| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cytomegalovirus (CMV) infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cytomegalovirus (CMV) is a common virus in the herpes family of viruses that can infect anyone. CMV disease is a common complication in patients receiving stem cell transplants, which could be fatal |
|
| 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 |
| 1. To evaluate the efficacy of letermovir (LET) versus placebo in the prevention of clinically significant cytomegalovirus (CMV) infection when LET prophylaxis is extended from 100 to 200 days post-transplant |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of LET versus placebo when LET prophylaxis is extended from 100 to 200 days post-transplant based on the proportion of participants with adverse events from Week 14 post-transplant through Week 28 post-transplant.
2. To evaluate the efficacy of LET versus placebo when LET prophylaxis is extended from 100 to 200 days post-transplant as measured by:
A) Clinically significant CMV infection;
B) Initiation of anti-CMV pre-emptive therapy (PET) for documented CMV infection;
C) All-cause mortality.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant has documented positive CMV serostatus (CMV IgG seropositive) for recipient (R+) at the time of transplant.
2. Participant has history of allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant) within ~100 days prior to randomization.
3.Participant has undetectable CMV DNA or detectable/not quantifiable CMV DNA (central laboratory) from a plasma sample collected within 14 days prior to randomization.
4. Participant has received LET as primary prophylaxis that started within 28 days of HSCT and continued through Week 14 post-transplant (100 days) ± 1 week prior to randomization.
5.Participant is at high risk of CMV disease, defined as meeting one or more of the following criteria:
a. having a related donor with at least one mismatch at one of the specified three HLA gene loci (HLA-A, B, or DR);
b. having an unrelated donor with at least one mismatch at one of the specified four HLA gene loci (HLA-A, B, C, and DRB1);
c. having a haploidentical donor;
d. having umbilical cord blood as the stem-cell source;
e. having ex-vivo T-cell–depleted grafts;
f. receipt of anti-thymocyte globulin;
g. receipt of alemtuzumab;
h. having GVHD or other conditions, requiring the use of systemic prednisone (or equivalent) at a dose of ≥1 mg/kg of body weight per day within 6 weeks of randomization.
Demographics
6. Participant is ≥18 years of age at the time of signing the informed consent.
Female Participants
7. 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 Appendix 5.
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 28 days after the last dose of study medication.
Informed Consent
8. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. Participant has a history of CMV end-organ disease or preemptive treatment therapy for CMV after HSCT prior to randomization.
2. Participant has a history of >14 days total of LET interruption during the first 100 days post-transplant prior to randomization
3.Participant has suspected or known hypersensitivity to active or inactive ingredients of LET formulations.
4. Participant has severe hepatic insufficiency defined as Child-Pugh Class C within 14 days prior to randomization.
5. Participant has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5× the upper limit of normal (ULN) within 14 days prior to randomization.
6. Participant has end-stage renal impairment with a creatinine clearance less than 10 mL/min, as calculated by the Cockcroft-Gault equation using serum creatinine within 14 days prior to randomization
7. Participant has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency.
8. Participant has an uncontrolled infection on the day of enrollment.
9. Participant requires mechanical ventilation or is hemodynamically unstable at the time of enrollment.
10. Participant has a documented positive result for an human immunodeficiency virus antibody (HIV-Ab) test at any time prior to screening, or for hepatitis C virus antibody (HCV-Ab) with detectable HCV RNA, or hepatitis B surface antigen (HBsAg) within the 6 months prior to screening.
11. Participant has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer
Prior/Concomitant Therapy
12. Received within 7 days prior to screening any of the following:
- ganciclovir or 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 (at doses greater than those recommended for HSV/VZV prophylaxis;
13. Participant received within 30 days prior to screening any of the following:
- cidofovir
- CMV immunoglobulin
Prior/Concurrent Clinical Study Experience
14. Participant is currently participating or has participated in a study with an unapproved investigational compound, monoclonal antibody, or device within 28 days or 5× half-life of the investigational compound or monoclonal antibody, whichever is longer, of initial dosing in this study.
15. Participant has previously participated in this study or any other study involving LET, 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.
Other Exclusions
16. Participant 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 therapy.
17. Participant is expecting to donate eggs or sperm starting from the time of consent through 28 days after the last dose of study therapy.
18. Participant 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.
19. Participant has a 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.
20. 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. Percentage of participants with clinically significant CMV infection from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to Week 28 (up to approximately 200 days) |
|
| E.5.2 | Secondary end point(s) |
1. A) Percentage of participants experiencing ≥1 adverse events (AEs);
B) Percentage of participants withdrawing from study drug due to an adverse event (AE)
2. A) Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 38 post-transplant; B) Percentage of participants with clinically significant CMV infection from Week 14 post-transplant through Week 48 post-transplant; C) Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 28 post-transplant;
D) Time to onset of clinically significant CMV infection from Week 14 post-transplant to Week 48 post-transplant;
E) Percentage of participants with pre-emptive therapy (PET) for CMV viremia from Week 14 post-transplant to Week 28 post-transplant;
F) Percentage of participants with pre-emptive therapy (PET) for CMV viremia from Week 14 post-transplant to Week 48 post-transplant;
G) Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 28 post-transplant;
H) Percentage of participants with all-cause mortality from Week 14 post-transplant to Week 48 post-transplant;
I) Time to all-cause mortality from Week 14 post-transplant to Week 28 post-transplant;
J) Time to all-cause mortality from Week 14 post-transplant to Week 48 post-transplant
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. A) Up to 24 weeks (from Week 14 post-transplant to Week 38);
B) Up to 14 weeks (from Week 14 post-transplant to Week 28)
2. A) Up to 14 weeks (from Week 14 post-transplant to Week 28);
B) Up to 34 weeks (from Week 14 post-transplant to Week 48);
C) Up to 14 weeks (from Week 14 post-transplant to Week 28);
D) Up to 34 weeks (from Week 14 post-transplant to Week 48);
E) Up to 14 weeks (from Week 14 post-transplant to Week 28);
F) Up to 34 weeks (from Week 14 post-transplant to Week 48);
G) Up to 14 weeks (from Week 14 post-transplant to Week 28);
H) Up to 34 weeks (from Week 14 post-transplant to Week 48);
I) Up to 14 weeks (from Week 14 post-transplant to Week 28);
J) Up to 34 weeks (from Week 14 post-transplant to Week 48);
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| France |
| Germany |
| Italy |
| Japan |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
Print
