| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cytomegalovirus Infection in Hematopoietic Stem Cell Transplant Recipients |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cytomegalovirus Infection in Hematopoietic Stem Cell Transplant patients |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021819 |
| E.1.2 | Term | Infection in marrow transplant recipients |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 compare the efficacy of maribavir to valganciclovir in CMV viremia clearance at the end of Study Week 8 in
asymptomatic CMV infection in hematopoietic stem cell transplant (HSCT) recipients. |
|
| E.2.2 | Secondary objectives of the trial |
| The key secondary objective of this study is to compare the efficacy of maribavir and valganciclovir on maintenance of CMV viremia clearance, achieved at the end of Study Week 8 through Study Week 16 (8 weeks of post-treatment/follow-up Phase). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures. As applicable, a parent/both parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the subject before completing any study-related procedures. During the COVID-19 public health emergency, informed consent from a potential or current trial participant may, if permitted by local laws and regulations, be obtained via electronic informed consent (eIC) capabilities or an electronic face-to-face consent interview when these individuals are unable to travel to the site (FDA COVID-19 Guidance, 27Janv2021, Q11).
2.Be ≥16 years of age at the time of consent.
3.Be a recipient of hematopoietic stem cell transplant.
4.Have a documented asymptomatic CMV infection, with a screening value of CMV DNA ≥1365 IU/mL to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤ 91000 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to
randomization with second sample obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator. Subjects with CMV DNA <910 and ≥455 IU/mL in plasma or <2730 and ≥1365 IU/mL in whole blood will also need to meet at least 1 of the following criteria for high-risk CMV infection to be eligible:
- Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 1 of the following 3 HLA-gene loci: HLA-A, -B or -DR,
- Haploidentical donor,
- Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: HLA-A, -B, -C and -DRB1,
- Use of umbilical cord blood as stem cell source,
- Use of ex vivo T-cell-depleted grafts,
- Grade 2 or greater GVHD, requiring the use of systemic corticosteroids (defined as the use of ≥1 mg/kg/day of prednisone or equivalent dose of another corticosteroid).
5.Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation, which in the investigator’s opinion requires treatment.
6.Per investigator’s judgment, be eligible for treatment with valganciclovir.
7.Have all of the following results as part of screening laboratory assessments (results from either the central laboratory or a local laboratory can be used for qualification):
a.Absolute neutrophil count ≥1000/mm3 [1.0 x 109/L]
b.Platelet count ≥25,000/mm3 [25 x 109/L]
c.Hemoglobin ≥8g/dL.
d.Estimated creatinine clearance ≥30mL/min
8.Have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test at screening, if a
female of childbearing potential. Urine pregnancy tests may be done per institutional requirements;
however they are not sufficient for eligibility determination. Sexually active females of childbearing
potential must agree to comply with any applicable contraceptive requirements of the protocol. If male,
must agree to use an acceptable method of birth control, as defined in the protocol, during the study
treatment administration period and for 90 days afterward the last dose of study treatment.
9.Be able to swallow tablets.
10.Have life expectancy of ≥ 8 weeks.
11.Have weight ≥40 kg.
12.Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0.
2. Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence.
3. Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a subject who had at least one previously documented episode of CMV infection post-transplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes (during active surveillance, based on same local laboratory and same sample type). The subject must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection.
4. Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] co-infection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection.
5. Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated. NOTE: Subjects who may be receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Subjects receiving letermovir must discontinue use 3 days prior to first dose of study treatment. Subjects receiving artesunate must discontinue the use prior to the first dose of study treatment.
6. Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or letermovir) for the current CMV infection for longer than 72 hours.
7. Have known hypersensitivity to the active substance or to an excipient of the study treatments.
8. Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the first dose of study treatment that would preclude administration of oral medication.
9. Require mechanical ventilation or vasopressors for hemodynamic support at the time of randomization.
10. Be female and pregnant or nursing.
11. Have previously completed, discontinued, or have been withdrawn from this study.
12. Have received any investigational agent with known anti-CMV activity within 30 days before initiation of
study treatment or CMV vaccine at any time.
13. Have received any unapproved agent or device within 30 days before initiation of study treatment.
14. Have any clinically significant medical or surgical condition that, in the investigator’s opinion, could interfere with interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the subject.
15. Have previously received maribavir.
16. Have serum aspartate aminotransferase (AST) >5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) >5 times ULN at screening, or total bilirubin ≥3.0 x ULN at screening (except for documented Gilbert’s syndrome), as analyzed by local or central laboratory.
17. Have known (previously documented) positive results for human immunodeficiency virus (HIV). Subjects must have a confirmed negative HIV test result within 3 months of study entry or, if unavailable, be tested by a local laboratory during the screening period.
18. Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Subjects who experience relapse or progression of their underlying malignancy (for which HSCT was performed), as determined by the investigator, are not to be enrolled.
19. Be undergoing treatment for acute or chronic hepatitis C. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed clearance of plasma CMV DNA (CMV viremia clearance) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of Study Week 8. |
|
| E.5.2 | Secondary end point(s) |
| Maintenance of CMV viremia clearance |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After the end of Study wee 8 through Study Week 16 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Serbia |
| Singapore |
| Turkey |
| Austria |
| Belgium |
| Canada |
| Croatia |
| Czechia |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
| France |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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