Clinical trial NCT04904614: Letermovir Use in Heart Transplant Recipients
Official title: Evaluation of the Tolerability and Clinical Effectiveness of Letermovir in Heart Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cytomegalovirus Disease
Cytomegalovirus Infections
Heart Transplant Infection
Antiviral Toxicity
Neutropenia
Keywords: cytomegalovirus, letermovir, heart transplantation
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-05-27
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label trial
Primary purpose: OTHER

Brief summary: This is an open label trial in which letermovir will be given as prophylaxis for the prevention of CMV infection and disease to all heart transplants who are at risk for cytomegalovirus. The study will compare a 30 patient prospective cohort to a retrospective cohort of 374 heart transplant recipients for the rates of neutropenia. In addition, the tolerability of letermovir will be assessed in this population.

Detailed description: This open label trial will follow 30 heart transplant recipients at Tufts Medical Center who will receive letermovir in a dose of 480 mg daily for either 3 or 6 months depending on the CMV risk category, and who will be followed for one year. Comparison will be made to a cohort of heart transplant recipients as historical controls in a recently presented study (Chow, J, et al ISHLT 2021). Standard follow up will be provided as if the patients were receiving valgancilcovir prophylaxis. Post prophylaxis T cell immunity to all subjects enrolled will be tested. Clinical outcomes are detailed below.

Eligibility criteria: Inclusion Criteria:

1. Adults between 18-70 will be eligible for participation
2. Written informed consent and able to participate with follow up
3. Heart transplant recipients who are not CMV donor negative and CMV recipient negative (CMV -/-)
4. Not enrolled in competing clinical trials

Exclusion Criteria:

1. Dual heart and kidney transplant recipients
2. Patients who do not survive 72 hours post transplant
3. HIV infection
4. Patients with creatinine clearance less than 10 ml per min at time of enrollment
5. Hypersensitivity to letermovir
6. On CVVH or renal dialysis at the time of enrollment
7. Received a previous solid organ transplant or HSCT.
8. Has Child Pugh Class C severe hepatic insufficiency at screening.
9. Has both moderate hepatic insufficiency AND moderate to severe renal insufficiency at screening.

   Note: Moderate hepatic insufficiency is defined as Child Pugh Class B; moderate to severe renal insufficiency is defined as CrCl \<50 mL/min, as calculated by the Cockcroft-Gault equation (as above), respectively.
10. 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.
11. 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.
12. Is expecting to donate eggs or sperm starting from the time of consent through at least 90 days following cessation of study therapy.
13. 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.
14. Has exclusionary laboratory value at screening, as listed in Table 1. Table 1 Laboratory Exclusion Criteria Laboratory Assessment Exclusionary Value

    Hemoglobin \<8 g/dL Platelets \<25,000 cells/µL Absolute neutrophil count \<1,000 cells/µL Total bilirubin \>2.5 × ULN ALT \>5 × ULN AST \>5 × ULN ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; IgG = immunoglobulin G; ULN = upper limit of normal
15. 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.

    Note: Investigational regimens involving combinations of approved agents are not permitted. Other non-interventional or other observational studies are allowed.
16. Has previously participated in this study or any other study involving LET.
17. 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.

    -

Primary outcomes:
measure: Proportion of patients with neutropenia
timeFrame: 12 months
Secondary outcomes:
measure: Rate of CMV infection in letermovir recipients
timeFrame: 1 year
measure: Rate of opportunistic infections in letermovir arm compared to historic controls
timeFrame: 1 year
measure: Tolerability and Compliance of Letermovir
timeFrame: 1 year
measure: Use of GCSF in letermovir recipients compared to historic controls
timeFrame: 1 year
measure: Measure of CMV specific T cell immunity in letermovir recipients compared to controls
timeFrame: 2 weeks post prophylaxis, at either 3-4 months or 6-7 months depending on duration of prophylaxis
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
Study officials:
References:
citation: Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191.
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