Extension of Letermovir (LET) From Day 100 to Day 200 Post-transplant for the Prevention of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant (HSCT) Participants (MK-8228-040)

• ClinicalTrials.gov Identifier: NCT03930615
• Recruitment Status: Completed
• First Posted: April 29, 2019
• Results First Posted: November 1, 2022
• Last Update Posted: November 1, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Cytomegalovirus Infection
• Interventions: Drug: Letermovir; Drug: Placebo
• Enrollment: 220

Participant Flow

Recruitment Details	Cytomegalovirus (CMV)-seropositive recipients (R+) of a hematopoietic stem cell transplant (HSCT) who had received letermovir (LET) prophylaxis through Week 14 (~100 days) post-transplant and were at high risk for CMV infection and/or disease were enrolled in this study.
Pre-assignment Details

Arm/Group Title	Letermovir	Placebo
Arm/Group Description	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Period Title: Overall Study
Started [1]	145	75
Treated	144	74
Completed	118	63
Not Completed	27	12
Reason Not Completed
Death	9	3
Lost to Follow-up	1	2
Physician Decision	3	4
Withdrawal by Subject	13	2
Not treated	1	1
[1] Randomized

Baseline Characteristics

Arm/Group Title		Letermovir	Placebo	Total
Arm/Group Description		Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.	Total of all reporting groups
Overall Number of Baseline Participants		144	74	218
Baseline Analysis Population Description		Treated participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	144 participants	74 participants	218 participants
		51.9 (14.3)	52.7 (12.9)	52.2 (13.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	144 participants	74 participants	218 participants
	Female	52 36.1%	31 41.9%	83 38.1%
	Male	92 63.9%	43 58.1%	135 61.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	144 participants	74 participants	218 participants
	Hispanic or Latino	13 9.0%	8 10.8%	21 9.6%
	Not Hispanic or Latino	106 73.6%	53 71.6%	159 72.9%
	Unknown or Not Reported	25 17.4%	13 17.6%	38 17.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	144 participants	74 participants	218 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	16 11.1%	8 10.8%	24 11.0%
	Native Hawaiian or Other Pacific Islander	2 1.4%	0 0.0%	2 0.9%
	Black or African American	3 2.1%	1 1.4%	4 1.8%
	White	113 78.5%	60 81.1%	173 79.4%
	More than one race	2 1.4%	1 1.4%	3 1.4%
	Unknown or Not Reported	8 5.6%	4 5.4%	12 5.5%
Donor Stratum; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	144 participants	74 participants	218 participants
Haploidentical		45 31.3%	22 29.7%	67 30.7%
Non-haploidentical		99 68.8%	52 70.3%	151 69.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Clinically Significant CMV Infection From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
Description	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV preemptive therapy (PET) with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the observed failure (OF) approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 28 post-transplant. It was hypothesized that LET is superior to placebo in the prevention of clinically significant CMV infection when LET prophylaxis is extended from 100 to 200 days.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	2.8	18.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	It was hypothesized that LET is superior to placebo in the prevention of clinically significant CMV infection.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	A one-sided p-value ≤0.0249 was used for declaring statistical significance
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-16.1
	Confidence Interval	(2-Sided) 95%; -25.8 to -6.5
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

2. Secondary Outcome

Title	Percentage of Participants Experiencing ≥1 Adverse Events (AEs) From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
Description	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention according to the study intervention they received.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	88.9	93.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 95%; -11.8 to 4.7
	Estimation Comments	Letermovir minus Placebo
Other Statistical Analysis		Miettinen & Nurminen method

3. Secondary Outcome

Title	Percentage of Participants Withdrawing From Study Drug Due to an AE From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
Description	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention according to the study intervention they received.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	4.9	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -2.7 to 8.6
	Estimation Comments	Letermovir minus Placebo
Other Statistical Analysis		Miettinen & Nurminen method

4. Secondary Outcome

Title	Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 38 Post-transplant
Description	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 38 post-transplant.
Time Frame	From Week 14 post-transplant to Week 38 post-transplant (approximately 24 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	14.6	20.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1591
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 95%; -16.8 to 5.4
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

5. Secondary Outcome

Title	Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 48 Post-transplant
Description	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Missing values were handled by the OF approach where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 (~100 days) through week 48 post-transplant.
Time Frame	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	14.6	20.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1591
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 95%; -16.8 to 5.4
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

6. Secondary Outcome

Title	Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 28 Post-transplant
Description	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA means that due to the less than 50% incidence of clinically significant CMV infection, the median time was not reached.

7. Secondary Outcome

Title	Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 48 Post-transplant
Description	Clinically significant CMV infection is either the onset of probable or proven CMV end-organ disease or initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and the clinical condition of the participant. Time to onset of clinically significant CMV infection is the elapsed time from transplant to the onset of CMV end-organ disease or to the initiation of anti-CMV PET. Time to onset was determined from the Kaplan-Meier method for censored data.
Time Frame	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA means that due to the less than 50% incidence of clinically significant CMV infection, the median time was not reached.

8. Secondary Outcome

Title	Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 28 Post-transplant
Description	The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 28 post-transplant.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	2.1	16.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0012
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-14.1
	Confidence Interval	(2-Sided) 95%; -23.3 to -5.0
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

9. Secondary Outcome

Title	Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 48 Post-transplant
Description	The percentage of participants with CMV viremia who initiated PET of anti-CMV agents (ganciclovir, valganciclovir, foscarnet, and/or cidofovir) was determined. Missing values were handled with the OF approach, where failure was defined as all participants who develop clinically significant CMV infection or discontinue prematurely from the study with CMV viremia from week 14 through week 48 post-transplant.
Time Frame	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	13.2	18.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1494
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.7
	Confidence Interval	(2-Sided) 95%; -16.5 to 5.1
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

10. Secondary Outcome

Title	Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant
Description	The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 28 was determined.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	2.1	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6244
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -3.8 to 5.3
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

11. Secondary Outcome

Title	Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant
Description	The percentage of participants who died due to any cause (all-cause mortality) from Week 14 to Week 48 was determined.
Time Frame	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Measure Type: Number; Unit of Measure: Percentage of participants
	8.3	8.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letermovir, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5264
	Comments	[Not Specified]
	Method	Mantel Haenszel
	Comments	Stratum adjusted
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -7.9 to 8.4
	Estimation Comments	Letermovir minus placebo
Other Statistical Analysis		95% CIs for the treatment differences in percent response were calculated using stratum adjusted Mantel Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no).

12. Secondary Outcome

Title	Time to All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant
Description	Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data.
Time Frame	From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA means that as participants were followed for less than a year after transplant, this was insufficient time to reach a median survival time.

13. Secondary Outcome

Title	Time to All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant
Description	Time to all-cause mortality is the time elapsed after Week 14 post-transplant and death due to any cause, and was determined from the Kaplan-Meier method for censored data.
Time Frame	From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study intervention.

Arm/Group Title	Letermovir	Placebo
Arm/Group Description:	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
Overall Number of Participants Analyzed	144	74
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA means that as participants were followed for less than a year after transplant, this was insufficient time to reach a median survival time.

Adverse Events

Time Frame	All-cause mortality: From 14 weeks post-transplant up to 48 weeks post-transplant (approximately 34 weeks); adverse events (AEs) and serious AEs (SAEs): From 14 weeks post-transplant up to 30 weeks post-transplant (approximately 16 weeks).
Adverse Event Reporting Description	The population analyzed for all-cause mortality (death due to any cause) was all randomized participants. The population analyzed for AEs was all randomized participants who received at least 1 dose of study intervention according to the study intervention they received. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Arm/Group Title	Letermovir		Placebo
Arm/Group Description	Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.		Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.
All-Cause Mortality
	Letermovir		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	16/145 (11.03%)		8/75 (10.67%)
Serious Adverse Events
	Letermovir		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/144 (34.03%)		27/74 (36.49%)
Blood and lymphatic system disorders
Anaemia † 1	1/144 (0.69%)	1	1/74 (1.35%)	2
Leukopenia † 1	1/144 (0.69%)	1	1/74 (1.35%)	1
Neutropenia † 1	0/144 (0.00%)	0	2/74 (2.70%)	2
Pure white cell aplasia † 1	1/144 (0.69%)	2	0/74 (0.00%)	0
Thrombotic microangiopathy † 1	0/144 (0.00%)	0	2/74 (2.70%)	2
Cardiac disorders
Cardiac failure congestive † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pericarditis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Congenital, familial and genetic disorders
Aplasia † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Endocrine disorders
Thyroiditis subacute † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Gastrointestinal disorders
Diarrhoea † 1	2/144 (1.39%)	2	0/74 (0.00%)	0
Gastrointestinal haemorrhage † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Haematochezia † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Intestinal perforation † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pneumatosis intestinalis † 1	0/144 (0.00%)	0	1/74 (1.35%)	2
Stomatitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
General disorders
Multiple organ dysfunction syndrome † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pyrexia † 1	4/144 (2.78%)	4	1/74 (1.35%)	2
Immune system disorders
Graft versus host disease † 1	9/144 (6.25%)	9	6/74 (8.11%)	6
Infections and infestations
Acute sinusitis † 1	1/144 (0.69%)	1	1/74 (1.35%)	1
Adenoviral haemorrhagic cystitis † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Adenovirus infection † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Anal abscess † 1	0/144 (0.00%)	0	2/74 (2.70%)	2
Appendicitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Bronchopulmonary aspergillosis † 1	0/144 (0.00%)	0	2/74 (2.70%)	2
COVID-19 † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
COVID-19 pneumonia † 1	0/144 (0.00%)	0	2/74 (2.70%)	4
Cellulitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Cerebral toxoplasmosis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Clostridium difficile colitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Cytomegalovirus chorioretinitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Cytomegalovirus infection † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Cytomegalovirus infection reactivation † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Cytomegalovirus viraemia † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Escherichia infection † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Gastroenteritis viral † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Herpes simplex † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Human herpesvirus 6 infection † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Influenza † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Lower respiratory tract infection fungal † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Lymph node tuberculosis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Mastoiditis † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Myelitis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Neutropenic sepsis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pneumocystis jirovecii pneumonia † 1	1/144 (0.69%)	1	1/74 (1.35%)	1
Pneumonia † 1	4/144 (2.78%)	4	5/74 (6.76%)	5
Pneumonia aspiration † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Pneumonia bacterial † 1	2/144 (1.39%)	2	0/74 (0.00%)	0
Pneumonia fungal † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pneumonia influenzal † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pneumonia klebsiella † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Pneumonia pseudomonal † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Pneumonia viral † 1	1/144 (0.69%)	1	1/74 (1.35%)	1
Pseudomonal sepsis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Rhinovirus infection † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Sepsis † 1	2/144 (1.39%)	2	2/74 (2.70%)	2
Septic shock † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Staphylococcal infection † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Urinary tract infection † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Vascular device infection † 1	0/144 (0.00%)	0	2/74 (2.70%)	2
Viral upper respiratory tract infection † 1	1/144 (0.69%)	1	1/74 (1.35%)	1
Injury, poisoning and procedural complications
Subdural haematoma † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Transplant failure † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Investigations
Escherichia test positive † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Platelet count decreased † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Troponin increased † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Metabolism and nutrition disorders
Hypoproteinaemia † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Musculoskeletal and connective tissue disorders
Pathological fracture † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia recurrent † 1	2/144 (1.39%)	2	0/74 (0.00%)	0
Acute myeloid leukaemia recurrent † 1	8/144 (5.56%)	8	3/74 (4.05%)	3
Chloroma † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Large granular lymphocytosis † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Lymphoma † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Myelodysplastic syndrome † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Peripheral T-cell lymphoma unspecified recurrent † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Plasma cell myeloma recurrent † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Post transplant lymphoproliferative disorder † 1	2/144 (1.39%)	3	1/74 (1.35%)	1
Nervous system disorders
Guillain-Barre syndrome † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Psychiatric disorders
Confusional state † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Renal and urinary disorders
Nephrolithiasis † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Reproductive system and breast disorders
Heavy menstrual bleeding † 1	1/144 (0.69%)	2	0/74 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
Hypoxia † 1	0/144 (0.00%)	0	1/74 (1.35%)	1
Pulmonary embolism † 1	1/144 (0.69%)	1	0/74 (0.00%)	0
1 Term from vocabulary, MedDRA 25.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Letermovir		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	100/144 (69.44%)		58/74 (78.38%)
Blood and lymphatic system disorders
Anaemia † 1	8/144 (5.56%)	9	3/74 (4.05%)	3
Gastrointestinal disorders
Diarrhoea † 1	16/144 (11.11%)	19	11/74 (14.86%)	12
Nausea † 1	17/144 (11.81%)	19	15/74 (20.27%)	17
Vomiting † 1	9/144 (6.25%)	10	3/74 (4.05%)	4
General disorders
Fatigue † 1	5/144 (3.47%)	6	5/74 (6.76%)	5
Oedema † 1	0/144 (0.00%)	0	4/74 (5.41%)	4
Oedema peripheral † 1	12/144 (8.33%)	12	9/74 (12.16%)	10
Pyrexia † 1	12/144 (8.33%)	13	9/74 (12.16%)	13
Immune system disorders
Graft versus host disease † 1	45/144 (31.25%)	61	22/74 (29.73%)	34
Infections and infestations
Cytomegalovirus infection † 1	3/144 (2.08%)	4	4/74 (5.41%)	4
Cytomegalovirus infection reactivation † 1	6/144 (4.17%)	6	5/74 (6.76%)	6
Upper respiratory tract infection † 1	6/144 (4.17%)	7	5/74 (6.76%)	5
Investigations
Alanine aminotransferase increased † 1	5/144 (3.47%)	5	4/74 (5.41%)	5
Neutrophil count decreased † 1	4/144 (2.78%)	4	4/74 (5.41%)	6
Metabolism and nutrition disorders
Decreased appetite † 1	6/144 (4.17%)	7	11/74 (14.86%)	13
Hypokalaemia † 1	5/144 (3.47%)	5	4/74 (5.41%)	4
Musculoskeletal and connective tissue disorders
Arthralgia † 1	6/144 (4.17%)	6	5/74 (6.76%)	5
Nervous system disorders
Dizziness † 1	3/144 (2.08%)	3	4/74 (5.41%)	5
Headache † 1	10/144 (6.94%)	11	4/74 (5.41%)	4
Respiratory, thoracic and mediastinal disorders
Cough † 1	8/144 (5.56%)	8	9/74 (12.16%)	11
Oropharyngeal pain † 1	9/144 (6.25%)	10	6/74 (8.11%)	7
Skin and subcutaneous tissue disorders
Pruritus † 1	11/144 (7.64%)	11	2/74 (2.70%)	3
Rash † 1	9/144 (6.25%)	11	8/74 (10.81%)	8
1 Term from vocabulary, MedDRA 25.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission.

Results Point of Contact

• Name/Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC
• Phone: 1-800-672-6372
• EMail: ClinicalTrialsDisclosure@merck.com

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03930615
• Other Study ID Numbers: 8228-040; MK-8228-040 ( Other Identifier: Merck Sharp & Dohme Corp. ); 194797 ( Registry Identifier: JAPIC-CTI ); 2018-001038-17 ( EudraCT Number )
• First Submitted: April 26, 2019
• First Posted: April 29, 2019
• Results First Submitted: October 5, 2022
• Results First Posted: November 1, 2022
• Last Update Posted: November 1, 2022