Cytomegalovirus Disease, Cytomegalovirus Infection
Conditions
Brief summary
This study aims to evaluate the safety, efficacy and pharmacokinetics (PK) of Letermovir (LET) administered as prevention of cytomegalovirus (CMV) infection and disease in adult Japanese kidney transplant recipients.
Interventions
A single 240 mg tablet or two 240 mg tablets letermovir administered orally, once daily for 28 weeks
DRUGLetermovir IV
IV solution of 240 mg (one vial) or 480 mg (2 vials) letermovir in 250 mL infused over 60 minutes, once daily for 28 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets recipient and/or donor CMV Immunoglobulin G (IgG) serostatus. * Anticipates receiving a primary or secondary allograft kidney at the time of screening and have received a primary or secondary allograft kidney at the time of allocation. * Is within 0 (i.e., day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of allocation. * Is a Japanese male or female from 18 years to any years of age inclusive, at the time of signing the informed consent. * Female is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP); but if a WOCBP, she is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse, and must have a negative highly sensitive pregnancy test within 72 hours before the first dose of study intervention.
Exclusion criteria
* Has received a previous solid organ transplant or hematopoietic stem cell transplant (HSCT). * Is a multi-organ transplant recipient (e.g., kidney-pancreas). * Has a history of CMV disease or suspected CMV disease within 6 months prior to allocation. * Has positive results on CMV assay and/or CMV antigen test at any time between the completion of the transplant surgery and time of allocation. * Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations. * Is on dialysis (for the purposes of this protocol dialysis includes hemofiltration) or plasmapheresis at the time of allocation. * Has Child-Pugh Class C severe hepatic insufficiency at screening. * Has post-transplant renal function of creatinine clearance (CrCl) ≤10 mL/min at allocation (measured locally). * Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at screening. * Has any uncontrolled infection on the day of allocation. * Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to allocation, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV RNA within 90 days prior to allocation or hepatitis B surface antigen (HBsAg) within 90 days prior to allocation. * Requires mechanical ventilation, or is hemodynamically unstable, at the time of allocation. * Has a history of malignancy ≤5 years prior to signing informed consent. * Has received within 30 days prior to allocation or plans to receive during the study any of the following: CMV immune globulin; any investigational CMV antiviral agent/biologic therapy. * Has received any dose of LET prior to allocation. * Has received within 7 days prior to allocation or plans to receive during the study any anti-CMV drug therapy. * Is a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence. * Is taking or plans to take any of the prohibited medications listed in the protocol. * 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. * Has previously participated in this study or any other study involving LET. * 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. * Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through at least 28 days following cessation of study therapy. * Is expecting to donate eggs starting from the time of consent through at least 28 days following cessation of study therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | Up to week 52 post-transplant | Percentage of participants with one or more adverse events (AEs) |
| Percentage of Participants Who Discontinued From Study Drug Due to an AE | Up to week 28 post-transplant | Percentage of participants who discontinued from study drug due to an AE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Quantifiable CMV DNAemia | Up to Week 52 post-transplant | Quantifiable CMV DNAemia (central) was defined as any case with a numeric value or \>910,000,000 (not including reporting of PCR results as detected, not quantifiable) using the Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which was performed by the central laboratory. |
| Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir-oral Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an oral administration of letermovir. |
| Trough Concentration (Ctrough) of Plasma Letermovir - Oral Treatment | Any day between Days 6-10: 24hrs post-dose | Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an oral administration of letermovir. |
| Maximum Concentration (Cmax) of Plasma Letermovir - Oral Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | Cmax was defined as the maximum concentration of letermovir observed in plasma following an oral administration of letermovir. |
| Time to Reach Cmax (Tmax) of Plasma Letermovir - Oral Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | Tmax was defined as the time required post dosing to reach a maximum plasma concentration of letermovir following an oral administration of letermovir. |
| Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | Up to Week 52 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. Participants who have undergone anti-CMV treatment was defined as initiation of approved anti-CMV agents based on at least one positive cell on CMV antigenemia and/or quantifiable CMV DNA PCR assay performed locally. |
| Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir - IV Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an IV administration of letermovir was intended to measure. |
| Trough Concentration (Ctrough) of Plasma Letermovir - IV Treatment | Pre-dose on Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28 | Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an IV administration of letermovir was intended to measure. |
| Concentration at the End of Infusion (Ceoi) of Plasma Letermovir - IV Treatment | Any day between Days 6-10: at end of infusion (1 hours post dose) | Ceoi is defined as the amount of letermovir in plasma following an IV administration of letermovir was intended to measure. |
| Clearance at Steady State (CLss) of Plasma Letermovir - IV Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | Clearance at steady state (CLss) of plasma letermovir following an IV administration of letermovir was intended to measure. |
| Apparent Clearance at Steady State (CLss/F) of Plasma Letermovir - Oral Treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | Apparent clearance at steady state (CLss/F) of plasma letermovir following an oral administration of letermovir. |
| Percentage of Participants With Adjudicated CMV Disease | Up to Week 52 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. |
Countries
Japan
Participant flow
Recruitment details
This study enrolled adult Japanese kidney transplant recipients who are organ donor (D) or organ recipient (R) seropositive (D+/R-, D+/R+ or D-/R+) for Cytomegalovirus (CMV) as participants.
Pre-assignment details
Intravenous (IV) infusion of letermovir (LET) was intended to administer participants who cannot tolerate swallowing oral letermovir and/or does develop a condition that may interfere with the absorption of the oral LET. None of the participants received IV LET.
Participants by arm
| Arm | Count |
|---|---|
| Letermovir Letermovir oral or intravenous (IV) formulation was administered once daily for up to 28 weeks, beginning up to 7 days post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A (CsA) and 480 mg once daily for participants not receiving CsA. IV infusion was administered only to participants who were unable to swallow tablets or who had a condition that may have interfered with absorption of the tablets. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Letermovir |
|---|---|
| Age, Continuous | 48.5 Years STANDARD_DEVIATION 12.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 13 / 22 |
| serious Total, serious adverse events | 7 / 22 |
Outcome results
Primary
Percentage of Participants Who Discontinued From Study Drug Due to an AE
Percentage of participants who discontinued from study drug due to an AE
Time frame: Up to week 28 post-transplant
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants Who Discontinued From Study Drug Due to an AE | 13.6 Percentage of participants |
Primary
Percentage of Participants With Adverse Events (AEs)
Percentage of participants with one or more adverse events (AEs)
Time frame: Up to week 52 post-transplant
Population: All participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Adverse Events (AEs) | 90.9 Percentage of Participants |
Secondary
Apparent Clearance at Steady State (CLss/F) of Plasma Letermovir - Oral Treatment
Apparent clearance at steady state (CLss/F) of plasma letermovir following an oral administration of letermovir.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letermovir | Apparent Clearance at Steady State (CLss/F) of Plasma Letermovir - Oral Treatment | 3.08 L/hr | Geometric Coefficient of Variation 47.3 |
Secondary
Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir - IV Treatment
AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an IV administration of letermovir was intended to measure.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample. None of the participants received letermovir IV.
Secondary
Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir-oral Treatment
AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an oral administration of letermovir.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable pharmacokinetic (PK) sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letermovir | Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir-oral Treatment | 156000 ng*hr/mL | Geometric Coefficient of Variation 47.3 |
Secondary
Clearance at Steady State (CLss) of Plasma Letermovir - IV Treatment
Clearance at steady state (CLss) of plasma letermovir following an IV administration of letermovir was intended to measure.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample. None of the participants received letermovir IV.
Secondary
Concentration at the End of Infusion (Ceoi) of Plasma Letermovir - IV Treatment
Ceoi is defined as the amount of letermovir in plasma following an IV administration of letermovir was intended to measure.
Time frame: Any day between Days 6-10: at end of infusion (1 hours post dose)
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample. None of the participants received letermovir IV.
Secondary
Maximum Concentration (Cmax) of Plasma Letermovir - Oral Treatment
Cmax was defined as the maximum concentration of letermovir observed in plasma following an oral administration of letermovir.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letermovir | Maximum Concentration (Cmax) of Plasma Letermovir - Oral Treatment | 17900 ng/mL | Geometric Coefficient of Variation 31.1 |
Secondary
Percentage of Participants With Adjudicated CMV Disease
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 Week 52 post-transplant
Population: All allocated participants who received at least one dose of study treatment, who were organ donor (D) or organ recipient (R) seropositive (D+/R-, D+/R+ or D-/R+) for Cytomegalovirus (CMV) and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letermovir | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 52 Post-Transplant | 9.5 Percentage of Participants |
| Letermovir D+/R- | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir D+/R- | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 52 Post-Transplant | 16.7 Percentage of Participants |
| Letermovir R+ | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir R+ | Percentage of Participants With Adjudicated CMV Disease | With CMV Disease Through Week 52 Post-Transplant | 0.0 Percentage of Participants |
Secondary
Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment
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. Participants who have undergone anti-CMV treatment was defined as initiation of approved anti-CMV agents based on at least one positive cell on CMV antigenemia and/or quantifiable CMV DNA PCR assay performed locally.
Time frame: Up to Week 52 post-transplant
Population: All allocated participants who received at least one dose of study treatment, who were organ donor (D) or organ recipient (R) seropositive (D+/R-, D+/R+ or D-/R+) for Cytomegalovirus (CMV) and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letermovir | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 52 Post-Transplant | 19.0 Percentage of Participants |
| Letermovir D+/R- | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir D+/R- | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 52 Post-Transplant | 33.3 Percentage of Participants |
| Letermovir R+ | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 28 Post-Transplant | 0.0 Percentage of Participants |
| Letermovir R+ | Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment | With CMV Disease or Started Anti-CMV Treatment Through Week 52 Post-Transplant | 0.0 Percentage of Participants |
Secondary
Percentage of Participants With Quantifiable CMV DNAemia
Quantifiable CMV DNAemia (central) was defined as any case with a numeric value or \>910,000,000 (not including reporting of PCR results as detected, not quantifiable) using the Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which was performed by the central laboratory.
Time frame: Up to Week 52 post-transplant
Population: All allocated participants who received at least one dose of study treatment, who were organ donor (D) or organ recipient (R) seropositive (D+/R-, D+/R+ or D-/R+) for Cytomegalovirus (CMV) and had no detectable CMV viral DNA (measured by central laboratory) on Day 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Letermovir | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 28 Post-transplant | 4.8 Percentage of participants |
| Letermovir | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 52 Post-transplant | 23.8 Percentage of participants |
| Letermovir D+/R- | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 28 Post-transplant | 8.3 Percentage of participants |
| Letermovir D+/R- | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 52 Post-transplant | 41.7 Percentage of participants |
| Letermovir R+ | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 28 Post-transplant | 0.0 Percentage of participants |
| Letermovir R+ | Percentage of Participants With Quantifiable CMV DNAemia | Quantifiable CMV DNAemia Through Week 52 Post-transplant | 0.0 Percentage of participants |
Secondary
Time to Reach Cmax (Tmax) of Plasma Letermovir - Oral Treatment
Tmax was defined as the time required post dosing to reach a maximum plasma concentration of letermovir following an oral administration of letermovir.
Time frame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letermovir | Time to Reach Cmax (Tmax) of Plasma Letermovir - Oral Treatment | 2.50 hr |
Secondary
Trough Concentration (Ctrough) of Plasma Letermovir - IV Treatment
Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an IV administration of letermovir was intended to measure.
Time frame: Pre-dose on Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample. None of the participants received letermovir IV.
Secondary
Trough Concentration (Ctrough) of Plasma Letermovir - Oral Treatment
Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an oral administration of letermovir.
Time frame: Any day between Days 6-10: 24hrs post-dose
Population: The analysis population consisted of all participants who received at least 1 dose of study treatment and had at least one measurable PK sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Letermovir | Trough Concentration (Ctrough) of Plasma Letermovir - Oral Treatment | 1700 ng/mL | Geometric Coefficient of Variation 121.9 |