E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of CMV disease in D+/R- kidney transplant recipients |
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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 organ transplatation, which could be fatal. |
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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 |
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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 the efficacy of letermovir (LET) versus valganciclovir (VGCV), as measured by the proportion of participants with adjudicated CMV disease through 52 weeks post-transplant. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of LET versus VGCV, as measured by the proportion of participants with adjudicated CMV disease through 28 weeks post-transplant.
2. To evaluate the efficacy of LET versus VGCV, as measured by the time to onset of adjudicated CMV disease through 52 weeks post-transplant.
3. To evaluate the safety and tolerability of LET versus VGCV. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and plasma) specimens collected during this clinical trial. Additionally, samples will be collected from a selected group of participants for Viral resistance studies. Such research is for biomarker and testing and to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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E.3 | Principal inclusion criteria |
1. Have a documented negative serostatus for CMV (ie, recipient CMV IgG seronegative [R-]) within 90 days prior to randomization.
2. Anticipate receiving a first allograft kidney from a CMV IgG seropositive (D+) donor at the time of screening AND have received a first allograft kidney from a documented D+ donor at the time of randomization.
3. Be within 0 (ie, day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of randomization.
4. Be ≥18 years of age on day of signing informed consent.
5. A male participant must agree to use contraception as detailed in Appendix 5 of the protocol during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
6. A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least one 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 contraception guidance in Appendix 5 during the treatment period and for at least 90 days after the last dose of study treatment.
7. Understand the study procedures, alternative treatment available, and risks involved with the study, and he/she voluntarily agrees to participate by giving written informed consent and is willing to adhere to dose and visit schedules. Participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
8. Be able to read, understand, and complete questionnaires and diaries. |
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E.4 | Principal exclusion criteria |
1. Received a previous solid organ transplant or HSCT.
2. Is a multi-organ transplant recipient (eg, kidney-pancreas).
3. Has a history of CMV disease or suspected CMV disease within 6 months prior to randomization.
4. Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations, VGCV, GCV, and/or ACV formulations.
5. Is on dialysis at the time of randomization.
6. Has post-transplant renal function of CrCl ≤10 mL/min at randomization (measured locally). For this exclusion criterion, CrCl will be calculated using the Cockcroft-Gault equation using the most recently obtained and available serum creatinine value collected within 3 calendar days prior to and including the day of randomization and after the conclusion of any clinically warranted (at the discretion of the investigator) post-transplant dialysis.
7. Has Child-Pugh Class C severe hepatic insufficiency (Appendix 8 of the protocol) at screening.
8. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at screening.
9. Has any uncontrolled infection on the day of randomization.
10. Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to randomization, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV ribonucleic acid (RNA) or hepatitis B surface antigen (HBsAg) within 90 days prior to randomization.
11. Requires mechanical ventilation, or is hemodynamically unstable, at the time of randomization.
12. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy.
13. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through at least 90 days following cessation of study therapy.
14. Is expecting to donate eggs or sperm starting from the time of consent through at least 90 days following cessation of study therapy.
15. 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 put the participant 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.
16. Has exclusionary laboratory value at the screening visit, as listed in the protocol.
17. Has received within 30 days prior to randomization or plans to receive during the study any of the following anti-CMV IgG antibody treatment or anti CMV drug therapy including:
a. Cidofovir
b. CMV hyper-immune globulin
c. Any investigational CMV antiviral agent/biologic therapy.
18. Has received within 7 days prior to randomization or plans to receive during the study any of the following anti-CMV drug therapy including:
a. LET
b. GCV
c. VGCV
d. Foscarnet
e. ACV (at doses > 3200 mg PO per day or > 25 mg/kg IV per day)
f. Valacyclovir (at doses > 3 g PO per day)
g. Famciclovir (at doses > 1500 mg PO per day)
19. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence.
20. Is taking or plans to take any of the prohibited medications listed in the protocol (see Section 7.7).
21. Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5× half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. Participants previously treated with an investigational monoclonal antibody will be eligible to participate after a 150 day washout period.
22. Has previously participated in this study or any other study involving LET.
23. 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.
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants with adjudicated CMV disease through 52 weeks post-transplant |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Proportion of paticipants with adjudicated CMV disease through 52 weeks post-transplant. |
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E.5.2 | Secondary end point(s) |
1. 28 weeks post-transplant
2. 52 weeks post-transplant |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Proportion of participants with adjudicated CMV disease through 28 weeks post transplant.
2. Time to onset of adjudicated CMV disease through 52 weeks post-transplant. |
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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 | 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) | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Acyclovir (ACV) as Standard Prophylaxis |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Canada |
Colombia |
France |
Germany |
Hungary |
Italy |
Mexico |
New Zealand |
Poland |
Spain |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 40 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 40 |
E.8.9.2 | In all countries concerned by the trial days | 0 |