV formulation: 1 hour post-dose
6. Weeks 2-14, after 5 consecutive days of administration of IV formulation: Pre-dose
7. Weeks 2, 4, 6, 8, 12, 14: Pre-dose
8. Weeks 2, 4, 6, 8, 12, 14: Pre-dose
|
|
| E.5.2 | Secondary end point(s) |
1. Percentage of participants with one or more adverse event (AE).
2. Percentage of participants who discontinued study medication due to an AE.
3. Percentage of participants with clinically significant CMV infection (CS-CMVi) through Week 14 post-transplant.
4. Percentage of participants with CS-CMVi through Week 24 post-transplant.
5. Score on a palatability scale for participants receiving oral granules.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to Week 48 post-transplant
2. Up to Week 14 post-transplant
3. Through Week 14 post-transplant
4. Through Week 24 post-transplant
5. On the first and 8th day of administration of oral formulation (up to Week 14 post-transplant)
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Colombia |
| Israel |
| Japan |
| Mexico |
| Turkey |
| United States |
| France |
| Germany |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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