Conditions: Cytomegalovirus Disease Cytomegalovirus Infections Heart Transplant Infection Antiviral Toxicity Neutropenia
Keywords: cytomegalovirus, letermovir, heart transplantation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is an open label trial in which letermovir will be given as prophylaxis for the prevention of cytomegalovirus (CMV) infection and disease to all heart transplants who are at risk for cytomegalovirus. The study will compare a 30 patient prospective cohort to a retrospective cohort of 374 heart transplant recipients for the rates of neutropenia. In addition, the tolerability of letermovir will be assessed in this population.

Detailed description:
This open label trial will follow 30 heart transplant recipients at Tufts Medical Center who will receive letermovir in a dose of 480 mg daily for either 3 or 6 months depending on the CMV risk category, and who will be followed for one year. Comparison will be made to a cohort of heart transplant recipients as historical controls in a recently presented study (Chow, J, et al ISHLT 2021). Standard follow up will be provided as if the patients were receiving valganciclovir prophylaxis. Post prophylaxis T cell immunity to all subjects enrolled will be tested. Clinical outcomes are detailed below.

Arms:
arm 1: Letermovir 480 mg daily for cmv prophylaxis

Interventions: intervention 1: Letermovir
Intervention descriptions: intervention 1: Open label trial of the licensed drug, letermovir, in a population of heart transplant recipients for which it is not yet licensed

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
EVALUATION OF THE TOLERABILITY AND CLINICAL 
EFFECTIVENESS OF LETERMOVIR IN HEART 
TRANSPLANT RECIPIENTS 
 
NCT04904614 
Date: 2/17/2025 
 
 
Principal Investigator: Jennifer K. Chow, MD, FIDSA, FAST  
Co-Investigators: David Denofrio, MD 
 
Address: 
Tufts Medical Center 
Division of Geographic Medicine and Infectious Diseases 
800 Washington Street, Box 238 
Boston, MA  02111 
 
Phone: 
 
617-636-5244 
 
e-mail: 
Jennifer.Chow@tuftsmedicine.org 
 
Sponsor:  
Merck and Company  
 
 


 
2 
 
 
 
STATEMENT OF COMPLIANCE 
 
: 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following [use applicable regulations depending on study location 
and sponsor requirements; samples follow]: 
• U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
• ICH GCP E6 
• Completion of Human Subjects Protection Training 
 
http://www.fda.gov/cder/guidance/959fnl.pdf 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html 
http://cme.cancer.gov/c01/ 
 
 


 
3 
 
 
SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, 
and provides the necessary assurances that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
 
Site Investigator:* 
 
Signed:  
Date: 
 
 
Name 
Title 
 
 
 
* The protocol should be signed by the local investigator who is responsible for the study 
implementation at his/her specific site; i.e., if Investigational New Drug study, the individual who signs 
the Form FDA 1572. 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
1.1 
 Study Objectives 
6 
 
2.1 
Specific Aims 
6 
2.1.1 
Clinical Hypothesis 
6 
2.2 
Background and Rationale 
6 
2.3 
Preliminary Data 
7 
2.4 
Rationale for Letermovir 
7 
2.5 
The Environment 
8 
3.1 
Study Design 
9 
3.1.1 
Inclusion Criteria 
9 
3.1.2 
Exclusion Criteria 
10 
3.2 
Analysis Plan 
12 
3.2.1 
Primary Endpoint 
12 
3.2.2 
Secondary Endpoints 
12 
3.2.3 
Power Analyses 
12 
3.3 
Definitions 
12 
4.0 
Study Procedures 
13 
4.1 
Dosing of Letermovir Prophylaxis 
17 
4.2 
Dose Modification 
17 
4.3 
Dietary Restrictions 
18 
5.1 
Treatment Compliance 
18 
5.2 
Concomitant Therapy 
19 
6.0 
CMV Disease Assessments and Management 
23 


 
5 
 
6.1 
CMV Viral Resistance Testing 
24 
 
6.2 
Quantiferon-CMV Measurements 
24 
6.3 
Rescue Medications and Supportive Care 
24 
6.4 
Treatment after End of Study 
25 
7.1 
Safety Endpoints 
25 
7.1.1 
Leukopenia and Neutropenia 
25 
7.2 
Method of Detecting AE, SAE, and Other Reportable Safety  
 
 Event Information 
25 
7.3 
Follow up of AE, SAE and Other Reportable Safety Event  
 Information 
26 
7.4 
Regulatory Reporting Requirements for SAE 
26 
8. 
Discontinuation/Withdrawal Criteria 
26 
8.1 
Discontinuation of Study Treatment  
26 
8.2 
Withdrawal from Study 
28 
8.3 
Lost to Follow-up 
28 
8.3.1 
Pregnancy and Exposure During Breastfeeding 
28 
8.3.2 
Events of Clinical Interest 
28 
8.4 
Treatment of Overdose 
29 
8.4.1 
Adverse Events Monitoring 
29 
 
8.4.2 
Laboratory Safety Evaluations 
29 
 
9.0 
Literature Cited 
30 
 
 


 
6 
 
Evaluation of the tolerability and clinical effectiveness of letermovir in heart 
transplant recipients 
1.1 Study objectives  
We propose to study letermovir prophylaxis for cytomegalovirus (CMV) prevention in 
heart transplant recipients to establish tolerability and clinical effectiveness in a 
cohort of patients followed prospectively.  
2.1 Specific Aims 
1. To establish that letermovir can be well tolerated in cardiac transplant 
recipients and be associated with a lower rate of neutropenia in this 
population compared to historic controls in our well defined prior cardiac 
transplant cohort 
 
2. To assess the rates of CMV infection and disease in cardiac transplant 
recipients who receive letermovir prophylaxis.   
 
3. To compare this prospective cohort to our historic controls of 274 heart 
transplant recipients in the data base established through the Merck IISP 
program (accepted at ISHLT in April 2020) for all clinical outcomes including 
CMV infection, CMV disease, opportunistic infections, graft rejection and 
death 
 
2.1.1 Clinical hypotheses 
1. The clinical hypothesis is that letermovir will be well tolerated and less 
marrow toxic than valganciclovir or ganciclovir in a cohort of heart transplant 
recipients. We know that about 30% of heart transplants develop neutropenia 
in the first year post transplant and that valganciclovir use is one of the 
associated risk factors. Knowing that letermovir is a less marrow toxic agent 
we hypothesize it will be better tolerated than valganciclovir or ganciclovir in 
this population. 
 
2. We also hypothesize that letermovir will be clinically effective in preventing 
CMV disease in this population.   
 
2.2 Background and Rationale 
There is a need for alternative medications to prevent cytomegalovirus in organ 
transplantation (1). The current regimen of valganciclovir prophylaxis is often 


 
7 
 
associated with neutropenia, as well as the development of late onset CMV infection 
and disease, especially in the high risk subset of CMV donor positive to CMV 
recipient negative mismatched transplants (2). Letermovir has been licensed for 
prevention of CMV in stem cell transplantation (3). It is being studied in renal 
transplant recipients currently (4). We have had some experience in using letermovir 
to treat or provide secondary prophylaxis among heart transplant recipients who 
have had prolonged courses of CMV viremia, as an alternative to the toxicity which 
was associated with valganciclovir use. In addition, we have seen frequent relapse 
following cessation of secondary prophylaxis with valganciclovir as well as 
development of resistance.  
2.3 Preliminary Data 
In a cohort of heart transplant recipients we found that 30% of 274 patients 
developed neutropenia at a median of 142 days post transplant. Half required 
GCSF. In a multivariate analysis of causes of neutropenia in heart transplant 
recipients, being at high risk for CMV infection (D+/R-), lower baseline WBC at time 
of transplant, prior CMV infection and having a VAD pre heart transplant were all 
independently related to the development of neutropenia (5). We also have data on 
all clinical outcomes, including rates of CMV disease, rates of rejection, 1year 
mortality and the development of opportunistic infections to which we can compare 
the prospectively followed letermovir patients.  
 
2.4 Rationale for Letermovir  
 
Letermovir (LET) belongs to a new class of anti-CMV agents with a novel 
mechanism of action with: 
 
(1) Significant anti-CMV activity in in vitro and in vivo pre-clinical studies; 
(2) A favorable clinical safety profile demonstrated in Phase 1 and 2 studies, as 
well as in the Phase 3 P001 study in hematopoietic stem cell transplant 
(HSCT) recipients; 
(3) Clinical efficacy as demonstrated in a study in HSCT recipients (3); and 
(4) Activity against viral isolates resistant to marketed anti-CMV agents, also 
demonstrated in a case of multi-organ disease due to multi-resistant CMV 
(6).  The activity of these agents map to the UL54 or UL97 genes, while LET 
activity maps to the UL56 (terminase) gene (7). 
Letermovir inhibits the viral terminase complex (UL51/UL56/UL89), an enzyme that 
plays an important role in cleavage of concatenated viral DNA into individual unit-
length genomes that are subsequently inserted into CMV procapsids to generate 


 
8 
 
infectious CMV virions (7).  Letermovir has demonstrated potent, selective, and 
reversible inhibition of CMV activity in preclinical studies in vitro and efficacy against 
the virus in vivo (7,8). 
Letermovir has been shown to be generally well tolerated in 28 Phase 1 studies, 2 
Phase 2 studies, and a pivotal Phase 3 study, P001, in HSCT recipients.  In P001, in 
which CMV seropositive allogeneic HSCT recipients received letermovir or placebo 
from the early post-transplant period (within 4 weeks post-transplant) through Week 
14 post-transplant and were followed for an additional 34 weeks, Letermovir was 
superior to placebo in the prevention of clinically significant CMV infection (defined 
as onset of CMV end-organ disease OR initiation of anti-CMV preemptive therapy 
based on documented CMV DNAemia as measured by the central laboratory) and 
the clinical condition of the participant through Week 24 post-transplant (3).  
Letermovir prophylaxis also resulted in lower all-cause mortality relative to placebo 
through Week 24 post-transplant and Week 48 post-transplant in HSCT recipients. 
Based on its mechanism of action that is distinct from other available anti-CMV 
agents, patients who are given Letermovir for prophylaxis and experience CMV 
infection or disease, i.e., a clinical and/or virological CMV “breakthrough” event, are 
still expected to retain available treatment options using existing anti-CMV 
medications.  
2.5 The Environment 
The Advanced Heart Failure Program, Tufts Medical Center 
 
The Tufts Medical Center Heart Transplantation Program placed within the top 10 
nationally both for volumes and outcomes in 2018. In 2019 there were 43 heart 
transplants. Our 1 year survival has been 94.7% with a 3-year survival of 94.1% and 
a 5-year survival 86.3% (from Jan 2020 SRTR data). We are the only hospital in 
Boston with a consistent 5 tier rating for 1year outcomes. The Tufts Advanced Heart 
Failure (HF) Program is located on the main campus of Tufts Medical Center and 
receives approximately 120 new referrals annually for advanced HF therapy 
evaluations – left ventricular assist device (LVAD) implantations and heart 
transplantations. The program also has a robust Mechanical Circulatory Support 
Program, accredited by the Joint Commission, with 30-40 durable LVAD 
implantations annually. We implant the FDA-approved HeartMate II®, HeartMate III® 
and HeartWare® LVADs and participate in the INTERMACS registry as well as 
several industry device trials such as the APOGEE study. 
 
The Advanced HF Program research program also participates in a range of 
industry, federal and investigator-initiated trials. Tufts Medical Center has been a site 
in National Institutes of Health (NIH)-funded Heart Failure Network trials and 
participates in drug and device trials for patients with both HF with reduced ejection 
fraction and HF with preserved ejection fraction.  


 
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Division of Geographic Medicine and Infectious Diseases 
Dr. Snydman has been conducting studies of CMV prophylaxis for 40 years, both in 
solid organ and stem cell transplantation. He has also been doing data base 
analyses of CMV infection and disease for over 35 years, as well as cost 
effectiveness analyses, and cohort studies. Dr. Snydman has experience and 
expertise in writing IND, and NDA reports as well as performing investigator initiated 
IND’s, both for drugs, biologics, and probiotics. 
The transplant ID program is fully integrated into the cardiac transplant program and 
follows about 100 heart transplants in the heart ID program lead by Dr. Helen 
Boucher, the Chief of the Division. Dr. Jennifer Chow has been involved in transplant 
ID studies for over a decade, and has experience in clinical trial cohort management, 
study design and data analysis in this population. She is an attending in the heartID 
program. 
 
We propose to study letermovir prophylaxis in heart transplant recipients to 
establish tolerability and comparable efficacy at CMV prevention in a cohort of 
patients followed prospectively and compared to a well defined historic 
control group.  
3.1 Study Design 
We propose to enroll 100 heart transplant recipients over two years in order to have 
35 heart transplant recipients to receive letermovir prophylaxis in an open label trial 
to prevent CMV infection and disease. This number is based on an estimate of about 
40-45 transplants per year, of whom 30 (75%) would be eligible for CMV prophylaxis 
based on CMV donor and recipient status (we would not enroll CMV D-/R- transplant 
patients). There are competing clinical trials with immunosuppressive modalities so 
we anticipate enrolling about 15 patients per year who will consent and are able to 
be followed for the one year follow up.  
Eligibility would be limited to heart transplant recipients who are not CMV D-/R- who 
are not enrolled in competing clinical trials and who are willing and able to participate 
in the trial. Written informed consent will be required.  
3.1.1 Inclusion criteria 
1.      Adults between 18-70 will be eligible for participation  
2. Written informed consent and able to participate with follow up  
3. Heart transplant recipients who are not CMV donor negative and CMV recipient 
negative (CMV -/-) 
4. Not enrolled in competing clinical trials 


 
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3.1.2  Exclusion Criteria 
1. Dual heart and kidney transplant recipients 
2. Patients who do not survive 72 hours post transplant 
3. HIV infection  
4. Patients with creatinine clearance less than 10 ml per min at time of enrollment 
5. Hypersensitivity to letermovir 
6. On CVVH or renal dialysis at the time of enrollment  
7. Received a previous solid organ transplant or HSCT. 
8. Has Child-Pugh Class C severe hepatic insufficiency at screening. 
9. Has both moderate hepatic insufficiency AND moderate-to-severe renal 
insufficiency at screening. 
Note:  Moderate hepatic insufficiency is defined as Child-Pugh Class B; 
moderate-to-severe renal insufficiency is defined as CrCl <50 mL/min, as 
calculated by the Cockcroft-Gault equation (as above), respectively. 
10. Has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical 
cancer or carcinoma in situ; or is under evaluation for other active or suspected 
malignancy. 
11. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed 
from the time of consent through at least 90 days following cessation of study 
therapy. 
12. Is expecting to donate eggs or sperm starting from the time of consent through at 
least 90 days following cessation of study therapy. 
13. Has a history or current evidence of any condition, therapy, lab abnormality, or 
other circumstance that might confound the results of the study, interfere with the 
participant’s participation for the full duration of the study, or put the participant at 
undue risk, as judged by the investigator, such that it is not in the best interest of 
the participant to participate in this study. 
13. Has exclusionary laboratory value at screening, as listed in Table 1. 


 
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Table 1 
Laboratory Exclusion Criteria 
Laboratory 
Assessment 
Exclusionary Value 
 
 
Hemoglobin 
<8 g/dL 
Platelets 
<25,000 cells/µL 
Absolute neutrophil 
count 
<1,000 cells/µL 
Total bilirubin 
>2.5 × ULN 
ALT 
>5 × ULN 
AST 
>5 × ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus;  
IgG = immunoglobulin G; ULN = upper limit of normal 
 
14.  
15. 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 (excluding monoclonal antibodies), whichever is 
longer, of initial dosing on this study.  Participants previously treated with an 
investigational monoclonal antibody will be eligible to participate after a 150-day 
washout period. 
Note:  Investigational regimens involving combinations of approved agents 
are not permitted.  Other non-interventional or other observational studies are 
allowed. 
16. Has previously participated in this study or any other study involving LET. 
17. 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. 
No restriction will be made for CMV disease prior to transplant and up to 7 days of 
CMV prophylaxis with other medications will be allowed prior to enrollment. 
3.2 Analysis Plan 
The Principal Investigator and co-investigators will be responsible for maintaining the 
integrity of the data and analyzing it. We have considerable experience in this 
regard.  


 
12 
 
We will compare the historical cohort to the prospectively followed cohort. We will 
examine the following outcomes:  
3.2.1 Primary Endpoint:  
1. Proportion of patients with neutropenia at 12 months in the letermovir arm 
compared to historic controls. 
 
3.2.2 Secondary Endpoints: 
2. Rate of CMV infection at 1 year in the letermovir arm compared to the historic 
controls.  
3. Rate of rejection at 1 year in the letermovir arm compared to historic controls 
4. Rate of opportunistic infections or other infectious outcomes in the letermovir 
arm compared to historic controls.  
5. Tolerability and compliance of patients taking letermovir  
6. Use of GCSF in both groups. 
7. Measures of CMV specific immunity in the letermovir group at cessation of 
prophylaxis.  
 
 
3.2.3 Power Analyses  
The power analysis will be based on the rate of neutropenia occurring within one 
year.  
We know our baseline rate of neutropenia is 30% at 12 months (based on our cohort 
analysis of 274 heart transplant recipients) among ganciclovir/valganciclovir 
recipients (historic controls).  In the stem cell transplant trial, the rate of neutropenia 
was 3.8 % and leukopenia 2.9% among patients on letermovir. If we assume a rate 
of neutropenia of 5% in the letermovir arm, we have a 90% power to demonstrate a 
difference between the letermovir group and our historic controls (p<.05).Even 
assuming an upper boundary of 10% for the rate of neutropenia in the letermovir 
arm, 30 patients will give us 82% power (alpha of < .05) to show a significant 
difference between our historical cohort and the letermovir treated patients for 
development of neutropenia.  
3.3 Definitions 
CMV disease will be defined according to the criteria of the CMV consensus 
conference definitions (9,10) and used in other studies. Briefly these definitions will 
be:  
CMV infection: evidence of CMV replication regardless of symptoms; “defined as 
virus isolation or detection of viral proteins (antigens) or nucleic acid in any body 
fluid or tissue specimen” (9,10).  


 
13 
 
CMV disease: evidence of CMV infection with attributable symptoms. CMV disease 
can be further categorized as a viral syndrome (i.e. fever, malaise, leukopenia, 
and/or thrombocytopenia), or as tissue invasive (“end organ”) disease (9,10). 
Blood stream infection: Positive blood culture. Bacteremia caused by common skin 
contaminants will be considered significant if the same organism is isolated from two 
blood cultures in the presence of clinical signs of infection and/or an intravascular 
device (11).  
Invasive fungal infection: Identification of fungal or yeast species by cultures or 
histological examination from a normally sterile site (12). Solitary sputum, urine, or 
Foley catheter cultures were not counted as IFI events. Pulmonary and intracranial 
Nocardia infections will also be included in this category given that Nocardia is an 
opportunistic pathogen causing similar clinical disease to fungal organisms. 
Neutropenia will be defined as an absolute neutrophil count of < 1000 per mm3(5) 
Rejection 
Rejection will be defined as the composite of a first episode of biopsy-proven cellular 
rejection requiring admission for intravenous corticosteroids or other parenteral 
therapies, antibody mediated rejection requiring admission for intravenous 
corticosteroids, plasmapheresis, or other parenteral therapies, or any rejection 
episode causing hemodynamic compromise, graft loss, re-transplantation, or death.  
Data on type of treatment for rejection will be captured for all hospitalizations and 
outpatient visits. 
 
4.0 Study Procedures  
Once enrolled giving written informed consent, patients who are not CMV D+/R- 
would receive 3 months of letermovir prophylaxis at a dose of 480 mg orally or 
intravenously once per day starting within day 7 of transplantation. If patients are 
receiving cyclosporine, the letermovir dose would be reduced to 240 mg per day. If 
the cyclosporine is discontinued, the letermovir dose would be increased back to 
480 mg per day. Patients will receive HSV prophylaxis with famciclovir 500 mg orally 
twice a day as per our usual protocol (90 days).  The standard duration of letermovir 
prophylaxis for all but the group at high risk of CMV disease would be 3 months, the 
high risk (D+/R-) group would receive 6 months of prophylaxis which is our standard 
protocol with valganciclovir.   
We will collect demographic data including age, gender, underlying cardiac disease, 
use of ventricular assist device, other co-morbidities, labs including WBC at time of 
transplant, and infections at time of transplant well as donor information.  
Patients will be followed prospectively with data collection obtained at the time of 
each clinic visit. We routinely follow patients daily while hospitalized then weekly for 


 
14 
 
about a month post-transplant, then every other week for two months and then 
monthly thereafter. Routine clinical management labs (including electrolytes, BUN, 
creatinine, CDC and differential, LFT’s, immunosuppressive drug levels) are 
obtained at the time of each visit. We will assess compliance through pill counts at 
monthly visits. At each visit the tolerability of letermovir will be assessed as well 
using a standardized questionnaire for tolerability. Follow up phone calls will also be 
employed when necessary.   
Cardiac catheterization is done routinely (every week for first 4 weeks, then every 
other week for two months, then monthly for the first year) to assess rejection, and at 
any sign of concern for rejection. Patients will be followed as part of the study 
protocol for one year post transplant in order to capture late onset CMV infection and 
disease as well as other infectious outcomes including opportunistic infections, graft 
rejection, treatment for rejection, or death.  
With respect to CMV infection surveillance, we do not monitor patients for viral load 
during prophylaxis unless there is a suspicion of breakthrough viremia. Once 
patients discontinue prophylaxis, we do perform routine surveillance for CMV weekly 
for two months, then with any sign or symptom that might be consistent with CMV.  
At cessation of letermovir prophylaxis (+/- 2 weeks) we will obtain a sample of 
measurement of CMV specific T cell immunity.  
A schematic diagram and list of procedures is shown in Figure 1. 
 
 
 
 
 
 
 
 
 
Figure 1.  Schematic Diagram of Procedures 


 
15 
 
 
 
 
Each vertical line represents an outpatient follow up appointment after discharge.  
At each appointment, the following will be done: 
• Exam 
• AE assessment, and Compliance assessment (pill counts) 
• Lytes, BUN, creatinine 
• CBC with diff 
• LFTs 
• Cyclosporine or Tacrolimus levels 
• * CMV viral load routinely measured post prophylaxis 
• If clinical signs or symptoms compatible with CMV are suspected, CMV 
viral load will be performed  


 
16 
 
Table 1.  Exams, labs, and assessments performed during the study 
 
At the 
time of 
transplant 
(day 0) 
Post OHT 
weekly, 
week 1-4 
Post OHT 
week 6 
Post OHT 
Week 8 
Post OHT 
week 12 
Post OHT 
Month 4 
Post OHT 
Month 5 
Post OHT 
Month 6 
Post OHT 
Monthly, 
month 7-12 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Tacrolimus and/or 
sirolimus troughs 
 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chem 7, LFTs 
(AST, ALT, AP, tot 
bilirubin) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV IgG 
 
 
 
 
X* 
 
 
X** 
 
CMV Quantiferon 
 
 
 
 
X 
 
 
X 
 
Baseline physical 
exam 
X 
 
 
 
 
 
 
 
 
Visit for AE 
assessment and 
physical exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
Letermovir R+ 
X 
X 
X 
X 
X 
 
 
 
 
Letermovir D+/R- 
X 
X 
X 
X 
X 
X 
X 
X 
 
Compliance 
assessments (pill 
counts) 
 
X 
X 
X 
X 
X 
X 
X 
 
* For CMV R+ 
**For CMV D+/R- 
 


 
17 
 
 
Table 2.  CMV assessments at time of LET prophylaxis cessation 
 
 
Any Time of LET 
Prophylaxis 
cessation 
Weekly for 8 weeks  
CBC with differential 
X 
 
CMV DNA 
 
X 
CMV IgG 
X 
 
CMV Quantiferon 
X 
 
 
 
 
4.1 Dosing of Letermovir (LET) Prophylaxis  
From day of enrollment through either week 12 if CMV recipient is seropositive or 
Week 24 if the recipient is CMV seronegative (with CMV seropositive donor), 
participants will receive: 
• LET 480 mg once daily (QD) given orally (either as one 480 mg tablet or two 
240 mg tablets, based on participant’s swallowing capability or, if the 
participant is receiving concomitant cyclosporin A (CsA), LET 240 mg QD 
given orally. 
• Famciclovir 500 mg (FAM) given orally every 12 hours for prophylaxis against 
herpes simplex virus (HSV) and varicella zoster virus (VZV) as per our usual 
institutional protocol 
• If participants in the LET treatment arm are unable to tolerate swallowing 
and/or have a condition (e.g., vomiting, diarrhea, or a malabsorptive 
condition) that may interfere with the absorption of the oral formulation then 
such participants can receive an IV formulation of LET.  Participants on 
concomitant CsA will receive 240 mg IV LET QD, while participants not on will 
receive either 480 mg IV LET  
4.2 Dose Modification (Escalation/Titration/Other)  
Both oral (tablet) and IV formulations of LET will be available.   
The IV formulation of LET contains the excipient hydroxypropyl betadex.  
Cyclodextrins can cause nephrotoxic effects in animals at systemic exposure; 
however, there is currently no evidence of these effects in humans.  Hydroxypropyl 


 
18 
 
betadex amounts of approximately 250 mg/kg/day for 21 days were found to be safe 
in humans older than 2 years (13).  Given this tolerability information in humans and 
the amount of cyclodextrin (3600 mg) contained in the highest dose (480 mg) of the 
IV formulation of LET administered in P001, nephrotoxic effects due to cyclodextrin 
were not expected in the trial population of adult HSCT recipients.  Data from P001 
suggest that the use of the cyclodextrin-containing IV formulation in this trial was not 
associated with renal toxicity and that dosing with the IV formulation is justified when 
it is necessary (3). 
Based on the above, the use of IV LET is permitted in participants with renal 
insufficiency, provided CrCl is >10 mL/min.  The IV formulation should only be used 
when participants are either unable to swallow or have a condition that may interfere 
with the absorption of the oral formulation at or after Day 1.  Participants on IV LET 
should be switched to the oral formulation (ie, at the next planned dose) as soon as 
they are able to swallow and/or the condition that warranted the use of the IV 
formulation has resolved. 
4.3 Dietary Restrictions for Taking Letermovir 
Study therapy should be taken with food. Participants must avoid consumption of 
grapefruit, Seville oranges or their respective juices, and other quinine-containing 
drinks or food during the study from 2 weeks prior to study treatment administration 
until 72 hours after the final administration of study treatment 
5.1 Treatment Compliance 
The investigator/study coordinator will train the participant in the use of the Study 
Medication Diary.  The participant will be instructed to record the number of tablets 
or capsules of study therapy taken during the study therapy period.  At visits when 
used/unused study therapy are returned, site personnel will verify the accuracy of 
the dosing diary by comparing entries with amounts of returned study therapy.  If a 
discrepancy is noted, the investigator/study coordinator must discuss the 
discrepancy with the participant, and the detailed explanation will be documented in 
the participant’s study record.  
If oral medication is administered by clinical personnel during any hospitalization or 
comparable inpatient setting (including but not limited to skilled nursing facility or 
rehabilitation facility) in which non-study and study medications are administered by 
clinical personnel), the site personnel will be responsible for documenting the 
adequacy of dosing adherence. We will document the compliance in the study case 
report form.  
When administering IV formulation of study medication, the volume and the duration 
of infusion will be documented. The investigator/study coordinator will be responsible 
for transferring the appropriate information to the case report form. 
Study therapy may be interrupted for any reason for a time period of ≤7 consecutive 
days (including suspected CMV Disease). Interruption from the protocol specified 


 
19 
 
treatment for a time period of ≤7 consecutive days due to an AE followed by re-
starting of protocol specified treatment upon resolution of the AE is permitted. 
5.2  Concomitant Therapy 
Medications/therapies listed in this section pertain to co-administration with LET.  
When used, these agents should be administered in a manner consistent with the 
local product circular for these agents (if available for LET) including the complete 
list of prohibited medications (ie, those that are contraindicated or not 
recommended.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the time periods specified by this protocol.   
It is important for investigators to review each medication (prescription and non-
prescription) the participant is taking before starting the study and at each study visit. 
• At each visit, participants should be questioned about any new drug they are 
taking. 
• To minimize the risk of adverse drug interactions, every effort should be made 
to limit the number of concomitant drugs to those that are truly essential. 
Listed below are specific restrictions for concomitant therapy during the course of 
the trial. 
• 
It should be noted that the magnitude of CYP3A- and OATP1B1/3-mediated 
drug interactions on co-administered drugs may be different when LET is co-
administered with CsA (please also consult current prescribing information for 
CsA and for co-administered medication for drug interactions with CsA). 
The following medications/therapies are prohibited during the dosing period and for 
14 days after the dosing period: 
• Certain HMG-CoA reductase inhibitors (statins): When LET is co-
administered with CsA, the magnitude of the increase in statin plasma 
concentrations is expected to be greater than with LET alone.   
o Simvastatin or pitavastatin with LET or when LET is co-administered 
with CsA. 
o Atorvastatin or lovastatin when LET is co-administered with CsA. 
§ Note: see below for co-administration of LET with atorvastatin, 
fluvastatin, lovastatin, rosuvastatin, or pravastatin. 
• Fixed dose combination products containing statins are not allowed because 
the dosage of statins should be adjusted when LET is co-administered. 


 
20 
 
• Strong inducers, such as rifampin, phenytoin, carbamazepine, St John’s wort 
(Hypericum perforatum), rifabutin and phenobarbital 
• Moderate inducers, such as nafcillin, thioridazine, modafinil and bosentan 
• Cytochrome P450 3A (CYP3A) substrates with narrow therapeutic range 
(NTR) that can lead to SAEs, including but not limited to: 
o Pimozide: Concomitant administration of LET may result in increased 
concentrations of pimozide due to inhibition of CYP3A by LET, which 
may lead to QT prolongation and torsade de pointes. 
o Ergot alkaloids: Concomitant administration of LET may result in 
increased concentration of ergot alkaloids (ergotamine and 
dihydroergotamine) due to inhibition of CYP3A by LET, which may lead 
to ergotism. 
• Repaglinide when LET is co-administered with CsA (Note: see below for co-
administration of LET with repaglinide). 
• Everolimus when LET is co-administered with CsA (Note: see below for 
co-administration of LET with everolimus). 
• The following medications/therapies are prohibited for the 
prevention/treatment of CMV while participants are on study therapy (except 
for cases of suspected CMV Disease).  ACV, valacyclovir, and famciclovir 
may be used at thresholds lower than specified below (for a subset of these 
medications for which such thresholds are specified): 
o Foscarnet (see above) 
o Cidofovir (see above) 
o ACV (at doses >3200 mg PO per day or >25 mg/kg IV per day) 
o Valacyclovir (at doses >3000 mg or ≤500 mg PO per day, and not for 
HSV/VZV prophylaxis; see below) 
o Famciclovir (at doses >1500 mg  
• Imipenem-cilastatin  
• Investigational Agents:  Unapproved investigational agents or investigational 
regimens involving combinations of approved agents (eg, immunosuppressive 
agents) are not permitted. 
• Herbal Supplements:  Herbal supplements are not permitted. 


 
21 
 
The following medications/therapies may require dose adjustment or closer 
monitoring during the dosing period and for 14 days after the dosing period: 
• 
Inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) 
transporters: 
o CsA:  Co-administration of LET with CsA, a potent OATP1B1/3 
inhibitor, increases the concentrations of LET. If LET is 
co-administered with CsA, the recommended dose of LET is 240 mg 
once daily. 
• 
Substrates of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) 
and/or CYP3A: 
o Statins: 
§ Atorvastatin:  The dose of atorvastatin should not exceed a daily 
dose of 20 mg.  Atorvastatin is prohibited when co-administered 
with LET and CsA (see above). 
§ Fluvastatin, lovastatin, rosuvastatin, or pravastatin:  The dose of 
fluvastatin, lovastatin, rosuvastatin, or pravastatin may need to 
be adjusted when co-administered with LET.  Lovastatin is 
prohibited when co-administered with LET and CsA (see 
above).  Monitoring for statin-associated adverse reactions (eg, 
myalgias, rhabdomyolysis) is recommended during 
co-administration. 
o Glyburide, a substrate of OATP1B1/3: Frequent monitoring of glucose 
concentrations is recommended during co administration of glyburide 
with LET. 
• 
Substrates of CYP2C8 (repaglinide, rosiglitazone): 
o Repaglinide, rosiglitazone:  LET is an in vitro inhibitor of CYP2C8.  
Co-administration of LET with CYP2C8 substrates (eg, repaglinide, 
rosiglitazone) may increase the plasma concentrations of CYP2C8 
substrates.  Frequent monitoring of glucose concentrations is 
recommended during co-administration of repaglinide and rosiglitazone 
and LET. 
• 
CYP3A substrates: 
o Co-administration of LET with drugs that are CYP3A substrates may 
result in clinically relevant increases in the plasma concentrations of 
co-administered CYP3A substrates (examples:  alfentanil, fentanyl, 
midazolam, quinidine).  Therefore, frequent monitoring for adverse 
reactions related to these agents is recommended during co-


 
22 
 
administration.  When LET is co-administered with CsA, the combined 
effect on CYP3A substrates may be similar to a strong CYP3A 
inhibitor. Refer to the prescribing information for CsA and for 
co-administered medication for dosing of the CYP3A substrate with a 
strong CYP3A inhibitor. 
o Substrates of CYP3A with NTR (examples given below; please also 
consult current prescribing information for monitoring and dosing these 
products with inhibitors of CYP3A); dose adjustment of CYP3A 
substrates with NTR may be needed. 
§ CsA:  Co-administration of LET with CsA increases CsA 
concentrations.  Frequent monitoring of CsA whole blood 
concentrations should be performed during and at 
discontinuation of LET and the dose of CsA adjusted 
accordingly. 
§ Sirolimus:  Co-administration of LET with sirolimus increases 
concentrations of sirolimus.  Frequent monitoring of sirolimus 
whole blood concentrations should be performed during and at 
discontinuation of LET and the dose of sirolimus adjusted 
accordingly. 
When LET is co-administered with CsA, refer to the sirolimus 
prescribing information for specific dosing recommendations for 
use of sirolimus with CsA. 
§ Tacrolimus:  Co-administration of LET with tacrolimus increases 
tacrolimus concentrations.  Frequent monitoring of tacrolimus 
whole blood concentrations should be performed during and at 
discontinuation of LET and the dose of tacrolimus adjusted 
accordingly. 
§ Everolimus:  Co-administration of LET with everolimus may 
increase everolimus concentrations.  Frequent monitoring of 
everolimus blood concentrations should be performed during 
and at discontinuation of LET and the dose of everolimus 
adjusted accordingly.  The administration of everolimus when 
LET is co-administered with CsA is prohibited (see above). 


 
23 
 
§ Amiodarone:  LET may increase the plasma concentrations of 
amiodarone (CYP3A and CYP2C8 substrates).  Frequent 
monitoring for adverse reactions related amiodarone is 
recommended during co-administration.  Frequent monitoring of 
amiodarone concentrations should be performed when co-
administered with LET. 
• 
Substrates of CYP2C9 and CYP2C19 (voriconazole, warfarin, omeprazole, 
and pantoprazole): 
o Voriconazole:  Co-administration of LET with voriconazole decreases 
the plasma concentrations of voriconazole likely due to induction of 
CYP2C9 and/or 2C19.  If concomitant administration is necessary, 
close monitoring for reduced effectiveness of voriconazole is 
recommended. 
o Warfarin:  LET may decrease the plasma concentrations of CYP2C9 
and/or CYP2C19 substrates (eg, warfarin).    Frequent monitoring of 
international normalized ratio (INR) should be performed while warfarin 
is co-administered with LET. 
o Proton Pump Inhibitors, omeprazole and pantoprazole:  LET may 
decrease the plasma concentrations of CYP2C19 substrates.  Clinical 
monitoring and dose adjustment may be needed 
6.0 CMV Disease Assessments and Management 
All potential cases of CMV disease, as identified the study investigators will be 
assessed. Comparison will be made to our historical control cohort.  
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or 
nucleic acid in any body fluid or tissue specimen. 
CMV Definitions  
CMV disease consists of the two following clinical definitions:  1) CMV end-organ 
disease; and 2) “probable CMV syndrome” (which will be termed “CMV syndrome” 
throughout this protocol). 
• CMV end-organ disease will be further described by: 
o The specific type of end-organ disease (eg, pneumonia, 
gastrointestinal disease, or hepatitis); and 
o By categorization based on appropriate clinical signs/symptoms with 
detection/documentation of CMV: 
§ Proven CMV end-organ disease 


 
24 
 
§ Probable CMV end-organ disease. 
Table 4.  CMV assessment at time of treatment for CMV infection or disease 
 
 
At time of 
Initiation of 
Treatment for 
CMV 
Infection/Disease 
Weekly 
During 
Treatment 
At time of 
CMV 
Treatment 
Cessation 
Weekly for 2 
Months After 
Cessation of 
Treatment 
CBC with 
Differential 
X 
X 
X 
 
CMV DNA 
 
X 
X 
X 
CMV IgG 
X 
 
X 
 
CMV 
Quantiferon 
X 
 
X 
 
 
6.1 CMV Viral Resistance Testing 
We do not routinely perform CMV resistance testing. Decisions to do so will be 
based on the judgement of the clinical investigators.  
6.2 QuantiFERON-CMV Measurements 
The development of CMV-specific T cell responses, which is the predominant 
adaptive immune response that confers protection against CMV (14-17) will be 
measured using the QuantiFERON-CMV assay within two weeks of the 
discontinuation of CMV prophylaxis or CMV treatment.   
6.3 Rescue Medications & Supportive Care 
In the event of CMV disease (suspected or confirmed by the study team) during the 
study therapy period (ie, prior to completion or early discontinuation of study 
therapy) or a clinical decision by the investigator to start CMV treatment due to any 
other reason. LET will be discontinued and the participant will be treated according 
to the local SOC.  
In the event of HSV/VZV infection (as diagnosed by the investigator; herpes labialis, 
herpes zoster, and genital herpes) during the study therapy period (ie, prior to 
completion or early discontinuation of study therapy), will be treated according to the 
local SOC.   


 
25 
 
6.4 Treatment After the End of the Study  
There is no study-specified treatment following the end of the study. 
7.1 Safety Endpoints 
The safety and tolerability of LET will be assessed by a clinical evaluation of AEs 
and inspection of other study parameters including vital signs, physical examination, 
and laboratory studies. 
7.1.1 Leukopenia and Neutropenia 
An evaluation of the safety and tolerability of LET, as assessed by review of the 
accumulated safety data, will be assessed as an endpoint in this study.  For each 
episode of leukopenia or neutropenia that is reported as an AE during the treatment 
period, the corresponding laboratory values and normal ranges of total white blood 
cell (WBC) and absolute neutrophil count (ANC) will be collected (ie, local and 
central laboratory values). 
 
Table 3.  Assessment performed when ANC <1000 
 
 
Any Time ANC <1000 
Weekly Until ANC >1000 for 
2 Consecutive Weeks 
CBC with differential 
X 
X 
CMV DNA 
X 
 
 
7.2  Method of Detecting AE, SAE and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AE and/or SAE and other 
reportable safety events. Open-ended and non-leading verbal questioning of the 
participant is the preferred method to inquire about AE occurrence. 
7.3 Follow-up of AE, SAE and Other Reportable Safety Event Information  
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety 
events including pregnancy and exposure during breastfeeding, ECI, Cancer and 
Overdose will be followed until resolution, stabilization, until the event is otherwise 
explained, or the participant is lost to follow-up. We will make every attempt to follow 
all non-serious AEs that occur.  


 
26 
 
7.4 Regulatory Reporting Requirements for SAE 
• Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety 
of participants and the safety of a study treatment under clinical investigation are 
met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, 
IRB/IECs and investigators in accordance with all applicable global laws and 
regulations, i.e., per ICH Topic E6 (R1) Guidelines for Good Clinical Practice. 
• Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
sponsor will file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8 Discontinuation/Withdrawal Criteria  
8.1 Discontinuation of Study Treatment  
Discontinuation of study treatment does not represent withdrawal from the study. 
As certain data on clinical events beyond study treatment discontinuation may be 
important to the study, they will be collected through the participant’s last scheduled 
follow-up, even if the participant has discontinued study treatment.  Therefore, all 
participants who discontinue study treatment prior to completion of the protocol-
specified treatment period will still continue to participate in the study.  
Participants may discontinue study treatment at any time for any reason or be 
dropped from the study treatment at the discretion of the investigator should any 
untoward effect occur.  In addition, a participant may be discontinued from study 
treatment by the investigator or the Sponsor if study treatment is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
A participant must be discontinued from study treatment but continue to be 
monitored in the study for any of the following reasons: 
○ The participant or participant’s legally acceptable representative requests to 
discontinue study treatment. 
o The participant develops confirmed or suspected CMV disease as determined by 
the investigator.  


 
27 
 
o The participant has a confirmed positive pregnancy test. 
o An investigator feels it is in the best interest of the participant to discontinue. 
o An elevated aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) lab value that is greater than or equal to 3 × upper limit of normal (ULN) 
and an elevated total bilirubin lab value that is greater than or equal to 2 × ULN 
and, at the same time, an alkaline phosphatase lab value that is less than 2 × 
ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. 
o The participant develops:  
§ Both moderate hepatic insufficiency (Child-Pugh Class B) and moderate-
to-severe renal insufficiency (defined as CrCl <50 mL/min as calculated by 
the Cockcroft-Gault equation),  
OR 
§ Severe hepatic insufficiency (Child-Pugh Class C). 
The participant may be discontinued from study therapy for any of the following 
reasons: 
o Any AE/SAE assessed by the investigator as possibly or probably related to 
study therapy.  The investigator may continue the participant in the study if it is 
deemed to be in the best interest of the participant to stay on study therapy. 
o Failure to comply with the dosing, evaluations, or other requirements of the 
study. 
o The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, places the participant at unnecessary 
risk through continued participation in the study or does not allow the participant 
to adhere to the requirements of the protocol (e.g., if there is a clinical indication 
for any medication or vaccination specifically prohibited during the trial, 
discontinuation from trial therapy may be required.  
Discontinuation from study treatment is “permanent.” Once a participant is 
discontinued, he/she shall not be allowed to restart study treatment.  
8.2 
Withdrawal from the Study 
A participant must be withdrawn from the study if the participant or participant’s 
legally acceptable representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study treatment 
or be followed at scheduled protocol visits. 


 
28 
 
8.3 
Lost to Follow Up 
If a participant fails to come to the clinic for one of their scheduled visits, and/or if the 
site is unable to contact the participant, the following procedures are to be 
performed: 
o We will attempt to contact the participant and reschedule the missed visit.  If 
the participant is contacted, the participant should be counseled on the 
importance of maintaining the protocol-specified visit schedule. 
o We will make every effort to regain contact with the participant at each missed 
visit (e.g., phone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
o Note:  A participant is not considered lost to follow-up until the last scheduled 
visit for the individual participant.   
8.3.1 Pregnancy and Exposure During Breastfeeding 
Pregnancy in the first two years post transplant is highly discouraged and as part of 
the transplant program counseling against pregnancy is routinely done in the 
appropriate age groups. The immunosuppressive medications can be toxic to the 
fetus and pregnancy itself could put a strain on the heart.  
Although pregnancy and infant exposure during breastfeeding are not considered 
adverse events, any pregnancy or infant exposure during breastfeeding in a 
participant (spontaneously reported to the investigator or their designee), including 
the pregnancy of a male participant's female partner, that occurs during the trial are 
reportable to the Sponsor. 
All reported pregnancies willbe followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events).  If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
8.3.2 Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported to the Sponsor. 
Events of clinical interest for this trial include:  
1.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 


 
29 
 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  
8.4 
Treatment of Overdose 
In this study, an overdose is any dose higher than two times the prescribed dose 
specified.  7.2 (Dose Modification [Escalation/Titration/Other]).  Overdose during the 
study will be a reportable safety event. . 
8.4.1 Adverse Events Monitoring 
Adverse event monitoring will include the collection of all AEs and SAEs from the 
time informed consent is signed through 14 days following the last dose of study 
treatment in all participants.  Thereafter, any SAEs related to study medication will 
be collected through Week 52. 
Clinical Safety Laboratory Assessments 
8.4.2 Laboratory Safety Evaluations 
The investigator will review the laboratory reports, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
If laboratory values from non-protocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in study participant management 
or are considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the appropriate case report form.   
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
treatment, every attempt will be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.  
 
9.0  Literature Cited 
1. Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus 
Guidelines on the Management of Cytomegalovirus in Solid-organ 
Transplantation. Transplantation. 2018;102(6):900-931. 


 
30 
 
 
2. Snydman DR. Epidemiology of infections after solid-organ transplantation. Clin 
Infect Dis. 2001;33 Suppl 1:S5-8. 
 
3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. 
Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell 
Transplantation. N Engl J Med. 2017; 377: 2433-2444. PMID: 29211658. 
 
4. Letermovir versus valganciclovir to prevent human cytomegalovirus disease in 
kidney transplant recipients (MK8228-002). ClinicalTrials.gov. 
 
5. Chow JLK, Ruthazer R, Boucher HW, Nierenberg N, Vest A, DeNofrio D, 
Snydman DR  Factors associated with neutropenia post heart transplantation. 
Abstract accepted to ISHLT, April 2020 (not presented due to COVID 19) 
 
6. Kaul DR, Stoelben S, Cober E, Ojo T, Sandusky E, Lischka P, et al. First report 
of successful treatment of multidrug-resistant cytomegalovirus disease with the 
novel anti-CMV compound AIC246. Am J Transplant 2011;11:1079-84. 
7. Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmerman H, 
Lischka P. The novel anticytomegalovirus compound AIC246 (letermovir) inhibits 
human cytomegalovirus replication through a specific antiviral mechanism that 
involves the viral terminase. J Virol 2011;85(20):10884-93. 
8. Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, et al. In 
vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. 
Antimicrob Agents Chemother. 2010 Mar;54(3):1290-7 
9. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus 
Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect 
Dis. 2017;64(1):87-91. 
 
10. Gardiner BJ, Nierenberg NE, Chow JK, Ruthazer R, Kent DM, Snydman DR. 
Absolute Lymphocyte Count: A Predictor of Recurrent Cytomegalovirus Disease 
in Solid Organ Transplant Recipients. Clin Infect Dis. 2018;67(9):1395-1402. 
 
11. Arbo MD, Snydman DR. Influence of blood culture results on antibiotic choice in 
the treatment of bacteremia. Arch Intern Med. 1994;154(23):2641-2645. 
 
12. George MJ, Snydman DR, Werner BG, et al. The independent role of 
cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver 
transplant recipients. Boston Center for Liver Transplantation CMVIG-Study 
Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med. 
1997;103(2):106-113. 
 
13. European Medicines Agency. Committee for Human Medicinal Products (CHMP): 
background review for cyclodextrins used as excipients 


 
31 
 
(EMA/CHMP/333892/2013) [Internet]. London: European Medicines Agency; 
2014. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/12/WC50
0177936.pdf. 
 
14. Fernandez-Ruiz M, Kumar D, Humar A. Clinical immune-monitoring strategies for 
predicting infection risk in solid organ transplantation. Clin Transl Immunology. 
2014 Feb 28;3(2):e12. 
15. Abate D, Saldan A, Mengoli C, Fiscon M, Silvestre C, Fallico L, et al. Comparison 
of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV 
quantiferon gamma interferon-releasing assays in assessing risk of CMV 
infection in kidney transplant recipients. J Clin Microbiol. 2013 Aug;51(8):2501-7. 
16. Cantisan S, Lara R, Montejo M, Redel J, Rodriguez-Benot A, Gutierrez-Aroca J, 
et al. Pretransplant interferon-γ secretion by CMV-specific CD8+ T cells informs 
the risk of CMV replication after transplantation. Am J Transplant. 2013 
Mar;13(3):738-45. 
17. Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, et al. 
Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction 
of cytomegalovirus disease in high-risk solid-organ transplant recipients: a 
multicenter cohort study. Clin Infect Dis 2013;56(6):817-24.