Clinical trial NCT03728426
Conditions: Cytomegalovirus Infections
Keywords: Cytomegalovirus Infections CMV
Sponsor: Amy C. Sherman, MD
Start date: 2019-01-11; Completion date: 2022-03-28
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active cytomegalovirus infection or cytomegalovirus disease in patients with infections that are refractory or resistant to available treatments or who are experiencing organ dysfunction that makes unsafe the use of available antiviral treatments.

Detailed description:
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved letermovir for treatment of cytomegalovirus infection, but it has approved letermovir for the prevention of cytomegalovirus infection in bone-marrow transplantation patients.

This is the first time that letermovir will be administered to children in a clinical trial.

Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at some time in their life. CMV remains in your body, but does not cause symptoms in the majority of people. Patients with a weakened immune system (a system that protects you from infections) may be more at risk for the virus becoming active and causing damage to some of your organs, especially in the gut and lungs. If the virus becomes present above a certain quantity, the doctor usually prescribes a drug to treat the infection at this stage to avoid damage to the organs.

In this case, the virus is no longer responding to the prescribed drug, and other drug options will be harmful to the participant's health. Participants are being invited to take part in a research study for an investigational drug called letermovir. The purpose of this study is to find out whether letermovir is as effective and as safe in treating CMV infection in patients who cannot tolerate standard treatments such as ganciclovir or foscarnet.

Arms: arm 1: Open label letermovir will be administered daily for up to 12 weeks. The study allows an optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated.
Interventions: intervention 1: Letermovir
Intervention descriptions: intervention 1: Patients will receive intravenous or oral letermovir at a dose of 480mg/day.

Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment.

For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day.

Protocol documents:
ICF_002.pdf: 
Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 1 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
Protocol Title:  
A Phase 2 Study of letermovir treatment for patients experiencing refractory or 
resistant cytomegalovirus infection or disease with concurrent organ dysfunction 
DF/HCC Principal Research Doctor / Institution:  
Amy Sherman, MD / Brigham and Women’s Hospital
DF/HCC Site-Responsible Research Doctor(s) / Institution(s):  
DFCI – Amy Sherman, MD
MGH – Sarah Hammond, MD
BCH – Leslie Lehmann, MD
If you are a parent or guardian of a child under 18 years old, the word “you” refers 
to your child.  You, the parent, will be asked to read and sign this document to give 
permission for your child to participate.  
A. INTRODUCTION
You are invited to take part in a clinical trial, a type of research study, because you 
have a cytomegalovirus infection resistant to standard treatments. This research 
study is studying a drug named letermovir as a possible treatment for this 
diagnosis.  
For purposes of this research, you will be referred to as a “participant”.  
It is expected that about 32 people will take part in this research study. Merck 
Dohme & Sharp Co. is the pharmaceutical company that is supporting this study by 
providing the research funding and study drug and will be referred to as the 
“sponsor”.
 
This research consent form explains why this research study is being done, what is 
involved in participating in the research study, the possible risks and benefits of 
participation, alternatives to participation, and your rights as a research participant.  
The decision to participate is yours.  If you decide to participate, please sign and 
date at the end of this form. We will give you a copy so that you can refer to it while 
you are involved in this research study. If you choose not to participate in this 
research study, the research doctors will discuss other treatment options with you 
and/or refer you back to your primary doctor. 
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 2 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
Because information about you and your health is personal and private, it generally 
cannot be obtained without your written permission. By signing this form, you are 
providing that permission and your information may be obtained and used in 
accordance with this informed consent and as required or allowed by law. This 
means that researchers may obtain information regarding your past medical 
history, as well as specimens and samples from previous health care providers 
such as hospitals and labs.
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future.
B. WHY IS THIS RESEARCH STUDY BEING DONE? 
This is a Phase II clinical trial.  Phase II clinical trials test the safety and 
effectiveness of an investigational drug to learn whether the drug works in treating 
a specific disease.  “Investigational” means that the drug is being studied.  
  
The FDA (the U.S. Food and Drug Administration) has not approved letermovir for 
treatment of cytomegalovirus infection, but it has approved letermovir for the 
prevention of cytomegalovirus infection in bone-marrow transplantation patients.
This is the first time that letermovir will be given to children in a clinical trial.
Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at 
some time in their life. CMV remains in your body, but does not cause symptoms in 
the majority of people. Patients with a weakened immune system (a system that 
protects you from infections) may be more at risk for the virus becoming active and 
causing damage to some of your organs, especially in the gut and lungs. If the 
virus becomes present above a certain quantity, your doctor usually prescribes a 
drug to treat the infection at this stage to avoid damage to your organs. 
In your case, the virus is no longer responding to the prescribed drug, and other 
drug options will be harmful to your health. You are being invited to take part in a 
research study for an investigational drug called letermovir. The purpose of this 
study is to find out whether letermovir is as effective and as safe in treating CMV 
infection in patients who cannot tolerate standard treatments such as ganciclovir or 
foscarnet.
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 3 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
C. WHAT OTHER OPTIONS ARE THERE?
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following 

Receive standard treatment, including oral valganciclovir; or intravenous 
ganciclovir, foscarnet, or cidofovir

Take part in another research study. 

Receive no therapy specific to your CMV infection
Please talk to the research doctor about your options before you decide whether you 
will take part in this research study.
D. WHAT IS INVOLVED IN THE RESEARCH STUDY?
Sometimes it is hard to keep track of all of the details and procedures that are part 
of a research study.  We will describe them in this consent form and you can refer 
to this at any time during the research study.
Before the research starts (screening):  
After signing this consent form, you will be asked to undergo some screening tests 
or procedures to find out if you can be in the research study.  Many of these tests 
and procedures are likely to be part of regular cancer care and may be done even 
if it turns out that you do not take part in the research study.  If you have had some 
of these tests or procedures recently, they may or may not have to be repeated.  
At this visit, we will: 

Ask you about your medical history including medications and procedures 

Gather basic information about you

Measure your vital signs, including height and weight 

Draw about 1 tablespoon of blood (to check your general health and the 
CMV in your body)

Test your blood for pregnancy, if you are a woman of child bearing potential. 
Pregnant women cannot take part in this research study.
If these tests show that you are eligible to participate in the research study, you 
may begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study.
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 4 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
Additional research procedures to be performed at the time of screening but not 
required to determine eligibility:  

A physical exam

An electrocardiogram (EKG) to measure your heart function

If there is no documentation of your HIV status, an HIV test will be done. 

Your transplant status and any other conditions you may have during the 
study will be assessed
Study Treatment Overview:
Letermovir will be given daily for up to 12 weeks, with a possible additional 12 
weeks depending on your transplant status, CMV status, and clinical status. 
If you take part in this research study you will be given a drug diary.  You will be 
asked to document information in the drug diary about the study treatment you are 
being asked to take.
Treatment Phase: 
Visits 1-10 (Weekly for first 6 weeks, Weeks 8, 10, 12)
This visit will involve the following:

Letermovir dosing

The investigator will ask you questions about side effects or health problems 
since your last visit

The investigator will ask you about what medications you are taking

There may be an evaluation of how you are able to carry on with your usual 
activities. 

Your vital signs will be taken

Your weight may be checked

About 1 tablespoon of blood will be drawn to check your general health, to 
check the CMV in your body, and to monitor your immune system 

About a quarter of a tablespoon of blood may be drawn to check the amount 
of letermovir in your body (not done at Visit 1) 
(Optional) Visits 10-12 (Weeks 16, 20, 24)
This visit will involve the following:

Letermovir dosing

The investigator will ask you questions about side effects or health problems 
since your last visit

The investigator will ask you about what medications you are taking
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 5 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 

There may be an evaluation of how you are able to carry on with your usual 
activities. 

Your vital signs will be taken

Your weight may be checked

About 1 tablespoon of blood will be drawn to check your general health and 
CMV in your body 

About a quarter of tablespoon of blood may be drawn to check the amount 
of letermovir in your body
Follow-up Phase: Post Treatment Visits 1-5 (Upon stopping study drug and at 
Weeks 1, 4, 8, and 12 afterwards )
We would like to keep track of your medical condition. There will be 4 visits after 
the end of treatment, up to 12 weeks after you stop taking study drug. 
This visit will involve the following:

A physical exam

Your vital signs will be taken

The investigator will ask you questions about side effects or health problems 
since your last visit

The investigator will ask you about what medications you are taking

About 1 tablespoon of blood will be drawn to check your general health and 
CMV in your body 
Research Study Plan:
Treatment phase:
Pre-
Study
Wk
0
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
8
Wk
10
Wk
12
Wk
16
Wk
20
Wk
24
Letermovir
X
X
X
*
*
*
*
*
*
*
*
*
*
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------------------------------------X
Physical exam (as 
indicated)
X
Eye exam
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 6 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
Weight
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
CBC w/diff a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistrya
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CMV viral loada 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CMV immunity panel
X
X
X
X
X
X
X
PK sample
(predose, if on drug)
X
X
X
X
X
X
EKG (as indicated)
X
X
Adverse event evaluation
X---------------------------------------------------------------------------------------------------------X
B-HCG
Xb
*:
Letermovir:  Dose as assigned if clinically indicated; once daily for 8 weeks. Refer to section 5.1 for detailed 
a:      These tests are done as part of routine clinical care and no extra tubes will be drawn for the study
Follow up phase:
End of 
Treatment
Post-
Treatment
Wk
1
Post-
Treatment
Wk
4
Post-
Treatment
Wk
8
Post-
Treatment
Wk
12
Medical history
Physical exam
X
X
X
X
X
Eye exam
X
Vital signs
X
X
X
X
X
Weight
X
X
X
X
X
Concurrent meds
X
X-----------------------X
Performance status
X
X
X
X
X
CBC w/diffa
X
X
X
X
X
Serum chemistrya
X
X
X
X
X
CMV viral loada
X
X
X
X
X
CMV immunity panel
X
X
EKG (as indicated)
X
Adverse event monitoring
X-----------------------X
a:      These tests are done as part of routine clinical care and no extra tubes will be drawn for the study
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 7 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
Blood samples will be sent to a third-party laboratory, Viracor, who will analyze the 
amount of CMV in your blood. They will also run tests to analyze your immune 
system in response to CMV.  Additionally, we will send blood samples to measure 
the amount of letermovir in your system to a third-party laboratory, PMRI.
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY?
You will be in this research study for up to 36 weeks.
You may be taken off the research study drug for many reasons including if:

It is considered to be in your best interest

The study treatment or procedures are found to be unsafe or ineffective

There is any problem with following study treatments and procedures

You are a female and become pregnant or plan to become pregnant

Your condition worsens

A decision is made to close the study

Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study
If you are removed from the research study, the research doctor will explain to you 
why you were removed.  The research doctor and research team will help arrange 
for your continued care. 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your primary 
doctor first.
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY?
There are risks to taking part in any research study. One risk is that you may get a 
study drug that does not help treat your disease or that makes your condition or 
disease worse.  Another risk is that there may be side effects.  
All antiviral treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 8 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
deal of variability among side effects of different antiviral treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the study 
team immediately if you experience any side effects. 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal. 
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you.
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  You 
may be asked to sign a new consent form that shows that you have been informed 
of new information relating to this research study.
Risks Associated with letermovir
Frequent side effects (greater than 10%):

Nausea 

Diarrhea 

Vomiting 

Swelling (usually in legs) 

Cough 

Headache 

Fatigue 
If left untreated, vomiting and diarrhea may lead to excessive loss of body fluids and 
nutritional problems, so it is important to let your study doctor know if you develop 
any new health problems or if the problems you had before the study get worse. 
Rare side effects (less than 10%)

Irregular heartbeat
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 9 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 

Kidney damage (may occur with the intravenous formulation only)
Reproductive Risks: 
The drugs used in this research study may affect a fetus.  While participating in this 
research study, you should not become pregnant or father a baby, and should not 
nurse a baby.  We can provide counseling about preventing pregnancy for either 
male or female study participants. Let your doctor know immediately if you become 
pregnant or find out that you are going to be the father of a child.
In the event that your partner becomes pregnant, it may be critical to share 
information regarding your participation in this research study with that person.  
Your research doctor should also be told if this happens.  The study sponsor may 
want to collect data on your partner’s pregnancy.  
Non-Physical Risks: 
Because of side effects or the time required for tests and clinic visits while you are 
on this research study, you may be unable to keep up with your normal daily 
activities. 
Unforeseen Risks
In addition to the risks described above, there may be unknown risks, or risks that 
were not anticipated, associated with being in this study. If new information becomes 
available about the study drug that might affect your willingness to continue 
participation your study doctor or staff will inform and discuss with you whether you 
want to continue to participate in the clinical study.
You may even be asked to sign a revised consent form if this occurs.  You have the 
right to decide either to continue with the clinical study or to withdraw.
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY?
We do not know if taking part in this study will help you. This study may help 
researchers learn information that could help people in the future.
H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS?
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study. 
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 10 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.  
If you choose not to participate, are not eligible to participate, or withdraw from this 
research study, this will not affect your present or future care and will not cause 
any penalty or loss of benefits to which you are otherwise entitled. 
It is important to tell the research doctor if you are thinking about stopping so your 
research doctor can evaluate the risks from stopping the drug. In some cases, the 
abrupt stopping of a drug can have risks in itself. Another reason to tell your 
research doctor that you are thinking about stopping is to discuss what follow-up 
care and testing could be most helpful for you.
I.
WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY?
You will not be paid for participating in this study. 
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor and hospital may benefit if this happens. There are no 
plans to pay you if your samples are used for this purpose. 
J. WHAT ARE THE COSTS?
Routine costs for standard clinical care will be charged to your insurance. You will 
not be charged for letermovir or for participation in this study.
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are:  

Brigham and Women’s Hospital: (617) 732-5524 or (617) 732-7485

Dana-Farber Cancer Institute: (617) 632-3455
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or can 
be provided by the study team:
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for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 11 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237)
K. WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN THIS 
RESEARCH STUDY?
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The research 
doctor’s name and phone number are listed in this consent form.
The treating hospital will offer you the care needed to treat injuries directly resulting 
from taking part in this research.  These treatments will be billed to your insurance 
company. You will be responsible for deductibles, co-insurance and co-payments. 
There are no plans to pay you or give you other compensation for the injury. You 
do not give up your legal rights by signing this form. 
 We will need to collect certain personal information about you for insurance or 
payment reporting purposes, such as your name, date of birth, gender, social 
security number or Medicare identification number and information related to this 
research study. We may be required to report this information to the Centers for 
Medicare & Medicaid Services. We will not use this information for any other 
purpose.
L. WHAT ABOUT CONFIDENTIALITY?
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data. 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. Information 
that does not become part of your medical record will be stored in your study file. It 
may also become part of a DF/HCC research database.  
The study team plans to publish the results of this research study and when we do, 
we may be asked to make the data we collect available to other researchers. We 
will not include information that identifies you in any publications or to the 
researchers who request the data to do additional research.
     
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
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DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
identify you.  At most, the Web site will include a summary of the results.  You can 
search this Web site at any time.
M. CERTIFICATE OF CONFIDENTIALITY
To help protect your privacy a Certificate of Confidentiality (CoC) from the 
Department of Health and Human Services (DHHS) has been issued on this 
research study.
With this Certificate, the sponsor of the study cannot be forced (for example, by 
court subpoena) to disclose information that may identify you in federal, state, or 
local civil, criminal, administrative, legislative or other proceedings. Disclosure will 
be necessary, however, upon request of the Department of Health and Human 
Services for audit or program evaluation purposes.
You should understand that a Certificate of Confidentiality does not prevent you or 
a member of your family or even the research doctor from voluntarily releasing 
information about yourself or your involvement in this research. Note however, that 
if an insurer or employer, learns about your participation, and obtains your consent 
to receive research information, then the sponsor may not use the Certificate of 
Confidentiality to withhold this information. This means that you and your family 
must also actively protect your own privacy.
N. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY?
If you have questions about the study, please contact the research doctor or study 
staff as listed below:
Amy Sherman, M.D. is the person in charge of this research study.  You can call 
her at 617-732-6660, pager 31811 (24 hours a day, 7 days a week), with questions 
about this research study or with Dana Farber site related questions.
Sandra Burchett, M.D. is the site responsible investigator for Boston Children’s 
Hospital. For questions at this site, please contact 617-875-4686.
Sarah Hammond, M.D. is the site responsible investigator for Massachusetts 
General Hospital. For questions at this site, please contact 857-753-1235.
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Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 13 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
If you need emergency medical treatment, contact the nearest available 
emergency medical center.
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at Dana-Farber Cancer 
Institute (617) 632-3029. This can include questions about your participation in the 
study, concerns about the study, a research related injury, or if you feel/felt under 
pressure to enroll in this research study or to continue to participate in this 
research study. 
O. FUTURE USE OF DATA AND SPECIMENS
Your personal information and/or biospecimens collected during this study may be 
stored and used for future research.  If so, any personal identifiers will be removed 
so that the information or samples cannot be linked back to you. As a result, we 
will no longer be able to identify and destroy them.
Investigators, including investigators from collaborating institutions, can request 
this data and samples for new research.  Samples and data may also be shared 
with outside non-profit academic investigators as well as with for-profit 
pharmaceutical investigators or commercial entities, with whom we collaborate.
You will not be asked to provide additional informed consent for the use of your de-
identified information or samples in future research.
Future research studies may include genetic research.  Your genes are unique to 
you.  At this time, you cannot be identified through this research.  There is a risk 
that you might be reidentified in the future as genetic research progresses
P. PRIVACY OF PROTECTED HEALTH INFORMATION
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to protect 
the privacy of information that identifies you and relates to your past, present, and 
future physical and mental health conditions (“protected health information”).  If you 
enroll in this research study, your “protected health information” will be used and 
shared with others as explained below.
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 14 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
1. What protected health information about me will be used or shared with 
others during this research?

Existing medical records, including mental health records.

New health information created from study-related tests, procedures, visits, 
and/or questionnaires
2. Why will protected information about me be used or shared with others?
The main reasons include the following:

To conduct and oversee the research described earlier in this form;

To ensure the research meets legal, institutional, and accreditation 
requirements; 

To conduct public health activities (including reporting of adverse events or 
situations where you or others may be at risk of harm); and

To provide the study sponsor with information arising from an adverse event 
or other event that relates to the safety or toxicity of the drug(s) used in the 
study and for the purpose of this or other research relating the study drug(s) 
and their use in cancer; 

To better understand the diseases being studied and to improve the design 
of future studies; and,

Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.)
3. Who will use or share protected health information about me?

DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information.
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 15 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
4. With whom outside of DF/HCC may my protected health information be 
shared?
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities:

Outside individuals or entities that have a need to access this information to 
perform functions relating to the conduct of this research such as analysis 
by outside laboratories on behalf of DF/HCC and its affiliates (for example, 
data storage companies, insurers, or legal advisors).

The sponsor(s) of the study, its subcontractors, representatives, business 
partners, and its agent(s): Merck Dohme & Sharp

Other research doctors and medical centers participating in this research, if 
applicable

Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National Institutes 
of Health, and/or the Office for Human Research Protections), or other 
domestic or foreign government bodies if required by law and/or necessary 
for oversight purposes. A qualified representative of the FDA and the 
National Cancer Institute may review your medical records.

Hospital accrediting agencies

A data safety monitoring board organized to oversee this research
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission. 
5. For how long will protected health information about me be used or 
shared with others?

There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.  
6. Statement of privacy rights:

You have the right to withdraw your permission for the research doctors and 
participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that already 
has been used or shared with others to carry out related activities such as 
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 16 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
oversight, or that is needed to ensure quality of the study. To withdraw your 
permission, you must do so in writing by contacting the researcher listed 
above in the section: “Whom do I contact if I have questions about the 
research study?”

You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?”
Q. DOCUMENTATION OF ASSENT
Signature of participant between age of 10 and 18: The person doing this 
research study has explained what will happen to me if I take part in this research 
study.  My signature below means that I want to be in this research study.  I can 
2/8/2023 11:00 AM


Research Consent Form
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
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DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
decide not to take part in this research study if I do not want to and nothing will 
happen to me if I decide I do not want to participate.  
____________________________________
__________________
Signature of Participant
Date
To be completed by person obtaining assent:
The assent discussion was initiated on  
 (date). 
The information was presented in age-appropriate terms.  The minor:
Agreed to take part in the study
Did not agree to take part in the study
An assent discussion was not initiated with the minor for the following reason(s):
Minor is incapacitated
Minor is under 10 years of age
Other
Signature of Individual obtaining assent: 
Printed name of above: 
Date: 
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 18 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
R. DOCUMENTATION OF CONSENT
My signature below indicates:

I have had enough time to read the consent and think about participating 
in this study;

I have had all of my questions answered to my satisfaction;

I am willing to participate in this study;

I have been told that my participation is voluntary and I can withdraw at 
any time
Signature of Participant
Date
or Legally Authorized Representative  
Relationship of Legally Authorized Representative to Participant   
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 19 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
To be completed by person obtaining consent:
Adult Participant
The consent discussion was initiated on  
 (date).
Signature of individual obtaining consent: 
Printed name of above: 
Date: 
A copy of this signed consent form will be given to the participant or legally authorized 
representative.
 1)  The participant is an adult and provided consent to participate.
1a)  Participant (or legally authorized representative) is a non-English speaker and
signed the translated Short Form in lieu of English consent document:
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation of 
the English consent form.  The participant was given the opportunity to ask questions. 
Signature of Interpreter/Witness: 
Printed Name of Interpreter/Witness: 
Date: 
1b)  Participant is physically unable to sign the consent form because: 
 The participant is illiterate.
 The participant has a physical disability.
 Other (please describe): _________________________________________
The consent form was presented to the participant who was given the opportunity 
to ask questions and who communicated agreement to participate in the research. 
Signature of Witness: 
Printed Name of Witness: 
Date: 
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 20 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative:
2a) gave permission for the adult participant to participate 
2b) did not give permission for the adult participant to participate 
To be completed by person obtaining consent:
Minor Participant
The consent discussion was initiated on  
 (date).
Signature of individual obtaining consent: 
Printed name of above: 
Date: 
A copy of this signed consent form will be given to the participant or legally authorized 
representative, or, where the participant is a minor, the participant’s parent or legal guardian.
1) The parent or legally authorized representative gave permission for the minor to participate.
1a) Parent or legally authorized representative is a non-English speaker and signed
the translated Short Form in lieu of English consent document
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation of 
the English consent form.  The participant was given the opportunity to ask questions. 
Signature of Interpreter/Witness: 
Printed name of Interpreter/Witness: 
Date: 
1b) Parent or legally authorized representative is physically unable to sign the consent form 
because: 
 The participant is illiterate.
 The participant has a physical disability.
 Other (please describe): _________________________________________
2/8/2023 11:00 AM


Research Consent Form
for Biomedical Research
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS 8.10.2018
Page 21 of 21
DFCI Protocol Number: 18-348 
Approved Date (DFCI IRB Approval): 06/10/2021 
Date Posted for Use: 12/09/2021 
The consent form was presented to the parent or legally authorized representative
who was given the opportunity to ask questions and who communicated agreement for the 
minor to participate in the research. 
Signature of Witness: 
Printed Name of Witness: 
Date: 
1c) The parent or legally authorized representative did not give permission for the minor to 
participate
2/8/2023 11:00 AM

Prot_SAP_000.pdf: 
DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 1 
 
 
NCI Protocol #: 
Not applicable 
DF/HCC Protocol #: [18-348] 
Sponsor Study #: Merck MISP 57433 
TITLE: A Phase 2 Study of letermovir treatment for patients experiencing refractory or 
resistant cytomegalovirus infection or disease with concurrent organ dysfunction 
 
Coordinating Center: 
Dana-Farber Cancer Institute (DFCI) 
 
Principal Investigator (PI): 
Amy Sherman, MD  
 
Brigham and Women’s Hospital  
 
acsherman@bwh.harvard.edu 
 
 
 
Other Investigators: 
Matthew P. Cheng, MD 
Dana-Farber Cancer Institute 
Brigham and Women’s Hospital 
mcheng@bwh.harvard.edu 
 
Leslie E. Lehmann, MD 
Dana-Farber Cancer Institute 
Boston Children’s Cancer and Blood Disorders Center 
Leslie_Lehmann@dfci.harvard.edu 
 
Sandra Burchett, MD 
Dana-Farber Cancer Institute 
Boston Children’s Hospital 
Sandra.Burchett@childrens.harvard.edu 
 
Sarah Hammond, MD 
Massachusetts General Hospital 
shammond@mgh.harvard.edu 
 
 
 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 2 
 
 
 
Statistician: 
Study Coordinator: 
                    Haesook T Kim, PhD 
 
 
  Eric Zhou    
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute 
450 Brookline, Boston MA 02215 
450 Brookline, Boston MA 02215 
Telephone: 617-632-6856 
Telephone: 617-525-8736 
Fax: 617-632-5444 
Fax: 617-278-6994 
Kim.Haesook@jimmy.harvard.edu 
eric_zhou1@dfci.harvard.edu  
 
Responsible Research Nurse: 
Responsible Data Manager: 
N/A 
Esther Arbona-Haddad 
Dana-Farber Cancer Institute 
450 Brookline, Boston MA 02215 
Telephone: 617-582-8467 
Fax: 617-278-6994 
earbonahaddad@bwh.harvard.edu 
 
 
IND #: 141107 
IND Sponsor: Amy Sherman, MD 
 
 
Protocol Type / Version # / Version Date: 
[Amendment 2 / Version #3/  3/31/2021] 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 3 
 
 
SCHEMA 
 
 
 
 
 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 4 
 
 
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives ...................................................................................................6 
1.3 
Secondary Objectives ...............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s) .......................................................................................................7 
2.2 
IND Agent ................................................................................................................8 
2.3 
Rationale ..................................................................................................................8 
2.4 
Correlative Studies Background ..............................................................................9 
3. 
PARTICIPANT SELECTION .............................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
REGISTRATION And Randomization PROCEDURES ..................................................11 
4.1 
General Guidelines for DF/HCC Institutions ........................................................11 
4.1 
Registration Process for DF/HCC Institutions .......................................................11 
4.2 
General Guidelines for Other Investigative Sites ..................................................11 
4.3 
Registration Process for Other Investigative Sites .................................................11 
5. 
TREATMENT PLAN ........................................................................................................12 
5.1 
Treatment Regimen ................................................................................................12 
5.2 
Agent Administration.............................................................................................12 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................14 
5.4 
Criteria for Taking a Participant Off Protocol Therapy .........................................14 
5.5 
Duration of Follow Up ...........................................................................................16 
5.6 
Criteria for Taking a Participant Off Study ...........................................................16 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................16 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................16 
7.1 
Expected Toxicities ................................................................................................16 
7.2 
Adverse Event Characteristics ...............................................................................17 
7.3 
Adverse Event Reporting .......................................................................................18 
7.4 
Reporting to the Food and Drug Administration (FDA)........................................20 
7.5 
Reporting to Hospital Risk Management ...............................................................20 
7.6 
Routine Adverse Event Reporting .........................................................................20 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................21 
8.1 
Letermovir..............................................................................................................21 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 5 
 
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................24 
9.1 
Biomarker Studies: N/A .........................................................................................24 
9.2 
Laboratory Correlative Studies: N/A .....................................................................24 
9.3 
Special Studies .......................................................................................................25 
10. 
STUDY CALENDAR .......................................................................................................25 
11. 
MEASUREMENT OF EFFECT ........................................................................................29 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................29 
12.1 
Data Reporting .......................................................................................................29 
12.2 
Data Safety Monitoring ..........................................................................................30 
12.3 
Collaborative Agreements Language: N/A ............................................................30 
13. 
STATISTICAL CONSIDERATIONS ...............................................................................30 
13.2 
Endpoints ...............................................................................................................31 
13.3 
Sample Size/Power Calculation .............................................................................31 
13.4 
Monitoring Treatment Related Toxicity ................................................................32 
14. 
PUBLICATION PLAN .....................................................................................................34 
REFERENCES ..............................................................................................................................35 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................37 
APPENDIX B: Lanksy PERFORMANCE STATUS CRITERIA FOR PATIENTS AGE < 16 ..38 
APPENDIX C: STUDY PATIENT DRUG DIARY .....................................................................39 
APPENDIX D: POTENTIAL DRUG INTERACTIONS WITH LETERMOVIR .......................41 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 6 
 
 
1. OBJECTIVES 
 
 
1.1 
Study Design 
 
This is an investigator-initiated, single-arm, open-label trial of letermovir treatment for patients 
with documented cytomegalovirus (CMV) infection or CMV disease that is refractory or 
resistant to FDA-approved treatments and/or who have baseline organ dysfunction 
(myelosuppression or renal dysfunction) for which treatment with available antiviral agents 
would likely cause further dysfunction and increased risk of dialysis or death. We plan to enroll 
up to 32 immunocompromised patients including hematopoietic-cell (HCT) and solid-organ 
(SOT) transplant recipients who meet eligibility criteria (see section 3). 
 
CMV infection is defined as the detection of CMV nucleic acids by polymerase chain reaction 
(PCR) or other molecular methods in blood or plasma in immunocompromised patients at risk of 
CMV disease. CMV disease is defined as end-organ involvement with concurrent organ-specific 
clinical symptoms caused by CMV and usually demonstrated by involved tissue biopsies. The 
criteria of Ljungman and colleagues (CID 2017) will be used to classify CMV disease. 
 
Patients will receive letermovir treatment for up to 12 weeks with optional additional 12 weeks 
of treatment for secondary prophylaxis if clinically indicated. 
 
Clinical assessments and CMV viral load (VL) will be measured at each study visit. Samples will 
also be collected for CMV genotyping and pharmacokinetic evaluations. 
 
While on treatment, patients will be assessed weekly from Week 1 through Week 6, every other 
week from Week 8 through Week 12, and if necessary, once per month at Weeks 16, 20, and 24. 
 
Upon treatment discontinuation, patients will be followed for 12 weeks (with study visits at 1, 4, 
8, and 12 weeks after discontinuation). 
 
The study calendar (Section 10) provides detail of study visits and procedures. 
 
1.2 
Primary Objectives 
 
To evaluate the clinical efficacy, antiviral activity, and safety of letermovir treatment for patients 
with refractory or resistant CMV infection or CMV disease who have toxicities or baseline organ 
dysfunction for which treatment with available CMV treatments are either ineffective or will 
likely worsen organ dysfunction. 
 
1.3 
Secondary Objectives 
 
• To describe kinetics of viral clearance and potential emergence of letermovir-resistant CMV 
virus in patients treated in this setting. 
• Overall survival 


DF/HCC Protocol #:18-348 
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• CMV progression-free survival: time from study enrollment to CMV progression or death 
whichever occurs first 
• Characterize pharmacokinetics of letermovir in adolescent patients 
 
1.4 
Exploratory Objectives 
 
• To longitudinally describe CMV-specific CD4 and CD8 T-cell levels in patients with CMV 
infection or disease in this trial 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
CMV remains the most common viral infection in transplantation and in other patients who are 
immunocompromised.1 Rates of CMV infection and disease vary depending on baseline CMV- 
specific immunity and the overall state of immunosuppression.2 
 
The clinical effects of CMV can be divided into direct and indirect effects. Direct effects 
attributed to CMV include CMV syndrome and CMV end-organ disease, while indirect effects of 
CMV include an increased risk of opportunistic infections and metabolic derangements.3 
 
CMV disease (consisting of CMV end-organ disease and CMV syndrome) is associated with 
increased morbidity, mortality, as well as poor outcomes following SOT and HCT.4,5 
 
Current strategies to minimize the impact of CMV in transplant recipients include CMV antiviral 
prophylaxis during the initial period post-transplantation and preemptive antiviral treatment by 
surveillance of CMV infection by systematic monitoring of CMV nucleic acids in blood or 
plasma and antiviral administration for patients in whom CMV viremia is detected above 
prespecified thresholds.6 Both strategies have been effective in reducing the burden of CMV 
disease, but infections continue to occur after prophylaxis is discontinued and available antivirals 
to treat CMV frequently cause organ toxicity (myelosuppression with ganciclovir, renal toxicity 
with foscarnet and cidofovir), and resistance to these antivirals develops with certain frequency 
in transplant recipients, making imperative the need to develop and test new antivirals for 
treatment of CMV infection and CMV disease. 
 
The FDA approved letermovir in November 2017 for CMV prophylaxis in allogeneic HCT 
patients who are CMV seropositive (who have evidence of CMV infection prior to HCT),7 but 
there is minimal experience on its use to treat active infection.8,9 This trial is a proof-of-concept 
study to address the feasibility of using letermovir for treatment of active CMV infection. 
Letermovir use for treatment of active CMV infection and its use in SOT recipients and other 
immunocompromised hosts is considered off-label use. 


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2.2 
IND Agent 
 
Letermovir is an anti-CMV agent that recently received FDA approval for CMV prophylaxis in 
CMV seropositive, allogeneic hematopoietic-cell transplantation (HCT) recipients.7 Letermovir 
inhibits the viral terminase complex (UL51/UL56/UL89),10–12 an enzyme that plays an important 
role in cleavage of concatenated viral DNA into individual genomes that are subsequently 
inserted into CMV procapsids to generate infectious CMV virions. Letermovir has demonstrated 
potent, selective, and reversible inhibition of CMV activity in preclinical studies in vitro and 
efficacy against the virus in vivo.11,13 
 
Letermovir has been shown to be generally well tolerated in 28 Phase 1 studies, two Phase 2 
studies, and a pivotal Phase 3 study in HCT recipients. In the latter study, CMV seropositive 
allogeneic-HCT recipients received letermovir or placebo from the early post-transplant period 
(within 4 weeks post-transplant) through Week 14 post-transplant (Day +100) and were followed 
for an additional 34 weeks.7 In this study, letermovir demonstrated statistical significance in the 
prevention of clinically significant CMV infection compared to placebo, defined as onset of 
CMV end-organ disease or initiation of anti-CMV pre-emptive therapy based on documented 
CMV DNAemia as measured by the central laboratory. Letermovir prophylaxis also resulted in 
statistically significant lower all-cause mortality relative to placebo through Week 24 post- 
transplant. 
 
2.3 
Rationale 
 
Although letermovir prophylaxis will likely decrease the overall burden of CMV in HCT 
recipients, treatment of active CMV infection and CMV disease remains an area of unmet 
clinical need as we lack effective non-toxic options for treatment. Current CMV antiviral 
treatment relies on ganciclovir or valganciclovir, which is frequently myelosuppressive. 
Foscarnet is prescribed in patients who develop ganciclovir resistance or experience significant 
myelosuppression from ganciclovir, but it is associated with significant renal toxicities.14 
Cidofovir is uncommonly used for treatment of CMV infections, is not as effective as 
ganciclovir or foscarnet, and is nephrotoxic.15 
 
Given letermovir’s outstanding safety profile, especially its lack of myelosuppression or 
nephrotoxicity, and the efficacy results of the phase 3 prophylaxis trial, many clinicians will be 
inclined to start using letermovir for treatment of active CMV infections and CMV disease even 
though the drug lacks approval for this indication. There are very limited data regarding 
letermovir’s activity during active CMV infection. Stoelben and colleagues reported a phase 2 
trial where 40mg or 80mg twice-daily of letermovir were effective in preemptively treating 
CMV viremia in renal transplant recipients (67% were receiving concomitant cyclosporine).9 
Kaul and colleagues reported that a patient with multidrug-resistant CMV disease was 
successfully treated with letermovir 240mg/day after failing multiple previous treatments.8 The 
phase 3 study evaluating letermovir prophylaxis in allogeneic-HCT recipients included 70 
patients who had detectable CMV DNA at the time of randomization. Although not included in 
the main analysis of the trial, the 48 patients who received letermovir with detectable CMV at 
baseline were less likely than 22 patients on placebo to develop progressive infection requiring 


DF/HCC Protocol #:18-348 
Protocol Version Date: March 31, 2021 
Page 9 
 
 
preemptive treatment.7 
 
We believe that it is important to formally test letermovir’s ability to treat active CMV infection 
and CMV disease. We propose that treatment be studied initially in a proof-of-concept, open- 
label trial in patients who lack effective therapeutic options and in those with baseline organ 
dysfunction where currently available treatments would likely lead to poor clinical outcomes 
such irreversible kidney toxicity or severe myelosuppression. These patients would thus most 
likely benefit from letermovir treatment. The data generated will inform future development 
programs for CMV treatment with letermovir and will likely help patients in this situation. 
 
Given the safety profile and relatively wide therapeutic index of letermovir to date,7 there is 
equipoise at this time to consider letermovir use for patients 12 years of age or older, who weigh 
30 or more kilograms, who are experiencing CMV infections or disease that meet the eligibility 
criteria for the trial, for whom available treatment options are likely to be unsuccessful or lead to 
greater toxicity and morbidity. 
 
2.4 
Correlative Studies Background 
 
Not applicable 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 
Participants in the study must meet the following eligibility criteria: 
 
• Age ≥12 years 
• Weight ≥30 kg 
• Transplant recipient (HCT, SOT) or other immunocompromised patients who require 
antiviral treatment for CMV. 
• Documented CMV disease or persistent CMV infection (CMV virus load above 500 
IU/mL on consecutive measurements, at least one day apart). 
• CMV infection is refractory to treatment (defined as ≥14 days of standard CMV 
treatment without clinical improvement for CMV disease, or failure to achieve >1 log 
reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17 
• Current CMV infection has documented genotypic resistance to ganciclovir or 
foscarnet. Please see Appendix E for the full list of amino acid substitutions that 
qualify as drug-resistant mutations. 
• For patients with any prior CMV infection episode that broke through letermovir 
prophylaxis, but not during the current CMV infection, documentation of letermovir 
susceptibility testing should demonstrate absence of letermovir mutations known to 
confer resistance to letermovir. 
• Severe myelosuppression (ANC <1000/µL, Hemoglobin <8g/dL, or Platelets 
<25,000/µL)17 or renal dysfunction (estimated creatinine clearance <60 mL/min by 


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Protocol Version Date: March 31, 2021 
Page 10 
 
 
MDRD in adults or < 60 ml/min/1.73 m2 by bedside Schwartz equation in < 18 years- 
old) at baseline or which develops during antiviral treatment. 
o Patients who develop severe myelosuppression or renal dysfunction during 
antiviral treatment as defined above are eligible without having to meet the 
refractoriness/antiviral resistance criterion. See Table below for further details on 
eligibility. 
o Combinations of genotypic antiviral resistance and organ dysfunction that lead to 
eligibility are presented in the following table. 
• The effects of letermovir on the developing human fetus are unknown. For this 
reason, women of child-bearing potential and men must agree to use adequate 
contraception (barrier method of birth control; abstinence) prior to study entry, for 
the duration of study participation, and 3 months after completion of letermovir 
administration. Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating 
physician immediately. Men treated or enrolled on this protocol must also agree to 
use adequate contraception prior to the study, for the duration of study participation, 
and 3 months after completion of letermovir administration. 
o Patients must have a negative serum or urine pregnancy test 
• Able to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to letermovir. 
• Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at 
screening 
• Acute liver injury at baseline meeting Hy’s law. 
• Current CMV infection broke through letermovir prophylaxis. 
• Patients with life expectancy of less than a week. Determination of life expectancy 
will be discussed with the patient’s primary treatment physician. 
• Have known human immunodeficiency virus (HIV) infection 
 
 
Refractory 
Ganciclovir 
Resistant 
Foscarnet 
Resistant 
Myelosuppression 
Criteria* 
Renal 
dysfunction* 
Eligible? 
≥2 weeks of anti- 
Genotypic 
Genotypic 
ANC <1000/µL, or 
GFR <60 mL/min 
CMV treatment 
resistance based 
resistance based 
Hemoglobin <8g/dL, or 
by MDRD or < 60 
and <1 log 
on reference lab 
on reference lab 
Platelets <25,000/µL 
ml/min/1.73 m2 by 
decline in CMV 
results 
results 
bedside Schwartz 
VL from start of 
equation if < 18 
treatment 
years-old 
Yes 
Yes or No 
Yes or No 
Yes or No 
Yes or No 
Yes 
No 
Yes 
No 
No 
Yes 
Yes 
No 
No 
Yes 
Yes 
No 
Yes 
No 
Yes 
Yes 
No 
No 
Yes 
No 
No 
No 
Yes 
Yes 
Yes 
No 
No 
No 
Yes 
No 
No 
No 
Yes 
No 
No 
No 
No 
No 
No 
No 
No 
Yes 
No 


DF/HCC Protocol #:18-348 
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No 
No 
Yes 
No 
No 
No 
No 
Yes 
No 
Yes 
No 
No 
No 
No 
Yes 
No 
Yes 
No 
No 
No 
No 
No 
No 
No 
*Either at the onset of treatment or arising during treatment with other anti-viral therapy. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION AND RANDOMIZATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered. Protocol therapy will begin within 24 hours of registration. 
 
The study will be available to eligible patients seven days a week. If after hours, all standard 
procedures set forth by Dana-Farber Cancer Institute’s Office of Data Quality will be followed. 
 
4.1 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed. 
 
4.2 
General Guidelines for Other Investigative Sites 
 
Not applicable 
 
4.3 
Registration Process for Other Investigative Sites 
 
Not Applicable 


DF/HCC Protocol #:18-348 
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5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Letermovir will be administered daily for up to 12 weeks, with the optional additional 12 weeks 
of treatment for secondary prophylaxis if clinically indicated. Treatment will be administered on 
an inpatient or outpatient basis. Reported adverse events and potential risks are described in 
Section 7. No dose modifications will be permitted. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
participant's CMV infection or disease. 
 
Dosing for letermovir will be 480 mg PO/IV daily for patients not receiving concomitant 
cyclosporine. The dose is decreased to 240 mg PO/IV daily for patients receiving concomitant 
cyclosporine.18 
 
Given that the half-life of letermovir is ≤24 hours, a second dose on day 1 of treatment (~12 
hours apart) will be administered as a loading dose to patients who are ≥40 kg, to reach steady 
state drug levels on day 1. For patients who are 30 to 40 kg, no loading dose will be 
administered. 
 
Pediatric patients will receive the same daily dose, but will not receive the loading dose. Because 
of the weight-based inclusion requirement for study enrollment, the adult dose will be acceptable 
for the pediatric population. 
 
Merck conducted additional PK modeling and simulations which suggest that the letermovir 
exposure at the end of day 1 would be similar to exposures achieved at day 3-4 if a second dose 
of 480 mg is administered 12 hours after the first dose and that the exposure with 2 doses of 
letermovir 480 mg 12 hours apart is within the safety margin for participants who are ≥ 40 kg. 
Given that this protocol is enrolling patients with active CMV infection (i.e. not being 
administered for prophylaxis which is the approved indication) and it is desirable to reach steady 
state exposure as soon as possible to avoid the emergence of viral resistance, it is reasonable to 
test a loading dose in the context of treatment of active infection in this study. For participants 
who are between 30-39 kg, no loading dose is necessary given the exposures are predicted to be 
higher already due to lighter weight. 
 
Letermovir will be provided PO or IV as needed. 
 
If dosed with the oral formulation while outpatient, the participant will be requested to maintain 
a medication diary of each dose of medication. (See Appendix C) The medication diary will be 
reviewed during each study visit. 
 
5.2 
Agent Administration 
 
As applicable, describe in detail the following parameters for each agent used as part of the 
protocol therapy: 


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Administration – Letermovir 480 mg PO/IV daily, with administration per the FDA’s package 
insert with the addition of a second, loading dose on day 1 of treatment for patients ≥40 kg. 
 
Dosing – 480 mg daily in patients without concomitant cyclosporine therapy and 240 mg in 
patients with concomitant cyclosporine therapy. The drug should be taken at approximately the 
same time every day +/- 2 hours and can be taken without regard for food intake. Pediatric 
patients should not receive the loading dose. Otherwise, pediatric patients are given the same 
dose. 
 
Drug, Tubing and Filtration – Letermovir injection is compatible with the following 
IV bags and infusion set materials. PREVYMIS injection is not recommended for use with 
polyurethane-containing IV administration set tubing. 
 
IV Bags Materials: 
Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and 
polyethylene) 
 
Infusion Sets Materials: 
PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene 
copolymer 
(SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS) 
 
Plasticizers: 
Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl phthalate 
(BBP) 
Catheters: 
Radiopaque polyurethane 
 
Hydration – No pre-treatment, treatment or post-treatment hydration is required or 
recommended. 
 
Special Equipment – No special infusion pump or overfills will be required. 
Observation period – No specific observation period is required. 
Protocol specific procedures – No specific protocol procedures are required. 
 
Infusion Reactions – Infusion reactions were not observed in the phase III trial. Patients are not 
required to stay after infusion for monitoring, but institutional procedures should be followed. 
 
Oral Agents – Letermovir therapy can be taken without regard to food intake. The pill may not 
be crushed. If a dose is missed or vomited, the pill should be taken again and document this in 
the drug diary (see Appendix C). If a dose is missed or forgotten for any reason, it should be 
taken when possible. A minimum of 8 hours is suggested between doses when the dose is 
remembered. Otherwise, the missed dose should be skipped and the next dose should be taken at 
its scheduled time. 


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5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients who are receiving concomitant cyclosporine will receive 240 mg of letermovir per 
day owing to a drug–drug interaction that is mediated by the organic anion transporters 
OATP1B1 and OATP1B3. 
 
Because letermovir is a weak-to-moderate inhibitor of cytochrome P-450 3A (CYP3A) and a 
weak-to-moderate inducer of CYP2C9 and CYP2C19 enzymes (encoding cytochrome P-450, 
family 2, subfamily C, polypeptides 9 and 19, respectively), the case report form must capture 
the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Overall PI should be alerted if the participant is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. 
 
Appendix D presents guidelines for identifying medications/substances that could potentially 
interact with letermovir. 
 
Given the lack of pediatric experience for the use of letermovir, the study will hold enrollment 
for additional pediatric patients (<18 years-old) after 3 pediatric patients have been enrolled to 
assess their letermovir pharmacokinetic profiles and assure letermovir exposures are adequate 
from an efficacy and safety perspective. Treatment dosing may be adjusted depending on results 
of these analysis. For example, if letermovir blood levels are below the efficacy targets as 
determined in the adult phase III trial, the dose will be increased to achieve efficacy targets, and 
enrollment will resume with this new dose after obtaining permission form the IRB and FDA. 
 
With an estimated accrual rate of 5 patients per month and a total duration of follow-up of 6 
months from enrollment, we expected to finish the study within 1 year from trial start. 
 
5.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. 
 
Patient-level treatment response milestones: 
Patients will be required to achieve minimum virologic and clinical response milestones for 
treatment to continue. 
 
The CMV virological response milestones16 for patients without CMV disease are defined as: 
1) Any decrease in CMV DNA from baseline (week 0), measured on week 3 
2) A ≥2 log decreased from baseline, or an undetectable CMV DNA, on week 6. 
 
The clinical response milestones for patients with CMV disease are defined as: 
1) Stabilization of clinical disease by week 3 (i.e., no worsening signs or symptoms 
compared to week 1) as assessed by the site investigator and 
2) Improvement or resolution of clinical disease by week 6 as judged by investigator (i.e., 
improvement in signs and symptoms of affected organs [resolution of diarrhea, 
pneumonia, hepatitis, retinitis, etc.]) 


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Patients who do not meet the response milestones should discontinue letermovir treatment. If 
there are no other treatments available to a particular patient (because of known multidrug 
antiviral resistance), patients with stable CMV disease or CMV viremia that has not reached the 
virologic milestones could continue treatment. 
 
In the absence of treatment interruptions due to adverse event(s), treatment may continue for 12 
weeks of treatment, followed by an additional 12 weeks of secondary prophylaxis, or until one of 
the following criteria applies: 
 
Patient-level safety events that require holding or stopping letermovir 
• 
Drug-induced liver injury (DILI) meeting Hy’s law criteria without alternative 
explanation. Patients with confirmed liver GVHD, for example, will be allowed to 
continue treatment, or if patients have abnormal LFTs due to CMV hepatitis. 
 
• 
Any CTCAE grade 4 adverse event(s) with no alternative explanation whether 
attributable to drug or not 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant is removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off study, the relevant Off- 
Treatment/Off-Study information will be updated in OnCore. 
 
Study-level stopping rules 
 
The study-level stopping rules are detailed in section 13.3. If the number of responses is not met 
after the first stage or safety is compromised, then the trial will be placed on hold and available 
data analyzed to decide whether to terminate the study early or consider a higher dose of 
letermovir for treatment. 
 
Given the lack of pediatric experience for the use of letermovir, the study will hold enrollment 
for additional pediatric patients (<18 years-old) after 3 pediatric patients have been enrolled to 
assess their letermovir pharmacokinetic profiles and assure letermovir exposures are adequate 
from an efficacy and safety perspective. 


DF/HCC Protocol #:18-348 
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5.5 
Duration of Follow Up 
 
While on treatment, patients will be assessed weekly from Week 1 through Week 6, every other 
week from Week 8 through Week 12, and if necessary, once per month at Weeks 16, 20, and 24. 
 
 
Upon treatment discontinuation, patients will be followed for 12 weeks (at 1, 4, 8, and 12 weeks 
after discontinuation). 
 
Clinical assessments and CMV VL will be measured at each visit. Participants removed from 
protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
5.6 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
For patients who discontinue from active study participation we will request the possibility of 
passive follow up for survival and CMV events by review of their medical record. 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Interruptions of the trial regimen for up to a total of 7 days during the treatment period are 
allowed. 
 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
 
7.1 
Expected Toxicities 


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The safety of letermovir was evaluated in one Phase 3 randomized, double-blind, placebo- 
controlled trial in which 565 allogeneic-HCT recipients were randomized and treated with 
letermovir (N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were 
those reported while subjects were on study medication or within two weeks of study medication 
completion/discontinuation. 
 
Cardiac Adverse Events: The cardiac adverse event rate (regardless of investigator-assessed 
causality) was higher in subjects receiving letermovir (13%) compared to subjects receiving 
placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of 
letermovir subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of 
letermovir subjects and in 1% of placebo subjects). 
 
Common Adverse Events The rate of adverse events occurring in at least 10% of subjects in the 
letermovir group and at a frequency at least 2% greater than placebo are outlined in Table 1. 
 
Table 1: All Grade 
Adverse Events 
Reported in ≥ 10% of 
letermovir-Treated HCT 
Recipients at a 
Frequency at least 2% 
Greater than Placebo 
Adverse Events 
Letermovir (N=373) 
Placebo (N=192) 
nausea 
27% 
23% 
diarrhea 
26% 
24% 
vomiting 
19% 
14% 
peripheral edema 
14% 
9% 
cough 
14% 
10% 
headache 
14% 
9% 
fatigue 
13% 
11% 
abdominal pain 
12% 
9% 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 


DF/HCC Protocol #:18-348 
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- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Adverse Event Reporting 
 
7.3.1 
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
7.3.2 
Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form. 
 
7.3.3 
DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
 
7.3.4 
Protocol-Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Gastrointest 
inal 
disorders 
nausea 
Grade 
III and 
below 
Either requiring 
hospitalization or 
prolongation of 
hospitalization 
Either 
letermovir, 
other 
concomitant 
medication, 
or underlying 
disease 
Only Grade IV and 
above AEs should be 
reported 
Gastrointest 
inal 
disorders 
diarrhea 
Grade 
III and 
below 
Either requiring 
hospitalization or 
prolongation of 
hospitalization 
Either 
letermovir, 
other 
concomitant 
medication, 
Only Grade IV and 
above AEs should be 
reported 


DF/HCC Protocol #:18-348 
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or underlying 
disease 
Gastrointest 
Grade 
Either requiring 
Either 
Only Grade IV and 
inal 
III and 
hospitalization or 
letermovir, 
above AEs should be 
disorders 
vomiting 
below 
prolongation of 
hospitalization 
other 
concomitant 
medication, 
reported 
or underlying 
disease 
General 
Grade 
Either requiring 
Either 
Only Grade IV and 
disorders 
III and 
hospitalization or 
letermovir, 
above AEs should be 
peripheral 
edema 
below 
prolongation of 
hospitalization 
other 
concomitant 
medication, 
reported 
or underlying 
disease 
Respiratory, 
Grade 
Either requiring 
Either 
Only Grade IV and 
thoracic and 
III and 
hospitalization or 
letermovir, 
above AEs should be 
mediastinal 
disorders 
cough 
below 
prolongation of 
hospitalization 
other 
concomitant 
medication, 
reported 
or underlying 
disease 
Nervous 
Grade 
Either requiring 
Either 
Only Grade IV and 
system 
III and 
hospitalization or 
letermovir, 
above AEs should be 
disorders 
below 
prolongation of 
other 
reported 
headache 
hospitalization 
concomitant 
medication, 
or underlying 
disease 
General 
Grade 
Either requiring 
Either 
Only Grade IV and 
disorders 
III and 
hospitalization or 
letermovir, 
above AEs should be 
fatigue 
below 
prolongation of 
hospitalization 
other 
concomitant 
medication, 
reported 
or underlying 
disease 
Gastrointesi 
Grade 
Either requiring 
Either 
Only Grade IV and 
tnal 
III and 
hospitalization or 
letermovir, 
above AEs should be 
disorders 
abdominal 
pain 
below 
prolongation of 
hospitalization 
other 
concomitant 
medication, 
reported 
or underlying 
disease 


DF/HCC Protocol #:18-348 
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7.4 
Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
The PI will also report any events that merit communication with the DFCI IRB via email 
concurrently (within 1 business day) to Merck. 
 
7.5 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 


DF/HCC Protocol #:18-348 
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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
Letermovir 
 
8.1.1 
Description 
 
Letermovir has a molecular formula of C29H28F4N4O4 and a molecular weight of 572.55. The 
chemical name for letermovir is (4S)-2-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2- 
methoxy-5(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid. Letermovir is very 
slightly soluble in water. 
The chemical structure of letermovir is: 
 
 
 
 
 
 
 
The pharmacokinetic properties of letermovir are displayed below. 
 
Pharmacokinetics in HSCT Recipients 
Treatment Regimen 
Steady-state median (90% prediction interval) 
AUC (ng•hr/mL) of PREVYMIS 
480 mg oral once daily, no cyclosporine 
34,400 (16,900, 73,700) 
480 mg IV once daily, no cyclosporine 
100,000 (65,300, 148,000) 
240 mg oral once daily, with cyclosporine 
60,800 (28,700, 122,000) 
240 mg IV once daily, with cyclosporine 
70,300 (46,200, 106,000) 
Pharmacokinetics in Healthy Subjects 


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Treatment Regimen 
Steady-state geometric mean AUC and Cmax of 
480 mg oral once daily 
Cmax: 13,000 ng/mL 
AUC: 71,500 ng•hr/mL 
Dose proportionality 
Greater than proportional following single and 
multiple oral or IV doses of PREVYMIS 240 mg 
and 480 mg 
Accumulation ratio† 
Cmax: 1.03 
AUC: 1.22 
Time to steady-state 
9-10 days 
Absorption 
Bioavailability 
Healthy subjects administered PREVYMIS without 
cyclosporine: 94% at an oral dose range of 240 
mg to 480 mg 
HSCT recipients administered PREVYMIS without 
cyclosporine: 35% with 480 mg oral once daily 
HSCT recipients administered PREVYMIS with 
cyclosporine: 85% with 240 mg oral once daily 
Median Tmax (hr) 
45 min to 2.25 hr 
Effect of food (relative to fasting) ‡ 
AUC: 99.63% [84.27% - 117.80%] 
Cmax: 129.82% [104.35% -161.50%] 
Distribution 
Mean steady-state volume of distribution 
45.5 L following 
recipients 
IV administration in HSCT 
% In vitro bound to human plasma proteins 
99% across the concentration range of 0.2 to 50 
mg/L 
In vitro blood-to plasma ratio 
0.56 across the concentration range of 0.1 to 10 
mg/L 
Metabolism 
In vitro metabolism 
UGT1A1/1A3 (minor) 
Drug-related component in plasma 
97% unchanged parent 
No major metabolites detected in plasma 
Elimination 
Route of elimination 
Hepatic uptake (OATP1B1/3) 
Mean terminal t1/2 (hr) 
12 hrs after dosing of PREVYMIS 480 mg IV once 
daily 
% of dose excreted in feces§ 
93% 


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% of dose excreted in urine§ 
<2% 
% of unchanged drug excreted in feces§ 
70% 
* Values were obtained in studies of healthy subjects unless otherwise indicated. 
† Based on geometric mean data. 
‡ Values refer to geometric mean ratio [fed/fasted] percentage and 90% confidence interval back 
transformed from linear mixed-effects model performed on natural log-transformed values. The meal 
administered was a standard high fat and high calorie meal (33 grams protein, 65 grams 
carbohydrates, 58 grams fat; 920 total calories). 
§Single oral administration of radiolabeled letermovir in mass balance study. 
 
8.1.2 
Form 
 
Letermovir is available as 240 mg and 480 mg tablets. Letermovir tablets contain either 240 mg 
or 480 mg of letermovir and the following inactive ingredients: colloidal silicon dioxide, 
croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone 25, and film- 
coated with a coating material containing the following inactive ingredients: hypromellose 2910, 
iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, 
and triacetin, Carnauba wax is added as a polishing agent. 
 
Letermovir is also available as 240 mg and 480 mg injection for intravenous infusion. 
Letermovir injection is a clear, preservative-free sterile solution in single-dose vials of either 240 
mg or 480 mg per vial. Each 1 mL of solution contains 20 mg letermovir, hydroxypropyl betadex 
(150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and Water for Injection, USP. 
The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5. 
 
8.1.3 
Storage and Stability 
 
Letermovir tablets can be stored at room temperature at 20°C to 25°C (68°F to 77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Once mixed, the diluted solution should be stored for 
no longer than 24 hours at 2-8oC. 
 
8.1.4 
Compatibility 
 
See above description in section 8.1.2. 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the drug in a 
self-contained and protective environment. 
 
8.1.6 
Availability 
 
Letermovir will be distributed to investigators via the DFCI central pharmacy. DFCI will be 


DF/HCC Protocol #:18-348 
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maintaining the central drug supply and will distribute as patients are consented, registered, and 
enrolled in the trial. 
 
8.1.7 
Preparation 
 
See above description in section 8.1.2. 
 
8.1.8 
Administration 
 
The Letermovir IV formulation will be diluted in either 0.9% sodium chloride solution or 5% 
dextrose for a total volume of 250 mL, and the duration of infusion will be 60 minutes ±15 
minutes. No filter is needed for administration. 
 
8.1.9 
Ordering 
 
Pharmacy will email Merck Scientific Leadership and Research Manager (Boski Patel) when 
drug supplies are needed. Letermovir will be supplied from investigational supply and will be 
provided by Merck, free of charge, according to the internal protocol [Merck MISP 57433]. 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. 
 
8.1.11 Destruction and Return 
 
Unused supplies of the agent will be destroyed at respective site institutions if their standard 
operating procedure allows it. If not, unused drug supply will be returned to the DFCI central 
pharmacy and destroyed per standard operating procedures at DFCI. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies: N/A 
 
9.2 
Laboratory Correlative Studies: 
 
An additional whole blood sample will be collected for monthly measurements of CMV-specific 
CD4 and CD8 T-cell levels using the Viracor CMV T Cell Immunity Panel 
(https://www.viracor-eurofins.com/test-menu/30360-cmv-t-cell-immunity-panel/). This panel 
measures the relative strength of T cell responses to CMV specific antigens. It evaluates and 
reports the activity of CD4 and CD8 T cell responses independently. Effective T cell immunity 
against CMV is a factor in controlling CMV viral latency and a prospective characterization of T 
cell responses has not been performed in this patient population. 


DF/HCC Protocol #:18-348 
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Page 25 
 
 
9.3 
Special Studies: 
 
9.3.1 CMV Resistance variants 
9.3.1.1 
Outcome Measure: The presence of CMV isolates that are resistant to letermovir 
9.3.1.2 
Method of Assessment: Deep sequencing will be done on plasma DNA samples 
collected at the time of study assessments. Per usual practice, BWH lab keeps 
additional aliquots of samples collected for CMV testing, which is done at clinic 
visits as part of standard of care. Patients who have recurrent viremia while on 
letermovir treatment will have these aliquots tested for resistance variants. No 
additional specimens will be collected. 
Resistance to letermovir will be assessed by genotypic analysis of the CMV terminase 
complex genes UL 51, UL56 and UL89. Samples will be analyzed by PCR 
amplification and next-generation DNA sequencing at DDL Diagnostic Laboratory 
B.V. (Rijswijk, The Netherlands). These samples will be submitted through Merck. 
9.3.1.3 
Timing of Assessment: At the end of the study 
9.3.1.4 
Method of Data Recording: Electronically captured data 
9.3.1.5 
Timing of Data Recording: After genetic assays are complete 
 
 
10. STUDY CALENDAR 
 
Patients will receive letermovir treatment for up to 12 weeks with the option of an additional 12 
weeks of treatment for secondary prophylaxis if clinically indicated. 
 
While on treatment, patients will be assessed weekly from Week 1 through Week 6, every other 
week from Week 8 through Week 12, and if necessary, once per month on Week 16, 20, and 24. 
 
Upon treatment discontinuation, patients will be followed for 12 weeks (at 1, 4, 8, and 12 weeks 
after discontinuation). 
 
Clinical assessments and CMV VL will be measured at each visit. (See section 10.1 for details). 
Genotypic evaluations will be done retrospectively based from samples collected. 
 
Pre-study evaluations are to be conducted within 3 days prior to start of protocol therapy. 
Baseline evaluations are to be conducted within 1 day prior to start of protocol therapy. 
Assessments must be performed prior to administration of any study agent. Study assessments 
will be performed weekly of the protocol-specified date, unless otherwise noted. Weekly 
windows will be Monday through Friday independent of the day of the week letermovir is started 
on Week 1. 


DF/HCC Protocol #:18-348 
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Page 26 
 
 
Visit schedule while on therapya (Adult ≥ 18 years-old) 
Pre- 
Studyb,c 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Letermovir 
administration (diary 
review) 
X 
X 
X 
* 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X  
X 
Physical exam (as 
indicated) 
X 
Funduscopic examd 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Performance status 
(Karnofsky score)e 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV viral load 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV genotypeg 
X 
CMV immunity panel 
X 
X 
X 
X 
X 
X 
X 
PK sample 
(predose, if on 
drug) 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
X 
Adverse event evaluation 
X  
X 
B-HCG 
Xh 
Xh 
Xh 
Xh 
Xbh 
A: 
Letermovir: Dose as assigned; once daily for 12 to 24 weeks. Refer to section 5.1 for detailed administration regimen 
* If patient meets treatment continuation criteria. See sections 5.1 and 5.4. 
a: 
Study visits will be completed in outpatient clinic once patient is discharged. 
b: 
Pre-study evaluations are to be conducted within 3 days prior to start of protocol therapy 
c: 
If pre-study visit is completed on the same day as treatment initiation (week 0), the pre-study laboratory investigations  
need not be repeated.  
d: 
Patients with CMV retinitis at baseline will have funduscopic exams at each study visit. 
e: 
See appendix A. 
f: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
g: 
If not previously done for the current CMV infection. Can be repeated if letermovir resistance is clinically suspected. 
Letermovir genotyping and deep sequencing will be done in a reference laboratory at the end of the study. 
h: 
Serum or urine pregnancy test (in women of childbearing potential). 
 


DF/HCC Protocol #:18-348 
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Visit schedule while on therapya (Pediatric 12 to ≤ 18 years-old) 
Pre- 
Studyb,c 
Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
8 
Wk 
10 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Letermovir 
administration (diary 
review) 
X 
X 
X 
X 
* 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X  
X 
Physical exam (as 
indicated) 
X 
Funduscopic examd 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Performance status 
(Lansky score if < 16 years- 
old, Karnofsky score if ≥ 16 
years-old)e 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV viral load 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV genotypeg 
X 
CMV immunity panel 
X 
X 
X 
X 
X 
X 
X 
Routine PK sample 
(predose, if on drug) 
X 
X 
X 
X 
X 
X 
Intensive PK samplesh 
X or X 
EKG (as indicated) 
X 
X 
Adverse event evaluation 
X  
 
X 
B-HCG 
Xi 
Xi 
Xi 
Xi 
Xi 
A: 
Letermovir: Dose as assigned; once daily for 12 to 24 weeks. Refer to section 5.1 for detailed administration regimen 
* If patient meets treatment continuation criteria. See sections 5.1 and 5.4. 
a: 
Study visits will be completed in outpatient clinic once patient is discharged.  
b: 
Pre-study evaluations are to be conducted within 3 days prior to start of protocol therapy 
c: 
If pre-study visit is completed on the same day as treatment initiation (week 0), the pre-study laboratory investigations 
need not be repeated. 
d:  
Patients with CMV retinitis at baseline will have funduscopic exams at each study visit. 
e: 
See appendix A and B. 
f: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,   
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
g: 
If not previously done for the current CMV infection. Can be repeated if letermovir resistance is clinically suspected. 
Letermovir genotyping and deep sequencing will be done in a reference laboratory at the end of the study 
h: 
Pediatric patients (<18 years old) will undergo intensive PK sampling on Week 1 or Week 2 of treatment with time points 
of 0, 1, 2.5, 8 and 24 hours7 for better understanding of PK/PD given the current lack of pediatric data on letermovir. 
i: 
Serum or urine pregnancy test (in females of childbearing potential). 
 


DF/HCC Protocol #:18-348 
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Visit schedulea upon drug discontinuation (all ages) 
End of 
Treatmentb 
Post- 
treatment 
Week 
1 
Post- 
treatment 
Week 
4 
Post- 
treatment 
Week 
8 
Post- 
treatment 
Week 
12 
Medical history 
Physical exam 
X 
X 
X 
X 
X 
Funduscopic exam 
X 
Vital signs 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Concurrent meds 
X  
X 
Performance status (Lansky 
score if < 16 years-old, 
Karnofsky score if ≥ 16 
years-old)c 
X 
X 
X 
X 
X 
CBC w/diff 
X 
X 
X 
X 
X 
Serum chemistryd 
X 
X 
X 
X 
X 
CMV viral load 
X 
X 
X 
X 
X 
CMV genotypee 
CMV immunity panel 
X 
X 
X 
EKG (as indicated) 
Adverse event monitoringf 
X  
X 
a: 
 Study visits will be completed in outpatient clinic once patient is discharged. 
b: 
Visit to be conducted upon study treatment discontinuation 
c: 
See appendix A and B. 
d: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose,  potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
e: 
If not previously done for the current CMV infection. Can be repeated if letermovir resistance 
is clinically suspected. Letermovir genotyping and deep sequencing will be done in a reference 
laboratory at the end of the study 
f: 
Off-study evaluation. Note: for IND/IDE trials, follow up visits or other contact are required in 
order to identify SAEs during the 30 days following the end of study treatment. 
 
10.1 
CMV Viral Load Assessment 
 
Plasma CMV testing for study purposes will be obtained at each study visit. Testing will be done 
at Viracor Eurofins who will serve as the central laboratory for the trial. Quantitative testing of 
CMV in plasma will be done using the COBAS Amplicor/COBAS Taqman CMV test 
(https://www.viracor-eurofins.com/test-menu/5500-cytomegalovirus-cmv-quantitative-pcr/). 
Specific timepoints can be found in the study calendar in section 10.0. 
 
CMV virus load testing for clinical care will be at the discretion of the treating clinicians. Local 
laboratory CMV results will be captured in the study database. Please see Appendix F for assay 
details. 


DF/HCC Protocol #:18-348 
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Page 29 
 
 
11. MEASUREMENT OF EFFECT 
 
Each patient will be required to achieve a minimum virological and clinical response milestones 
for their treatment on study to continue. 
 
The virological response milestones are defined as: 
1) Any decrease in CMV DNA from baseline (Week 0), measured on week 3 and 
2) A ≥2 log decrease in CMV DNA from baseline, or an undetectable CMV DNA, 
measured on week 6. 
 
For patients with clinical CMV disease, the clinical response milestones are defined as: 
1) Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms 
compared to week 1) as assessed by the site investigator and 
2) Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and 
symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.]) 
3) Patients with clinical CMV disease should also meet virological response milestones 
outlined above to support the continuation of letermovir therapy. Patients who enter the 
study based solely on documented CMV disease by histopathology in the absence of 
quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL). 
4) Patients who are enrolled with CMV retinitis will be considered failures if they require 
additional intravitreal therapy after study week 3. Intravitreal therapy before this time 
will be at the discretion of the treating ophthalmologist. 
 
 
A complete virological response is defined as two consecutive CMV DNA levels <137 IU/mL in 
the central laboratory. 
 
CMV recurrence is defined as plasma CMV DNA ≥137 IU/mL in ≥2 consecutive samples in the 
central laboratory in a patient who had previously achieved plasma CMV DNA <137 IU/mL. 
 
Patients will be considered to have experienced virological failure if CMV virus load is 
unchanged or higher from baseline when measured on week 3. if the decline in CMV DNA is <2 
log on week 6, or if the patient experiences CMV recurrence while on letermovir treatment. 
 
CMV progression-free survival will be assessed from time from study enrollment to CMV 
progression or death whichever occurs first. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 


DF/HCC Protocol #:18-348 
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12.1.1 Method 
 
Data collection will be performed using InForm, which is an approved software which 
complies with Section 21 CFR, Part 11 requirements needed to use electronic data for 
supporting a New Drug Application. Case Report Forms will be developed by DF/HCC 
Clinical Trials Research Informatics Office (CTRIO), and the data will be maintained by 
the Office of Data Quality (ODQ). 
 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to ODQ in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research. 
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up- 
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request. 
 
12.3 
Collaborative Agreements Language: N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design and Objectives 
 
This is a single-arm, two-stage Phase II study of letermovir to treat refractory or resistant CMV 
infection or disease in patients who underwent hematopoietic cell or solid organ transplantation. 
The primary objective of the study is to formally test letermovir’s ability to treat active CMV 
infection and CMV disease in patients who lack effective therapeutic options and in those with 
baseline organ dysfunction where currently available treatments would likely lead to poor 
clinical outcomes such as irreversible kidney toxicity or severe myelosuppression. These patients 
would thus most likely benefit from letermovir treatment. The data generated will inform future 
development programs for CMV treatment with letermovir and will likely help patients in this 


DF/HCC Protocol #:18-348 
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Page 31 
 
 
situation. 
 
13.2 Endpoints 
 
13.2.1 Primary Endpoint 
 
The primary endpoint is complete virological response assessed on week 6 of treatment for 
patients with CMV infection or clinical response with concurrent virological response assessed 
by week 6 for patients with CMV disease. (See Section 11 for definitions). 
 
13.2.2 Secondary Endpoints 
 
• Proportion of patients with a clinically meaningful treatment response to letermovir 
treatment, defined as a virological response and a concomitant clinical response in 
patients with CMV disease by Week 6 of treatment. 
• Proportion of patients with a clinically meaningful treatment response to letermovir 
treatment, defined as a virological response and a concomitant clinical response in 
patients with CMV disease by Week 3 of treatment. 
• Proportion of patients with complete virological and clinical response at study week 12 
independent of duration of letermovir treatment. 
• Proportion of patients with complete virological and clinical response at study week 24 
independent of duration of letermovir treatment. 
• Frequency and time to recurrent CMV viremia in patients who have virological response 
to letermovir treatment 
• Overall survival 
• CMV progression-free survival 
• Kinetics of viral clearance and potential emergence of letermovir-resistant CMV virus in 
patients treated in this setting. 
 
13.3 Sample Size/Power Calculation 
 
We plan to enroll 32 evaluable patients. Based on a recent phase 2 trial of maribavir in the 
comparable patient population,16 the proposed treatment will be regarded as efficacious in 
treating refractory and resistant CMV if the success rate is 60% or higher and inefficacious if the 
success rate is 35% or lower. Here, response refers to complete virological response for CMV 
infection and clinical response with concurrent virological response for CMV disease (primary 
endpoint). With the sample size 32, there will be 91% power to detect a 25% difference in 
response rate. 
 
The study is a two-stage design with an early stopping rule if the proposed treatment shows no 
efficacy after the first stage. In the first stage, 12 evaluable patients will be accrued. Of these 12, 
if 4 or fewer patients respond, then the study will be terminated early for lack of efficacy. If, 
however, 5 or more patients respond, then additional 20 patients will be accrued. After the 
second stage, if 15 or more patients in a total of 32 respond, the proposed treatment will be 
considered efficacious. Conversely, if 14 or fewer patients respond, the proposed treatment will 


DF/HCC Protocol #:18-348 
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Page 32 
 
 
be regarded as inefficacious and the treatment will not be considered further. If 15 out of 32 
patients respond, the 95% confidence interval for the response rate is (30%, 68%). This 
confidence interval is calculated based on the Atkinson and Brown method (Biometric, 1985). 
 
With this design, the probability of concluding the proposed treatment is efficacious is 0.91 if the 
true but unknown response rate is 60% and 0.095 if the true rate is 35%. The probability of early 
stopping is 0.58 if the rate is 35% and 0.057 if the rate is 60%. This decision rule is calculated 
using an exact binomial distribution. Patients will be considered unevaluable for the primary 
endpoint if they are removed from the study due to death that is unrelated to the proposed 
treatment, withdrawal of consent or lost to follow up prior to the response assessment. These 
patients will be replaced. Table 1 below presents the operating characteristics of this design. 
 
Table 1. Operating Characteristics 
 
True but unknown response rate 
0.35 
0.4 
0.45 
0.5 
0.55 
0.6 
Prob. of stopping early (<=4 in 12) 
0.583 
0.438 
0.304 
0.194 
0.112 
0.057 
Overall prob. of accepting the treatment 
0.095 
0.231 
0.427 
0.636 
0.806 
0.913 
 
 
13.4 Monitoring Treatment Related Toxicity 
 
Continuous monitoring on treatment related toxicity will be conducted for all patients who 
receive any amount of the study drug. Data safety and monitoring will be performed per Dana- 
Farber/Harvard Cancer Center Data and Safety Monitoring Committee (DF/HCC DSMC) 
guidelines. The stopping guidelines serve as a trigger for consultation with the DF/HCC DSMC 
for additional review, and are not regarded as formal stopping rules that would mandate 
automatic closure of study enrollment. 
 
The treatment related toxicities would include the following events that occurring on therapy. 
 
• 
Drug-induced liver injury (DILI) meeting Hy’s law criteria without alternative 
explanation. 
• 
Any CTCAE grade 4 adverse event(s) potentially related to letermovir, with no 
alternative explanation. 
 
In the previous studies of letermovir16, letermovir was well tolerated. Based on this information, 
we project the treatment related toxicity rate <=15%. In this study, we will monitor DILI and 
grade 4 or higher treatment related adverse events in parallel. That is, in the first 10 patients, if 2 
or more patients experience DILI and/or if 3 or more patients experience grade 4 or higher 
treatment related adverse events, then the accrual will be halted and the DF/HCC DSMC will be 
consulted. With this design, the probability of halting accrual is 0.15 if the true but unknown 
rate of DILI (p1) is 5% and the true but unknown rate of grade 4 or higher treatment related 
adverse events (p2) is 10%; the probability of halting accrual is 0.63 if these rates are 15% and 
20%, respectively. Table 2 shows probabilities of halting accrual under various levels of p1 and 


DF/HCC Protocol #:18-348 
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p2. 
 
Table 2. Probability of Halting Accrual 
True but unknown rate of grade ≥4 treatment related AE (p2) 
True but unknown 
rate of DILI (p1) 
0.05 
0.1 
0.15 
0.2 
0.25 
0.05 
0.097 
0.150 
0.250 
0.381 
0.520 
0.1 
0.272 
0.316 
0.396 
0.501 
0.613 
0.15 
0.462 
0.494 
0.554 
0.631 
0.714 
0.2 
0.629 
0.651 
0.692 
0.745 
0.802 
0.25 
0.759 
0.773 
0.800 
0.835 
0.872 
 
The probability in this table is calculated based on the bivariate binomial distribution assuming 
that two events are independent. The independence assumption is made since the dependence of 
these two events is unknown. It is possible that two events might be slightly positively 
dependent. If that is the case, the probability of halting accrual will be slightly larger than the one 
presented in this table. If the accrual continues after the first 10 patients, the same rule will apply 
to the next 10 patients. 
 
13.5 Accrual 
 
Based on the current practice, the projected accrual rate will be 3-4 patients per month. 
Conservatively extrapolating this projection, we anticipate that the accrual will complete 
approximately in one year. 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
+ 
3 
= 
6 
Not Hispanic or Latino 
13 
+ 
13 
= 
26 
Ethnic Category: Total of all subjects 
16 
(A1) + 
16 
(B1) = 
32 
(C1) 
Racial Category 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
3 
+ 
3 
= 
6 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
12 
+ 
12 
= 
24 
Racial Category: Total of all subjects 
16 
(A2) + 
16 
(B2) = 
32 
(C2) 
(A1 = A2) 
(B1 = B2) 
(C1 = C2) 
 
13.6 Analysis of Secondary Endpoints 


DF/HCC Protocol #:18-348 
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Page 34 
 
 
 
Secondary endpoints include assessment of overall response rate, duration of response, CMV 
progression-free survival and overall survival. Due to the exploratory nature, the analysis for 
secondary endpoints will largely be descriptive. Response rate and duration of response will be 
summarized descriptively and the Kaplan Meier method will be used to estimate CMV 
progression-free survival and overall survival. A similar descriptive analysis will be performed 
for laboratory correlative studies of Kinetics of viral clearance. If feasible, association between 
clinical response and laboratory endpoints will be explored. 
 
 
14. PUBLICATION PLAN 
 
The results will be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. A full report of the outcomes will be made public no later than three (3) 
years after the end of the study. 


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2. 
Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant 
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3. 
Eid AJ, Razonable RR. New developments in the management of cytomegalovirus 
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4. 
Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains 
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5. 
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10. 
Melendez DP, Razonable RR. Letermovir and inhibitors of the terminase complex: a 
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11. 
Goldner T, Hewlett G, Ettischer N, et al. 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. 
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Ligat G, Cazal R, Hantz S, Alain S. The human cytomegalovirus terminase complex as an 
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13. 
Marschall M, Stamminger T, Urban A, et al. In vitro evaluation of the activities of the 
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other human pathogenic viruses. Antimicrob. Agents Chemother. 2011;(November): 
14. 
Avery RK, Arav-Boger R, Marr KA, et al. Outcomes in Transplant Recipients Treated 
With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. 
Transplantation. 2016;100(10):e74-80. 
15. 
Chou S. Approach to drug-resistant cytomegalovirus in transplant recipients. Curr. Opin. 
Infect. Dis. 2015;28(4):293–9. 
16. 
Papanicolaou G, Silveira FP, Langston A, et al. Maribavir for Treatment of 
Cytomegalovirus (CMV) Infections Resistant or Refractory to Ganciclovir or Foscarnet in 
Hematopoietic Stem Cell Transplant (SCT) or Solid Organ Transplant (SOT) Recipients: 
A Randomized, Dose-Ranging, Double-Blind, Phase 2 Study. Clin. Infect. Dis. 2018; 
10.1093/cid/ciy706. 


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17. 
U.S. National Library of Medicine. Efficacy and Safety of Maribavir in Transplant 
Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to 
Treatment. 2016; 
18. 
Food and Drug Administration F. PREVYMIS (letermovir) Tablets and PREVYMIS 
(letermovir) Injection. 2017; 
19. 
Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in 
phase II trials in oncology. Biometrics 61: 540-545. 
20. 
Song G, Ivanova A. Enrollment and Stopping Rules for Managing Toxicity Requiring 
Long Follow-Up in Phase II Oncology Trials. J Biopharm Stat. 2015;25(6):1206-14. doi: 
10.1080/10543406.2015.1086779. 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B 
LANKSY PERFORMANCE STATUS CRITERIA FOR PATIENTS AGE < 16 
 
Rating 
Description 
100 
Full active, normal 
90 
Minor restrictions with strenuous physical activity 
80 
Active, but gets tired more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Lying around much of the day, but gets dressed; no active play; participates in 
all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
Stuck in bed; needs help even for quiet play 
20 
Often sleeping; play is entirely limited to very passive activities 
10 
Does not play nor get out of bed 
0 
Unresponsive 


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APPENDIX C 
STUDY PATIENT DRUG DIARY 
 
General Instructions for oral tablet: 
• Can be taken without regard to food intake. 
• Do NOT crush pill to ingest. 
• Take the pill at approximately the same time every day (within 2 hours). 
• If a dose is missed or vomited, the pill should be taken again. If this occurs, 
document this in the drug diary. 
• If a dose is missed or forgotten for any reason, it should be taken when possible. If 
not remembered, the missed dose should be skipped and the next dose should be 
taken at its scheduled time. 
• Bring your Daily Dosing Diary to every visit with your doctor. 
 
Daily Subject Diary 
Study: 
Subject Number:  
 
Date 
Dose Taken 
(Y/N) 
Please circle 
Number of 
pills taken 
Time of Dose 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 


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Y / N 
Y / N 
Y / N 
Y / N 
Y / N 
Y / N 


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APPENDIX D 
POTENTIAL DRUG INTERACTIONS WITH LETERMOVIR 
 
Potential for other drugs to affect letermovir 
Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) 
transporters. Co-administration of letermovir with drugs that are inhibitors of OATP1B1/3 
transporters may result in increases in letermovir plasma concentrations (Table). 
 
Potential for letermovir to affect other drugs 
Co-administration of letermovir with midazolam results in increased midazolam plasma 
concentrations, indicating that letermovir is a moderate inhibitor of CYP3A. Co-administration of 
letermovir with drugs that are CYP3A substrates may result in clinically relevant increases in the 
plasma concentrations of co-administered CYP3A substrates (Table). 
 
Letermovir is an inhibitor of OATP1B1/3 transporters. Co-administration of letermovir with drugs 
that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma 
concentrations of co-administered OATP1B1/3 substrates (Table). 
 
The magnitude of CYP3A-and OATP1B1/3-mediated drug interactions on co-administered 
drugs may be different when letermovir is co-administered with cyclosporine. See the 
prescribing information for cyclosporine for information on drug interactions with cyclosporine. 
 
The following Table summarizes drug-drug interactions and precautions related to letermovir 
administration.18 
 
Concomitant Drug Class 
and/or Clearance 
Pathway: Drug Name 
Effect on 
Concentration† 
Clinical Comments 
Anti-arrhythmic agents 
amiodarone 
↑ amiodarone 
Close clinical monitoring for adverse events related to 
amiodarone is recommended during co- 
administration. Frequently monitor amiodarone 
concentrations when amiodarone is co-administered 
with letermovir. 
Anticoagulants 
warfarin 
↓ warfarin 
When letermovir is co-administered with warfarin, 
frequently monitor International Normalized Ratio 
(INR)§. 
Anticonvulsants 
phenytoin 
↓ phenytoin 
When letermovir is co-administered with phenytoin, 
frequently monitor phenytoin concentrations§. 
Antidiabetic agents 
Examples: glyburide, 
repaglinide, rosiglitazone 
↑ glyburide ↑ 
repaglinide ↑ 
rosiglitazone 
When letermovir is co-administered with glyburide, 
repaglinide, or rosiglitazone, frequently monitor 
glucose concentrations§. When letermovir is co- 
administered with cyclosporine, use of repaglinide is 
not recommended. 
Antifungals 


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voriconazole‡ 
↓ voriconazole 
If concomitant administration of voriconazole is 
necessary, closely monitor for reduced effectiveness 
of voriconazole§. 
Antimycobacterial 
rifampin 
↓ letermovir 
Co-administration of letermovir and rifampin is not 
recommended. 
Antipsychotics 
pimozide 
↑ pimozide 
Co-administration is contraindicated due to risk of QT 
prolongation and torsades de pointes 
Ergot Alkaloids 
ergotamine, 
dihydroergotamine 
↑ ergotamine, 
dihydroergotamine 
Co-administration is contraindicated due to risk of 
ergotism 
HMG-CoA Reductase Inhibitors 
atorvastatin
‡
 
↑ atorvastatin 
When letermovir is co-administered with atorvastatin, 
do not exceed an atorvastatin dosage of 20 mg daily§. 
Closely monitor patients for myopathy and 
rhabdomyolysis. 
When letermovir is co-administered with 
cyclosporine, use of atorvastatin is not 
recommended. 
pitavastatin, 
simvastatin 
↑ HMG-CoA 
reductase inhibitors 
Co-administration of letermovir and pitavastatin or 
simvastatin is not recommended. 
When letermovir is co-administered with 
cyclosporine, use of either pitavastatin or 
simvastatin is contraindicated due to significantly 
increased pitavastatin or simvastatin concentrations 
and risk of myopathy or rhabdomyolysis 
fluvastatin, lovastatin, 
pravastatin, rosuvastatin 
↑ HMG-CoA 
reductase inhibitors 
When letermovir is co-administered with these 
statins, a statin dosage reduction may be necessary
§. 
Closely monitor patients for myopathy and 
rhabdomyolysis. 
When letermovir is co-administered with 
cyclosporine, use of lovastatin is not 
recommended. 
When letermovir is co-administered with 
cyclosporine, refer to the statin prescribing 
information 
for 
specific 
statin 
dosing 
recommendations. 
Immunosuppressants 
cyclosporine
‡
 
↑ cyclosporine 
↑ letermovir 
Decrease the dosage of letermovir to 240 mg once 
daily 
Frequently monitor cyclosporine whole blood 
concentrations during treatment and after 
discontinuation of letermovir and adjust the dose of 
cyclosporine accordingly
§. 
sirolimus
‡
 
↑ sirolimus 
When letermovir is co-administered with sirolimus, 
frequently monitor sirolimus whole blood 
concentrations during treatment and after 
discontinuation of letermovir and adjust the dose of 
sirolimus accordingly
§. 


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When letermovir is co-administered with cyclosporine 
and sirolimus, refer to the sirolimus prescribing 
information for specific sirolimus dosing 
recommendations§. 
tacrolimus‡ 
↑ tacrolimus 
Frequently monitor tacrolimus whole blood 
concentrations during treatment and after 
discontinuation of letermovir and adjust the dose of 
tacrolimus accordingly§. 
Proton pump inhibitors 
omeprazole 
↓omeprazole 
Clinical monitoring and dose adjustment may be 
needed. 
pantoprazole 
↓ pantoprazole 
Clinical monitoring and dose adjustment may be 
needed. 
CYP3A Substrates 
Examples: alfentanil, 
fentanyl, midazolam, and 
quinidine 
↑ CYP3A substrate 
When letermovir is co-administered with a CYP3A 
substrate, refer to the prescribing information for 
dosing of the CYP3A substrate with a moderate 
CYP3A inhibitor§. When PREVYMIS is co- 
administered with cyclosporine, the combined effect 
on CYP3A substrates may be similar to a strong 
CYP3A inhibitor. Refer to the prescribing information 
for dosing of the CYP3A substrate with a strong 
CYP3A inhibitor§. CYP3A substrates pimozide and 
ergot alkaloids are contraindicated 
* This table is not all inclusive. † ↓ =decrease, ↑=increase ‡ These interactions have been studied. § Refer to the 
respective prescribing information. 
 
Drugs without Clinically Significant Interactions with letermovir 
No clinically significant interactions were observed in clinical drug-drug interaction studies of 
letermovir and acyclovir, digoxin, mycophenolate mofetil, posaconazole, ethinyl estradiol, and 
levonorgestrel. 


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APPENDIX E 
CMV GENOTYPE MUTATIONS THAT CONFER ANTIVIRAL RESISTANCE TO 
GANCICLOVIR, FOSCARNET, OR CIDOFOVIR 
 
Source: Viracor Eurofins Revision 6 (10/2018) 
 
Reportable Mutations - UL54 (DNA Polymerase)1 
 
Viral Phenotype Confirmed by Marker Transfer2 
Mutation 
Cidofovir 
Foscarnet 
Ganciclovir 
REFERENCE 
D301N 
R 
S 
R 
19,33,56 
E303D4 
R 
S 
R 
93 
E303G4 
R 
S 
R 
93 
N408D 
R 
S 
R 
9,12,23,31,33,35,56,72 
N408K 
R 
S 
R 
13, 74 
N408S 
R 
S 
R 
84, 88 
N410K 
R 
S 
R 
19, 23 
F412C 
R 
S 
R 
2,9,20,23,33,35,65,72 
F412L 
R 
S 
R 
74 
F412S 
R 
S 
R 
25,74,111 
F412V 
R 
S 
R 
9,23,72 
D413A 
R 
S 
R 
69,73 
D413E 
R 
S 
R 
19,23,31,33,52,56,72,73 
D413N 
R 
S 
R 
89 
D413Y4 
R 
S 
R 
79 
P488R 
R 
S 
R 
79,111 
N495K 
S 
R 
R 
73, 76,103 
K500N 
R 
S 
R 
79,111 
L501I 
R 
S 
R 
2,9,12,23,33,64,72 
T503I 
R 
S 
R 
12,19,33,35,72,73 
K513N 
R 
S 
R 
23,33,35,56,72 
K513E 
R 
S 
R 
9,23,33,34,35,72 
K513R 
R 
S 
R 
35, 72, 89 
D515E 
S 
S 
R 
90 
D515Y 
S 
R 
R 
91 
L516R 
R 
S 
R 
19, 33 
I521T 
R 
S 
R 
66, 68, 72 
P522A 
R 
S 
R 
9,19,25,33,37,68,72 
P522S 
R 
S 
R 
68, 72 
del524 
R 
S 
R 
88 
V526L 
R 
S 
R 
82 
C539G 
R 
S 
R 
89 
C539R 
R 
S 
R 
79,111 
1 Most UL54 mutations also have UL97 mutations. 
2 R and S denote resistant and sensitive, respectively. ND 
indicates Not Determined. 
3 Low-grade or variable resistance. 
4 Also confers resistance to CMX001. 


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Reportable Mutations - UL54 (DNA Polymerase)1 
 
Viral Phenotype Confirmed by Marker Transfer2 
Mutation 
Cidofovir 
Foscarnet 
Ganciclovir 
REFERENCE 
D542E4 
R 
S 
S 
81 
A543P 
R 
S 
R 
108 
L545S 
R 
S 
R 
9,12,33,72 
L545W 
R 
S 
R 
74,111 
T552N 
S 
R 
R 
79,103,111 
Q578H 
R 
R 
R 
24, 74,111 
Q578L 
S 
R 
S 
83 
S585A 
S 
R 
S 
79,111 
D588E 
S 
R 
S 
9,12,23,35,72 
D588N 
S 
R 
R 
12,23,27,33, 74 
F595I 
S 
R 
S 
79,111 
T700A 
S 
R 
S 
5,9,18,33,47,72 
V715A 
S 
R 
S 
92 
V715M 
S 
R 
S 
5,9,18,25,33,37,47,72 
I726T 
S 
S 
R 
83 
E756K 
R or S3 
R 
R 
12,19,23,33,36,74,82,110 
E756D 
S 
R 
S 
12,19,31,33 
E756Q 
S 
R 
S 
12,18,33,37 
L773V 
R 
R 
R 
24,89 
L776M 
S 
R 
R 
67,73 
V781I 
S 
R 
R3 
9,23,74 
V787A 
S 
R 
R 
91 
V787L 
S 
R 
R 
18,37,48,73 
L802M 
S 
R 
R or S3 
9,12,18,20,23,27,33,35,65,73 
K805Q 
R 
S 
S 
9,18,28,35,72 
A809V 
S 
R 
R 
18,19,25,28,33,47,72,103 
V812L4 
R 
R 
R 
12,18,20,27,28,33,72,73,78,93 
T813S 
R 
R 
R 
28,73 
T821I 
S 
R 
R 
9,18,28,33,35,72,73 
P829S 
S 
S 
R 
79,111 
A834P 
R 
R 
R 
13,73 
T838A 
S 
R 
S 
27,28,73 
G841A 
R 
R 
R 
28,72,73 
G841S 
S 
R 
R 
83 
V946L 
S 
R 
S 
79,111 


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L957F 
ND 
ND 
R 
79,111 
del981 to 982 
R 
R 
R 
11,19,33,63,72,73,108 
A987G 
R 
S 
R 
1,9,22,23,25,43,72 
S290R 
S 
R 
S 
103 
N495K+Q783R 
S 
R 
R 
103 
E951D 
S 
R 
R 
103 
 
Reportable Mutations - UL54 (DNA Polymerase)1 
 
Viral Phenotype found in Clinical Isolates (Unconfirmed by Marker Transfer)2 
Mutation 
Cidofovir 
Foscarnet 
Ganciclovir 
REFERENCE 
M393R 
R 
R 
R 
20, 72 
M393K 
R 
R 
R 
20, 72 
T419M 
S 
R 
S 
24 
L501F 
R 
S 
R 
23,25,31,56,72 
Y(I)722V 
R 
S 
R 
35, 72 
H729Y 
S 
R 
S 
74 
Y751H 
R 
S 
R 
35, 72 
V787I 
S 
R 
S 
33 
1 Most UL54 mutations also have UL97 mutations. 
2 R and S denote resistant and sensitive, respectively. ND indicates Not Determined. 
3 Low-grade or variable resistance. 
4 Also confers resistance to CMX001. 


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Reportable Mutations - UL56 (Terminase) 
Viral Phenotype Confirmed by Marker Transfer1 
Mutation 
Letermovir 
REFERENCE 
S229F 
R 
101 
V231A 
R 
99 
V231L 
R 
95,99,101,108 
N232Y 
R 
102 
V236A 
R 
108 
V236L 
R 
99 
V236M 
R 
94,95,101,110 
E237D 
R 
99,102 
L241P 
R 
95,99,100,101 
T244K 
R 
99,101 
L254F 
R 
101 
L257F 
R 
101 
L257I 
R 
99,101 
K258E 
R 
102 
F261L 
R 
99,101,102 
Y321C 
R 
99 
C325F 
R 
99 
C325W 
R 
108 
C325R 
R 
99 
C325Y 
R 
95,99 
M329T 
R 
99,102 
A365S 
R 
108 
N368D 
R 
101 
R369G 
R 
95 
R369M 
R 
95,101 
R369S 
R 
95,100 
E237D, T244K, F261L 
R 
99 
V236L, L257I 
R 
99 
V236M, L257I, M329T 
R 
99 
S229F, L254F, L257I 
R 
101 
1 R denotes resistance. 


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Reportable Mutations - UL97 (Phosphotransferase) 
 
Viral Phenotype Confirmed by Marker Transfer1 
Mutation 
Ganciclovir 
REFERENCE 
F342S 
R 
105,106,107 
V356G 
R 
106,107 
L405P 
R 
75 
M460I 
R 
3,5,6,7,8,10,12,23,25,33,109 
M460T 
R 
75 
M460V 
R 
6,7,8,10,11,17,24,33,43,50,109 
V466G 
R 
73,77 
C518Y 
R 
84,85 
H520Q 
R 
6,7,10,25,33,43,109 
del590 to 593 
R 
12,72 
del591 to 594 
R 
8,10,33,34,35,72,104 
del591 to 607 
R 
51,72 
C592G 
R2 
6,8,10,11,20,23,27,33,51,103,104,109 
A594E 
R 
73,75 
A594G 
R 
84,86 
A594P 
R 
6,25,59,72 
A594T 
R 
10,25,33,36,50,51,54 
A594V 
R 
5,6,8,10,11,17,25,27,33,50,104,109 
L595F 
R 
10,33,41,72 
L595S 
R 
5,6,8,10,11,12,17,23,25,33,109 
L595W 
R 
6,8,10,25,33,51,72 
del595 
R 
4,10,17,72,104 
del595 to 603 
R 
14,33,48,72,104 
E596G 
R 
10,20,33,35,36,51,72 
E596Y 
R 
90 
del597 to 599 
R 
92,104 
G598S 
R 
33,58,72 
K599T 
R 
60,72 
del600 
R 
10,33,36,51,72,104 
del601 to 603 
R 
69,104 
C603R 
R 
73,77,109 
C603W 
R 
6,8,10,20,23,25,33,35,72,109 
C607F 
R 
8,50,51,72 
C607Y 
R 
10,25,33,34,35,39,51,72 
I610T 
R 
90 
A613V 
R 
84, 87 
A591V 
R 
104 
del596 
R 
104 
del597 to 598 
R 
104 
del599 
R 
104 
del600 to 601 
R 
104 


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del601 
R 
104 
del601 to 602 
R 
104 
1 R denotes resistance. 2 Alone confers modest resistance. When found in conjunction with UL54 del 981 to 982, there is a much higher level of resistance. 
 
 
Viral Phenotype found in Clinical Isolates (Unconfirmed by Marker Transfer)1 
Mutation 
Ganciclovir 
REFERENCE 
M460L 
R 
49, 72 
A590T 
R 
10,49,72 
del590 to 600 
R 
17, 72 
del590 to 603 
R 
56, 72 
A591D 
R 
10,49,72 
C592F 
R 
72 
del594 to 601 
R 
unpublished clinical isolate 
L595T 
R 
10,35,72 
N597I 
R 
10,49,72 
del597 to 603 
R 
25 
G598V 
R 
10,49,72 
K599M 
R 
10,49,72 
C603Y 
R 
6,10,49,72 
A606D 
R 
10,49,72 
 
 
1 R denotes resistance. 
2 Alone confers modest resistance. When found in conjunction with UL54 del 981 to 982, there is a much higher level of resistance. 


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APPENDIX F 
DETAILS OF LOCAL CMV TESTING FOR PARTICIPATING HOSPITALS 
 
Boston Children’s Hospital uses a locally developed assay with their own primers and probes. 
The assay uses whole blood. The sample is extracted with Qiagen Qiacube extraction kit and the 
PCR is done in a Cepheid Smart Cycler. The lower limit of quantification is 500 copies/mL. 
 
Brigham and Women’s Hospital uses the COBAS Amplicor/COBAS Taqman CMV test 
developed by Roche Molecular Systems using plasma. The Lower limit of quantification is 137 
IU/mL. 
 
Massachusetts General Hospital uses the COBAS Amplicor/COBAS Taqman CMV test 
developed by Roche Molecular Systems using plasma. The Lower limit of quantification is 137 
IU/mL.