| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CMV infections resistant or refractory in transplant patients |
|
| E.1.1.1 | Medical condition in easily understood language |
| CMV infections resistant or refractory in 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021829 |
| E.1.2 | Term | Infection in solid organ 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 investigator-assigned anti CMV therapy in CMV viremia clearance after 8-week treatment in transplant recipients who are refractory or resistant to prior anti-CMV treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the efficacy of the 2 study treatment arms on CMV viremia clearance and symptomatic CMV infection (tissue invasive disease and CMV syndrome) improvement or resolution at the end of Study Week 8, nd maintenance of this treatment effect 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 beforecompleting 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.
2.Be a recipient of hematopoietic stem cell or solid organ transplant
3.Have a documented CMV infection in whole blood or plasma, with a screening value of ≥2730 IU/mL in whole blood or ≥910 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. The same laboratory and same sample type (whole blood or plasma) must be used for these assessments.
4. The subject must have a current CMV infection that is refractory to the
most recently administered of the four anti-CMV treatment agent(s). Refractory is defined as documented failure to achieve >1 loglO (common logarithm to base 10) decrease in CMV DNA level in whole blood or plasma after a 14 day or longer treatment period with IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir (or any combination thereof). Resistant is defined as documented failure to achieve >1 loglO (common logarithm to base 10) decrease
in CMV DNA level in whole blood or plasma after a 14 day or longer
treatment period with IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cldofovir. Subjects who have documentation of 1 or more CMV genetic mutations associated with resistance to ganclclovir/valganciclovir, foscarnet, and/or cldofovir must also meet the definition of refractory CMV infection.
5.Per investigator’s judgment, be eligible for treatment with at least 1 of the available anti-CMV therapy (ganciclovir, valganciclovir, foscarnet, or cidofovir)
6.Be ≥12 years of age at the time of consent
7.Weight ≥35 kg
8.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 (ANC) ≥1000/mm3 [1.0 x 109/L]
b.Platelet count ≥25000/mm3 [25 x 109/L]
c.Hemoglobin ≥8g/dL
d.Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73m2 as assessed by Modification of Diet in Renal Disease (MDRD) formula for subjects ≥18 years of age or Schwartz formula for subjects <18 years of age.
9.All females of child bearing potential must have a negative serum β-human chorionic gonadotropin (β-HCG) pregnancy test at screening. Sexually active females of child bearing 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 if treated with maribavir, ganciclovir, valganciclovir, or cidofovir and for 180 days afterward if treated with foscarnet.
10.Be able to swallow tablets
11.Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol
12.Be willing to provide necessary samples (eg, biopsy) for the diagnosis of tissue invasive CMV disease at baseline as determined by the investigator
13.Life expectancy of ≥8 weeks |
|
| E.4 | Principal exclusion criteria |
1.Have a current CMV infection that is considered refractory or resistant due to inadequate adherence to prior anti-CMV treatment, to the best knowledge of the investigator
2.Requires ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus (HSV) coinfection requiring use of any of these agents after the randomization) or would need a coadministration with maribavir for CMV infection
(example: intraocular administration of ganciclovir for CMV retinitis). NOTE: A subject who is not continuing with the same anti-viral drug(s)(ganciclovir, valganciclovir, or foscarnet) for the study treatment (if randomized to the investigator assigned anti-CMV treatment arm) must discontinue their use before the first dose of study drug. If subject is currently being treated with cidofovir and is assigned another anti-CMV therapy by the investigator, the subject must discontinue its use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment.
3.Be receiving leflunomide, letermovir or artesunate when study treatment is initiated. NOTE: Subjects receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit
2/Day O and the first dose of study treatment. Subjects receiving letermovir must discontinue at least 3 days prior to the first dose of
study treatment. Subjects receiving artesunate must discontinue the use
prior to the first dose of study treatment. Subjects receiving artesunate must discontinue the use prior to the first dose of study treatment.
4.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/enteral medication
5.Have known hypersensitivity to the active substance or to an excipient for a study treatment
6.Have tissue invasive CMV disease with central nervous system involvement, including the retina (eg CMV retinitis).
7.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), by local or central lab. NOTE: Subjects with biopsy confirmed CMV hepatitis will not be excluded from study participation despite AST or ALT >5 times ULN at screening.
8.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.
9.Require mechanical ventilation or vasopressors for hemodynamic support at the time of enrollment
10.Be female and pregnant or breast feeding
11.Have previously received maribavir
12.Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or investigational anti-CMV vaccine at any time
13.Have active malignancy with the exception of nonmelanoma skin cancer. Subjects who have had a HSCT and who experience relapse or progression of the malignancy, as per investigator’s opinion are not to be enrolled.
14.Undergoing treatment for acute or chronic hepatitis C
15.Have any clinically significant medical or surgical condition that, in the investigator’s opinion, could interfere with the interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the subject |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed CMV viremia clearance |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of 8 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
| Achievement of CMV viremia clearance and resolution or improvement of symptomatic CMV infection (tissue invasive CMV disease or CMV syndrome (in SOT subjects only) for subjects symptomatic at baseline or achievement of clearance of viremia and no symptoms of tissue invasive CMV disease or CMV syndrome for subjects asymptomatic at baseline at the end of Study Week 8, followed by maintenance of this treatment effect for an additional 8 weeks off-treatment (ie, Follow-up Week 16). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at the end of 8 weeks of treatment |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Croatia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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