Prevention of CMV Infection or Disease
Conditions
Brief summary
The study evaluated the efficacy and safety of letermovir (MK-8228) for the prevention of clinically-significant CMV infection in adult, CMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (HSCT). The hypothesis being tested was that MK-8228 is superior to placebo in the prevention of clinically-significant CMV infection through Week 24 post-transplant.
Interventions
DRUGLetermovir
Letermovir 240 mg / 480 mg tablets, or 240 mg / 480 mg intravenous solution in 250 mL to be infused over 60 minutes.
DRUGPlacebo
Placebo tablets, or intravenous solution in 250 mL to be infused over 60 minutes.
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
* Has documented seropositivity for CMV within 1 year before hematopoietic stem cell transplant (HSCT) * Receiving first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant) * Female or male participant who is not of reproductive potential, or, if of reproductive potential, agrees to true abstinence or to use (or have their partner use) 2 acceptable methods of birth control from the time of consent through 90 days after the last dose of study drug * Able to read, understand, and complete questionnaires and diaries
Exclusion criteria
* Received a previous allogeneic HSCT (previous autologous HSCT is acceptable) * History of CMV end-organ disease within 6 months before randomization * Has evidence of CMV viremia (if tested) at any time from either signing of the Informed Consent Form or the HSCT procedure, whichever is earlier, until the time of randomization. * Received the following within 7 days before screening or plans to receive during the study: ganciclovir, valganciclovir, foscarnet, acyclovir, valacyclovir, or famciclovir * Received the following within 30 days before screening or plan to receive during the study: cidofovir, CMV hyper-immune globulin, any investigational CMV antiviral agent or biological therapy * Has suspected or known hypersensitivity to ingredients of MK-8228 (letermovir) formulations * Has severe hepatic insufficiency within 5 days before randomization * Has end-stage renal impairment * Has an uncontrolled infection on the day of randomization * Requires mechanical ventilation or is hemodynamically unstable at the time of randomization * Has documented positive results for human immunodeficiency virus (HIV) antibody, hepatitis C virus (HCV) antibody with detectable HCV ribonucleic acid, or hepatitis B surface antigen (HBsAg) within 90 days before randomization * Has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (for example, lymphoma) * Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of study drug * Is expecting to donate eggs or sperm from the time of consent through 90 days after the last dose of study drug * Has participated in a study with an unapproved investigational compound (monoclonal antibodies are excepted) or device within 28 days of the first dose of study drug * Has previously participated in a MK-8228 (letermovir) study * Has, is, or is planning (during the study) to participate in any study involving administration of a CMV vaccine or another CMV investigational agent * Is a user of recreational or illicit drugs or has a recent history (\<=1 year) of drug or alcohol abuse or dependence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant | Up to Week 24 post-transplant | Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | Up to Week 24 post-transplant | Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically-significant CMV infection was defined from the day of transplantation to the day the participant developed clinically-significant CMV infection, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not develop clinically-significant CMV infection. |
| Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant | Up to Week 14 post-transplant | Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed. |
| Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant | Up to Week 24 post-transplant | CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed. |
| Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant | Up to Week 14 post-transplant | CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed. |
| Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant | Up to Week 24 post-transplant | Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed. |
| Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | Up to Week 24 post-transplant | The need for anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The outcome was calculated from the day of transplantation to the start of anti-CMV pre-emptive therapy, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not initiate pre-emptive therapy. |
| Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant | Up to Week 14 post-transplant | Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant | Up to Week 48 post-transplant | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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, is also an adverse event. |
| Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | Up to Week 14 post-transplant | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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, is also an adverse event. |
Participant flow
Recruitment details
A total of 738 participants were screened, 570 were randomized 2:1 letermovir:placebo, and 565 received at least one dose of study medication.
Pre-assignment details
Screening could occur up to 15 days before Hematopoietic Stem Cell Transplant (HSCT) and no more than Day 28 post-transplant. From the time of screening to randomization, participants were tested weekly for Cytomegalovirus (CMV) viremia; a positive test resulted in exclusion from the study.
Participants by arm
| Arm | Count |
|---|---|
| Letermovir Letermovir oral or intravenous (IV) formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The dose was 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets. | 376 |
| Placebo Placebo oral or IV formulation was administered once daily for up to 14 weeks, beginning up to Day 28 post-transplant. The number of placebo tablets was to mimic that for letermovir administration according to the concomitant cyclosporin A status. Intravenous infusion was administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets. | 194 |
| Total | 570 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Death | 71 | 44 |
| Overall Study | Lost to Follow-up | 8 | 4 |
| Overall Study | Non-compliance with study drug | 1 | 0 |
| Overall Study | Not treated | 3 | 2 |
| Overall Study | Physician Decision | 15 | 5 |
| Overall Study | Withdrawal by Subject | 28 | 17 |
Baseline characteristics
| Characteristic | Placebo | Total | Letermovir |
|---|---|---|---|
| Age, Continuous | 50.8 Years STANDARD_DEVIATION 14.8 | 50.8 Years STANDARD_DEVIATION 13.9 | 50.8 Years STANDARD_DEVIATION 13.4 |
| Risk Stratum for CMV Reactivation High risk | 54 Participants | 176 Participants | 122 Participants |
| Risk Stratum for CMV Reactivation Low risk | 140 Participants | 394 Participants | 254 Participants |
| Sex: Female, Male Female | 77 Participants | 239 Participants | 162 Participants |
| Sex: Female, Male Male | 117 Participants | 331 Participants | 214 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 360 / 373 | 186 / 192 |
| serious Total, serious adverse events | 202 / 373 | 115 / 192 |
Outcome results
Primary
Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant
Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed.
Time frame: Up to Week 24 post-transplant
Population: The Full Analysis Set (FAS) was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1 (randomization). Participants who prematurely discontinued or had a missing outcome through the 24-week visit window were considered treatment failure (i.e. Non-completers equal failure \[NC=F\] approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant | 37.5 Percentage of participants |
| Placebo | Percentage of Participants With Clinically-significant CMV Infection up to Week 24 Post-transplant | 60.6 Percentage of participants |
p-value: <0.000195% CI: [-32.5, -14.6]Mantel Haenszel
Secondary
Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant
Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with clinically-significant CMV infection was assessed.
Time frame: Up to Week 14 post-transplant
Population: The FAS was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1. Participants who prematurely discontinued or had a missing outcome through the 14-week visit window were considered treatment failure (i.e. NC=F approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant | 19.1 Percentage of participants |
| Placebo | Percentage of Participants With Clinically-significant CMV Infection up to Week 14 Post-transplant | 50.0 Percentage of participants |
p-value: <0.000195% CI: [-39.9, -22.6]Mantel Haenszel
Secondary
Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant
CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed.
Time frame: Up to Week 14 post-transplant
Population: The FAS was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1. A participant with a missing value up to Week 14 was excluded from the analysis (i.e., Data as observed \[DAO\] approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant | 0.4 Percentage of participants |
| Placebo | Percentage of Participants With CMV End-organ Disease up to Week 14 Post-transplant | 1.4 Percentage of participants |
p-value: 0.225895% CI: [-3.5, 1.5]Mantel Haenszel
Secondary
Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant
CMV end-organ disease met per-protocol diagnostic criteria for CMV-pneumonia, gastrointestinal disease, hepatitis, central nervous system disease, retinitis, nephritis, cystitis, myocarditis, pancreatitis, or other disease categories. Only Clinical Adjudication Committee-confirmed CMV end-organ disease was included in this analysis. The percentage of participants with CMV end-organ disease was assessed.
Time frame: Up to Week 24 post-transplant
Population: The FAS was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1. A participant with a missing value up to Week 24 was excluded from the analysis (i.e., Data as observed \[DAO\] approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant | 2.0 Percentage of participants |
| Placebo | Percentage of Participants With CMV End-organ Disease up to Week 24 Post-transplant | 2.4 Percentage of participants |
p-value: 0.405695% CI: [-4, 3.2]Mantel Haenszel
Secondary
Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant
Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed.
Time frame: Up to Week 14 post-transplant
Population: The FAS was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1. Participants who prematurely discontinued or had a missing outcome through the 14-week visit window were considered treatment failure (i.e. NC=F approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant | 18.8 Percentage of participants |
| Placebo | Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 14 Post-transplant | 49.4 Percentage of participants |
p-value: <0.000195% CI: [-39.6, -22.4]Mantel Haenszel
Secondary
Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant
Initiation of anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The percentage of participants with initiation of anti-CMV pre-emptive anti-CMV therapy was assessed.
Time frame: Up to Week 24 post-transplant
Population: The FAS was all randomized participants who received ≥1 dose of study drug and had no detectable CMV DNA on Day 1. Participants who prematurely discontinued or had a missing outcome through the 24-week visit window were considered treatment failure (i.e. NC=F approach was used).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant | 36.6 Percentage of participants |
| Placebo | Percentage of Participants With Pre-emptive Therapy for CMV Viremia up to Week 24 Post-transplant | 59.4 Percentage of participants |
p-value: <0.000195% CI: [-32.3, -14.3]Mantel Haenszel
Secondary
Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)
The need for anti-CMV pre-emptive therapy was based on documented CMV viremia and the clinical condition of the participant. The outcome was calculated from the day of transplantation to the start of anti-CMV pre-emptive therapy, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not initiate pre-emptive therapy.
Time frame: Up to Week 24 post-transplant
Population: All randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | 17.2 Percentage of participants |
| Placebo | Time to Initiation of Pre-emptive Therapy for CMV Viremia (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | 42.4 Percentage of participants |
p-value: <0.0001Log Rank
Secondary
Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant)
Clinically-significant CMV infection was defined as either one of the following: 1) onset of CMV end-organ disease, or 2) initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically-significant CMV infection was defined from the day of transplantation to the day the participant developed clinically-significant CMV infection, and was analyzed by the Kaplan-Meier method. Participants were censored at the last assessment for participants who discontinued or did not develop clinically-significant CMV infection.
Time frame: Up to Week 24 post-transplant
Population: All randomized participants who received at least one dose of study drug and had no detectable CMV viral DNA on the day treatment was initiated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | 18.9 Percentage of participants |
| Placebo | Time to Onset of Clinically-significant CMV Infection (Kaplan-Meier Estimate of Percentage of Participants With a Qualifying Event at Week 24 Post-transplant) | 44.3 Percentage of participants |
p-value: <0.0001Log Rank
Other Pre-specified
Percentage of Participants Discontinued From Study Medication Due to an Adverse Event
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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, is also an adverse event.
Time frame: Up to Week 14 post-transplant
Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 19.6 Percentage of participants |
| Placebo | Percentage of Participants Discontinued From Study Medication Due to an Adverse Event | 51.6 Percentage of participants |
Other Pre-specified
Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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, is also an adverse event.
Time frame: Up to Week 48 post-transplant
Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Letermovir | Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant | 98.4 Percentage of participants |
| Placebo | Percentage of Participants With One or More Adverse Events up to Week 48 Post-transplant | 100.0 Percentage of participants |