Antiviral Toxicity, Cytomegalovirus Disease, Cytomegalovirus Infections, Heart Transplant Infection, Neutropenia
Conditions
Keywords
cytomegalovirus, letermovir, heart transplantation
Brief summary
This is an open label trial in which letermovir will be given as prophylaxis for the prevention of cytomegalovirus (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 valganciclovir prophylaxis. Post prophylaxis T cell immunity to all subjects enrolled will be tested. Clinical outcomes are detailed below.
Interventions
DRUGLetermovir
Open label trial of the licensed drug, letermovir, in a population of heart transplant recipients for which it is not yet licensed
Sponsors
Merck Sharp & Dohme LLC
Tufts Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Open label trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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 Cytomegalovirus (CMV) donor negative and CMV recipient negative (CMV D-/R-) 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 continuous veno-venous hemofiltration or renal dialysis at the time of enrollment 7. Received a previous solid organ transplant or stem cell transplant. 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 Creatine Clearance \<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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Neutropenia Compared to Historical Controls | 12 months | We will count the number of patients with neutropenia seen over one year and calculate the proportion who become neutropenic. A comparison group of historic controls from a similar population is available for comparison. We know the control group has a 30% likelihood of becoming neutropenic at one year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of CMV Infection in Letermovir Recipients Compared to Historical Controls | 1 year | Number of patients who develop CMV infection, comparison will be made to historic control group who were taking valganciclovir for CMV prophylaxis |
| Rate of Opportunistic Infections in Letermovir Arm Compared to Historical Controls | 1 year | Number of patients who develop an opportunistic infection |
| Tolerability and Compliance of Letermovir | 1 year | Number of patients with adverse events will be collected using a data questionnaire, and examination of lab data, need for subsequent hospitalization. There is no comparator group for this purely descriptive outcome. |
| Use of Granulocyte Colony Stimulation Factor (GCSF) in Letermovir Recipients Compared to Historical Controls | 1 year | Comparison of Proportions |
| Measure of CMV Specific T Cell Immunity in Letermovir Recipients | single time point measured within 2 weeks after completion of prophylaxis therapy, at either 3 months or 6 months, depending on duration of prophylaxis | Single measurement of specific T-cell immune function to CMV. There is no comparator arm for this outcome because this test did not exist at time of historical controls. This is a measure of CMV specific T-cell immunity based on a commercial assay that yields one of 3 results: positive (CMV T-cell function is measured), indeterminate, negative (CMV T-cell function is not measured). A positive T-cell test is considered a better outcome. |
Countries
United States
Participant flow
Pre-assignment details
Participants in the historical control arm were not considered enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Intervention Arm Letermovir 480 mg daily for cmv prophylaxis
Letermovir: Open label trial of the licensed drug, letermovir, in a population of heart transplant recipients for which it is not yet licensed | 32 |
| Historical Controls A total of 204 CMV D+/R- and CMV R+ patients on valganciclovir for CMV prophylaxis formed our historical control group of adult HT recipients at Tufts Medical Center from January 2004 to December 2017 who were followed for one-year post-HT for development of neutropenia, as well as infection, rejection, and survival.
These patients were NOT enrolled in current study.
Chow JKL, Ruthazer R, Boucher HW, Vest AR, DeNofrio DM, Snydman DR: Factors associated with neutropenia post heart transplantation. Transpl Infect Dis 2021;23:e13634. | 204 |
| Total | 236 |
Baseline characteristics
| Characteristic | Intervention Arm | Historical Controls | Total |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 12 |
| CMV Donor IgG seropositive/Recipient IgG seronegative (CMV D+/R-) | 19 Participants | 85 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 24 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 180 Participants | 207 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 15 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 184 Participants | 211 Participants |
| Region of Enrollment United States | 32 participants | 204 participants | 236 participants |
| Sex: Female, Male Female | 6 Participants | 60 Participants | 66 Participants |
| Sex: Female, Male Male | 26 Participants | 144 Participants | 170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 10 / 204 |
| other Total, other adverse events | 0 / 32 | 0 / 204 |
| serious Total, serious adverse events | 0 / 32 | 0 / 204 |
Outcome results
Primary
Proportion of Patients With Neutropenia Compared to Historical Controls
We will count the number of patients with neutropenia seen over one year and calculate the proportion who become neutropenic. A comparison group of historic controls from a similar population is available for comparison. We know the control group has a 30% likelihood of becoming neutropenic at one year.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Proportion of Patients With Neutropenia Compared to Historical Controls | 0 Participants |
| Historical Controls | Proportion of Patients With Neutropenia Compared to Historical Controls | 30 Participants |
p-value: 0.02Fisher Exact
Secondary
Measure of CMV Specific T Cell Immunity in Letermovir Recipients
Single measurement of specific T-cell immune function to CMV. There is no comparator arm for this outcome because this test did not exist at time of historical controls. This is a measure of CMV specific T-cell immunity based on a commercial assay that yields one of 3 results: positive (CMV T-cell function is measured), indeterminate, negative (CMV T-cell function is not measured). A positive T-cell test is considered a better outcome.
Time frame: single time point measured within 2 weeks after completion of prophylaxis therapy, at either 3 months or 6 months, depending on duration of prophylaxis
Population: 3 missing data
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm | Measure of CMV Specific T Cell Immunity in Letermovir Recipients | positive CMV T-cell test | 20 Participants |
| Single Arm | Measure of CMV Specific T Cell Immunity in Letermovir Recipients | negative CMV T-cell test | 4 Participants |
| Single Arm | Measure of CMV Specific T Cell Immunity in Letermovir Recipients | Indeterminate CMV T-cell test | 5 Participants |
Secondary
Rate of CMV Infection in Letermovir Recipients Compared to Historical Controls
Number of patients who develop CMV infection, comparison will be made to historic control group who were taking valganciclovir for CMV prophylaxis
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Rate of CMV Infection in Letermovir Recipients Compared to Historical Controls | 11 Participants |
| Historical Controls | Rate of CMV Infection in Letermovir Recipients Compared to Historical Controls | 50 Participants |
p-value: 0.13Chi-squared
Secondary
Rate of Opportunistic Infections in Letermovir Arm Compared to Historical Controls
Number of patients who develop an opportunistic infection
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Rate of Opportunistic Infections in Letermovir Arm Compared to Historical Controls | 3 Participants |
| Historical Controls | Rate of Opportunistic Infections in Letermovir Arm Compared to Historical Controls | 25 Participants |
p-value: 0.6Fisher Exact
Secondary
Tolerability and Compliance of Letermovir
Number of patients with adverse events will be collected using a data questionnaire, and examination of lab data, need for subsequent hospitalization. There is no comparator group for this purely descriptive outcome.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Tolerability and Compliance of Letermovir | 0 Participants |
Secondary
Use of Granulocyte Colony Stimulation Factor (GCSF) in Letermovir Recipients Compared to Historical Controls
Comparison of Proportions
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Use of Granulocyte Colony Stimulation Factor (GCSF) in Letermovir Recipients Compared to Historical Controls | 9 Participants |
| Historical Controls | Use of Granulocyte Colony Stimulation Factor (GCSF) in Letermovir Recipients Compared to Historical Controls | 58 Participants |
p-value: 0.97Chi-squared