CMV Disease
Conditions
Brief summary
The primary objective of this study is to evaluate the efficacy of letermovir (LET) versus valganciclovir (VGCV) in preventing CMV disease in adult kidney transplant recipients. The primary hypotheses are that LET is non-inferior to VGCV; and if non-inferiority is demonstrated, that LET is superior to VGCV, in preventing CMV disease through 52 weeks post-transplant.
Interventions
DRUGLetermovir
LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) once daily for 28 weeks
DRUGValganciclovir
900 mg VGCV tablet orally, once daily for 28 weeks
DRUGAcyclovir (ACV)
400 mg over-encapsulated ACV tablet orally, every 12 hours for 28 weeks
DRUGPlacebo to ACV
Over-encapsulated placebo tablet orally, every 12 hours for 28 weeks
DRUGPlacebo to LET
Placebo to LET tablet orally, once daily for 28 weeks
DRUGPlacebo to VGCV
Placebo to VGCV tablet orally, once daily for 28 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a documented negative serostatus for CMV within 180 days prior to randomization. * Anticipate receiving a primary or secondary allograft kidney from a CMV IgG seropositive (D+) donor at the time of screening AND have received a primary or secondary allograft kidney from a documented D+ donor at the time of randomization. * Be within 0 (i.e. day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of randomization. * Males agree to use contraception 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. * Female is not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP), OR if a WOCBP, agrees to follow the contraception guidance during the treatment period and for at least 90 days after the last dose of study treatment.
Exclusion criteria
* Has received a previous solid organ transplant or hematopoietic stem cell transplant (HSCT). Note: Participants who have received a prior primary allograft kidney may be enrolled, provided that all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adjudicated Cytomegalovirus (CMV) Disease Through 52 Weeks Post-transplant | Up to 52 weeks | CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded Clinical Adjudication Committee (CAC). Only CAC-confirmed (adjudicated) cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant | Up to 28 weeks | CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded CAC. Only CAC-confirmed (adjudicated) cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included. |
| Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant | Up to 52 weeks | The time to onset of adjudicated CMV disease was calculated in days, from the day of randomization to the day of onset of CMV disease as determined by the CAC. |
| Percentage of Participants With Any AE | Up to 52 weeks | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, was also an AE. |
| Percentage of Participants With Any Drug-related Serious Adverse Event (SAE) | Up to 52 weeks | An SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. SAEs that the investigator determined the relationship of the AE to the treatment as at least possibly related were reported. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Colombia, France, Germany, Hungary, Italy, Mexico, New Zealand, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
Male/Female participants of at least 18 years of age with receipt of a kidney transplant were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Letermovir Letermovir (LET) 480 mg (or 240 mg when administered concomitantly with cyclosporin A) tablet orally; placebo to valganciclovir (VGCV) tablet orally once daily; and 400-mg capsule of acyclovir (ACV) orally every 12 hours for 28 weeks | 301 |
| Valganciclovir 900 mg VGCV tablet orally, once daily; placebo to LET tablet orally once daily; and placebo to ACV orally every 12 hours for 28 weeks | 300 |
| Total | 601 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Other | 4 | 4 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Withdrawal by Subject | 34 | 22 |
Baseline characteristics
| Characteristic | Valganciclovir | Total | Letermovir |
|---|---|---|---|
| Age, Continuous | 49.5 Years STANDARD_DEVIATION 15.1 | 49.6 Years STANDARD_DEVIATION 14.9 | 49.6 Years STANDARD_DEVIATION 14.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 45 Participants | 101 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 240 Participants | 470 Participants | 230 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 30 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 55 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) White | 246 Participants | 505 Participants | 259 Participants |
| Sex: Female, Male Female | 90 Participants | 174 Participants | 84 Participants |
| Sex: Female, Male Male | 210 Participants | 427 Participants | 217 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 301 | 3 / 300 |
| other Total, other adverse events | 239 / 292 | 243 / 297 |
| serious Total, serious adverse events | 118 / 292 | 129 / 297 |
Outcome results
Primary
Percentage of Participants With Adjudicated Cytomegalovirus (CMV) Disease Through 52 Weeks Post-transplant
CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded Clinical Adjudication Committee (CAC). Only CAC-confirmed (adjudicated) cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included.
Time frame: Up to 52 weeks
Population: All randomized participants who received at least one dose of study treatment, were CMV seropositive organ donor/CMV seronegative organ recipient (D+/R-), and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Adjudicated Cytomegalovirus (CMV) Disease Through 52 Weeks Post-transplant | 10.4 Percentage of Participants |
| Valganciclovir | Percentage of Participants With Adjudicated Cytomegalovirus (CMV) Disease Through 52 Weeks Post-transplant | 11.8 Percentage of Participants |
Comparison: The Observed failure (OF) approach was used to handle missing values, that is participants who had discontinued prematurely from the study for any reason were not considered failures95% CI: [-6.5, 3.8]
Secondary
Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant
CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded CAC. Only CAC-confirmed (adjudicated) cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included.
Time frame: Up to 28 weeks
Population: All randomized participants who received at least one dose of study treatment, were D+/R-, and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant | 0.0 Percentage of Participants |
| Valganciclovir | Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant | 1.7 Percentage of Participants |
Comparison: The Observed failure (OF) approach was used to handle missing values, that is participants who had discontinued prematurely from the study for any reason were not considered failures95% CI: [-3.4, 0.1]
Secondary
Percentage of Participants With Any AE
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, was also an AE.
Time frame: Up to 52 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Any AE | 92.8 Percentage of Participants |
| Valganciclovir | Percentage of Participants With Any AE | 92.9 Percentage of Participants |
95% CI: [-4.4, 4.2]
Secondary
Percentage of Participants With Any Drug-related Serious Adverse Event (SAE)
An SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. SAEs that the investigator determined the relationship of the AE to the treatment as at least possibly related were reported.
Time frame: Up to 52 weeks
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Any Drug-related Serious Adverse Event (SAE) | 1.4 Percentage of Participants |
| Valganciclovir | Percentage of Participants With Any Drug-related Serious Adverse Event (SAE) | 5.1 Percentage of Participants |
95% CI: [-7, -0.9]
Secondary
Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant
The time to onset of adjudicated CMV disease was calculated in days, from the day of randomization to the day of onset of CMV disease as determined by the CAC.
Time frame: Up to 52 weeks
Population: All randomized participants who received at least one dose of study treatment, were D+/R-, and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letermovir | Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant | NA Days |
| Valganciclovir | Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant | NA Days |