An Open-label Pilot Protocol to Evaluate the Efficacy of Letermovir for the Prevention of Human Cytomegalovirus (CMV) Infection and Disease in Adult Lung Transplant Recipients With Idiopathic Pulmonary Fibrosis
Phase: PHASE2
Conditions: Lung Transplant, CMV
Sponsor: Fernanda P Silveira, MD, MS

 
 
 
 
 
 
 
An open-label pilot protocol to evaluate the efficacy of letermovir for the 
prevention of human cytomegalovirus (CMV) infection and disease in adult lung 
transplant recipients with idiopathic pulmonary fibrosis  
 
NCT05041426 
 
August 27, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
1. Background 
a. General Information 
Cytomegalovirus (CMV) is a significant opportunistic pathogen and a major cause 
of morbidity and mortality in solid organ transplant recipients. Lung transplant 
recipients (LTRs) are disproportionally affected by CMV as compared to other 
organ recipients, and the incidence of CMV infection in LTRs is close to 30% 
despite prophylaxis [1]. CMV infection in LTRs is associated with an increased risk 
of bronchiolitis obliterans syndrome and decreased survival [2-4].  
Idiopathic pulmonary fibrosis (IPF) is currently the leading indication for lung 
transplantation, corresponding to about a third of all lung transplants performed 
[5]. IPF has been linked to genetic defects in telomerase and telomere length. In a 
previous study, we showed that 71% of IPF LTRs have significantly short 
telomeres. We also demonstrated that IPF LTRs have an increased incidence of 
CMV viremia and other CMV complications compared to age-matched non-IPF 
LTRs. The highest risk of CMV complications was seen in the subset of IPF LTRs 
who had short telomeres. Short telomeres were associated with significantly 
impaired CMV-specific proliferative responses, T-cell effector function, and 
induction of the major type-1 transcription factor T-bet (T-box 21;TBX21) [6].  
Short telomere syndrome is associated with an increased risk of bone marrow 
complications in the form of cytopenias. Valganciclovir and ganciclovir, which are 
utilized for CMV prophylaxis in LTRs, are associated with bone marrow 
suppression. This combination leads to a disproportionate amount of bone 
marrow complications in IPF LTRs, which often leads to frequent start and stops 
of (val)ganciclovir or dose reductions, which may cause breakthrough CMV 
viremia or, even worse, development of ganciclovir-resistance, which is 
associated with worse outcomes [7]. 
The use of letermovir (LET), an anti-CMV agent without bone marrow toxicity, in 
IPF LTRs may lead to decreased CMV burden and be bone marrow sparing.  
LET is currently approved for CMV prevention in allogeneic stem cell 
transplantation. A clinical trial is ongoing to evaluate its efficacy in the prevention 
of CMV in CMV donor positive/recipient negative (D+/R-) kidney transplant 
recipients. Data on prophylaxis in other organ transplant recipients is lacking. An 
abstract at the American Transplant Congress this year described the experience 

 
 
with LET in 46 thoracic transplant recipients, including 39 LTRs. Patients who 
received LET for primary prophylaxis were transitioned from valganciclovir at a 
median of 510 days post-transplant, primarily due to myelosuppression. No 
patient received LET prophylaxis as first-line therapy. There was no virologic 
failure with LET when used for prophylaxis [8]. 
We currently measure telomere length, and telomerase and telomere gene 
variance on all IPF patients listed for lung transplantation. After the completion of 
this protocol we will be able to characterize these patients extremely well. We 
will have their telomere data, CMV immune responses, bone marrow function, 
renal and liver function, and CMV data. We believe we will have enough data to 
show that in IPF LTRs LET reduces the burden of CMV and is bone marrow sparing, 
therefore creating the foundation for a larger study with valganciclovir as the 
comparator arm.   
2. Hypothesis and Objective 
a. Hypothesis  
Our hypotheses are: 
1) LET is effective for the prevention of CMV infection and disease following 
lung transplantation for IPF in patients who are CMV D+/R- and in patients 
who are CMV recipient positive (CMV R+) 
2) Impaired CMV immunity correlates with an increased risk of CMV DNAemia 
and disease after discontinuation of prophylaxis 
3) LET is well tolerated, and bone marrow sparing in LTRs with IPF 
 
b. Potential Risks and Benefits 
i. End points – Efficacy 
1) Proportion of LTRs with IPF with CMV infection or disease during LET 
prophylaxis. This will be compared to the proportion of CMV infection or disease 
in historical LTRs with IPF who received valganciclovir prophylaxis  
2) Proportion of LTRs with IPF with CMV infection or disease in the 3 months 
following completion of prophylaxis with LET. This will be compared to the 
proportion of CMV infection or disease in the 3 months following in historical 
LTRs with IPF who received valganciclovir prophylaxis. 

 
 
a. Definition of CMV infection: evidence of CMV replication without 
symptoms, defined as detection of CMV DNA in plasma or whole blood[9]. 
b. Definition of CMV disease: evidence of CMV infection with attributable 
symptoms. It can be further characterized as CMV viral syndrome or 
tissue invasive disease. Tissue invasive disease will be characterized by 
the specific type of tissue invasive disease (eg. hepatitis, pneumonitis, 
colitis, etc) and as proven or probable CMV tissue invasive disease[9].  
 
i. End points – Safety 
1) Tolerability of LET: 
a. Discontinuation events: This will be compared to discontinuation of 
valganciclovir in historical controls.   
b. Proportion of participants who develop any of the following while receiving 
LET: total WBC count ≤ 3,500 cells/mL or absolute neutrophil count ≤ 1,000 
cells/mL. This will be compared to the rate of total WBC count ≤ 3,500 
cells/mL or absolute neutrophil count ≤ 1,000 cells/mL in historical controls 
while receiving valganciclovir prophylaxis.   
 
b. Number of Subjects to be enrolled 
Approximately 30 patients with IPF listed for lung transplantation will be enrolled 
and 15 are expected to undergo lung transplantation during the study period and 
receive the intervention. 
c. Criteria for Recruitment 
The lung transplant program at UPMC currently performs about 30 transplants a 
year in patients with IPF. We intend to enroll patients with IPF who are active on 
the lung transplant list and within the first 72 hours post-transplant. Our goal is to 
recruit 30 participants and, from those, 15 will undergo lung transplantation 
during the study period and meet inclusion/exclusion criteria at the time of 
transplant. We estimate that it will take 6 to 9 months to transplant 15 patients 
who will be CMV D+/R- or R+ and who meet inclusion/exclusion criteria. 
d. Inclusion Criteria 

 
 
1) Age ≥18 years on day of signing informed consent 
2) Listed for lung transplantation (single or double) due to a diagnosis of IPF or 
receipt of a lung transplant (single or double) for IPF in the 72 hours prior to 
enrollment 
3) Have a documented positive serostatus for CMV (CMV IgG seropositive, R+) 
4) Have a documented negative serostatus for CMV (CMV IgG seronegative, R-) 
and anticipate receiving or having received a lung allograft from a CMV IgG 
positive donor, D+). Only participants who are R+ or who are CMV D+/R- will 
receive intervention. Participants who are CMV D-/R- will be considered screen 
failures 
5) Able to travel to UPMC for routine post-transplant visits for a minimum of 15 
months after transplantation 
6) Able to provide informed consent 
7) Be willing to use a contraceptive method while receiving LET and for at least 90 
days following last dose of LET 
 
e. Exclusion Criteria 
1) Receipt of a previous solid organ transplant or hematopoietic stem cell 
transplant 
2) Multi-organ transplant recipient, i.e., heart-lung or lung-liver 
3) HIV seropositive 
4) HCV antibody or HCV RNA positive 
5) Donor HCV NAT positive  
6) Anticipated need for use of ganciclovir, valganciclovir, foscarnet, or cidofovir at 
the time of transplant 
7) Known or suspected hypersensitivity to LET or acyclovir 
8) CrCl < 10 ml/min or dialysis on day of transplant 
9) Child-Pugh Class C severe hepatic insufficiency 
10) 
Pregnancy or expected to conceive while on LET and through at least 90 days 
following cessation of LET 
 
f. Withdrawal Criteria 
A participant must be withdrawn from the study if the participant or participant’s 
legally authorized representative withdraws consent from the study. If a 

 
 
participant withdraws from the study, they will no longer receive study treatment 
or be followed at scheduled protocol visits.  
g. Subject Replacement 
A participant who discontinues from the study will not be replaced.  
3) Trial Schedule 
a. Study Design 
This is an interventional, open-label, single center, pilot study with historical 
controls to test the efficacy of LET for the prevention of CMV infection and 
disease in adult LTRs with IPF.  
Approximately 30 patients with IPF listed for lung transplantation will be enrolled 
and 15 are expected to undergo lung transplantation during the study period and 
receive the intervention. Historical controls will be LTRs for IPF from 2010-2019 
who are CMV R+ or CMV D+/R-. CMV prophylaxis in the historical controls was with 
valganciclovir for 6 months for CMV R+ and for 12 months for CMV D+/R-.  Patients 
will be matched for CMV serostatus, induction immunosuppression, age, and 
telomere length.  
Participants who are CMV R+ will receive LET prophylaxis for 6 months, and 
participants who are CMV D+/R- will receive LET prophylaxis for 12 months. The 
duration of prophylaxis is per current standard of care. LET will be administered at 
a dose of 480 mg IV or oral once daily. IV administration will occur only for those 
patients unable to swallow tablets. If LET is co-administered with cyclosporine A 
(CsA), the dosage of LET should be decreased to 240 mg once daily. All patients will 
be followed for 12 weeks after completion of LET for the occurrence of CMV 
infection or disease after prophylaxis.  
Induction and maintenance immunosuppression, and antifungal and Pneumocystis 
prophylaxis will follow institution’s protocol. Induction therapy is with 
alemtuzumab for CMV R+, and with basiliximab for CMV D+/R- and those with a 
previous history of malignancy. Standard immunosuppression consists of 
tacrolimus, mycophenolate mofetil and prednisone. Participants on this protocol 
will receive acyclovir 400 mg orally BID for the duration of LET therapy for herpes 
simplex virus and varicella zoster virus prophylaxis.  

 
 
CMV immune response will be assessed at baseline immediately after transplant, 
half-way through LET administration, at the end of LET administration, when the 
patient develops CMV infection or disease, and at the end of study. The following 
assays will be performed at each of the specified time points.  
 CMV T-cell effector response assays: will evaluate peripheral blood 
mononuclear cell responses to in vitro stimulation with pooled overlapping 
peptides of phosphoprotein 65 (pp65) and immediate early Ag-1  (IE1) and 
CMV lysate in addition to unstimulated cells and Staph Enterotoxin B (SEB); 
positive control . Will measure pp-65 specific IFN-g, TNF-a, the cytotoxic 
degranulation marker CD107a, and loading of the cytotoxic molecule 
Granzyme B (GrzB) in CD8+ T cells in an ex vivo 6-hour assay.  Will also 
evaluate CMV-specific CD4+ effector responses to these antigens.  
 CMV T cell phenotyping:  Using a pool a 10 CMV HLA class I dextramers that 
span the HLA of 85% of patients (Hoji et al), we will perform T cell 
phenotyping to key markers such as KLRG1, CD57, PD1, CD27, CD28, CD45 
RA/RO and other markers to assess CMV T cell phenotypes.   
 CMV-specific T cell proliferation:  We will assess 6-day CMV proliferative 
responses in response to pp65 and IE1[6, 10].       
 
4) Methods and Assessment 
a. Study Visits and Procedures 
CMV PCR will be measured following the schedule of our lung transplant program 
standard of care protocol: at least monthly while on prophylaxis and at least 
biweekly x 12 weeks once prophylaxis is discontinued. CMV PCR will be 
performed at CLIA-certified laboratories and reported in IU/ml.  
CMV immune response will also be assessed if patient develops CMV 
infection/disease.  
Complete blood count and comprehensive metabolic panel are performed at least 
monthly. 
All laboratory tests will be performed at CLIA-certified laboratories. These tests 
will be done as part of routine clinical care and the choice of laboratory will be 

 
 
according to patient’s preference. CMV immune response assays will be 
performed at Dr. John McDyer’s research laboratory at the University of 
Pittsburgh. 
CMV R+ LTRs: 
 
 
 
 
 
                      0                 3 mos           6 mos                  9 mos                             15 mos                    
                     Transplant 
 
 
 
 
 
 
CMV immune response will also be assessed if patient develops CMV 
infection/disease.  
CMV D+/R- LTRs: 
 
 
 
 
 
                      0                                  6 mos                                 12 mos              15 mos                    
                     Transplant 
 
 
 
 
 
 
Pre-
transplant
LET 480 mg daily 
Post-
prophylaxis 
follow-up 
phase 
CMV 
immune 
response 
CMV 
immune 
response 
CMV 
immune 
response 
CMV 
immune 
response 
Pre-
transplant
LET 480 mg daily 
Post-
prophylaxis 
follow-up 
phase 
CMV 
immune 
response 
CMV 
immune 
response 
CMV 
immune 
response 
CMV 
immune 
response 

 
 
CMV immune response will also be assessed if patient develops CMV 
infection/disease.  
Screening visit – anytime from transplant listing at UPMC until 72h post-
transplant: 
The study procedures in the screening period will include: 
 Informed consent 
 Inclusion/exclusion criteria 
 Medical history 
 Current medications, therapies, and procedures 
 Review of CMV serology of donor and recipient (clinical test) 
 Creatinine and liver enzymes (clinical test obtained within 3 months prior to 
informed consent is acceptable) 
 Participants will be instructed that they are required to use birth control, 
starting from the time of consent through 90 days after the last dose of LET 
 
Prior to first dose administration of LET: 
The study procedures prior to the first dose administration of LET will include: 
 Current medications, therapies, and procedures 
 Review of donor and recipient serology  
 Complete blood count, creatinine and liver enzymes  
 Pregnancy test (urine or serum) for all females of childbearing potential 
 
Patients will receive the first dose of LET within 72h of lung transplantation. 
Valganciclovir/ganciclovir, if initiated by the clinical team, will be discontinued 
prior to first dose of LET.  
The screening and prior to first dose administration of LET visits can occur at the 
same time.  
CMV prophylaxis phase – LET administration:  
The study procedures during the LET administration phase will include: 
 Liver enzymes every other week for the first 12 weeks, then monthly 
 Complete blood count weekly for the first 8 weeks, then monthly 

 
 
 Creatinine weekly for the first 8 weeks, then monthly 
 CMV PCR per standard protocol at UPMC, no more than weekly and at least 
monthly, and during any symptomatic or clinically indicated time 
 CMV immune response assays within 72 h of first dose of LET, halfway 
through LET prophylaxis. CMV immune assays will be performed as detailed 
above and previously described [6, 10] 
 Adverse event assessment on weeks 1 and 2, then monthly 
 Medications, therapies, and procedures monthly 
 Confirmation that participant and his/her partner are using acceptable 
methods of contraception monthly 
 Assessment of graft function monthly 
 Assessment of patient survival monthly 
 
LET administration will be for 6 months for patients who are R+ and 12 months for 
CMV D+/R-, as per current standard of care protocol at UPMC’s lung transplant 
program. Patients will receive acyclovir 400 mg PO BID while on LET for HSV/VZV 
prophylaxis.  
Patients with CMV DNA detection ≥ 1,000 IU/ml while receiving LET will undergo 
detection of UL56 mutation. Sample will be sent to Viracor.  
End of prophylaxis with LET: 
The study procedures at the end of LET administration phase will include: 
 Liver enzymes 
 Complete blood count 
 Creatinine 
 CMV PCR 
 CMV immune response assays 
 Adverse event assessment 
 Medications, therapies, and procedures 
 Confirmation that participant and his/her partner are using acceptable 
methods of contraception  
 Assessment of graft function 
 Assessment of survival 
 

 
 
Post-LET follow-up phase: 
The study procedures in the post-prophylaxis follow-up phase will include: 
 CMV PCR no more than weekly and at least biweekly, and during any 
symptomatic or clinically indicated time 
 Complete blood count, creatinine, and liver enzymes monthly 
 CMV immune response assay 
 Adverse event assessment monthly 
 Medications, therapies, and procedures monthly 
 Confirmation that participant and his/her partner are using acceptable 
methods of contraception monthly 
 Assessment of graft function monthly 
 Assessment of patient survival monthly  
 
The following medications will be prohibited during LET administration: 
valganciclovir, ganciclovir, foscarnet, and cidofovir, except for cidofovir for 
treatment of severe adenovirus disease. 
The concomitant use of LET with certain drugs may result in potentially significant 
drug interactions, some of which may lead to adverse reactions or reduced 
therapeutic effect of LET or the concomitant drug. If oral or intravenous LET is co-
administered with CsA, the dosage of LET will be decreased to 240 mg once daily. 
Concomitant medications will be reviewed by one of the investigators and steps 
to prevent or manage possible or known significant drug interactions will be 
followed as suggested in the Prevymis™ Package Insert[11] and summarized in 
appendix A. Participants will be monitored for adverse reactions associated with 
LET and concomitant medications. 
 
5) Trial Material  
a. Trial Product 
Letermovir (Prevymis) 240 mg and 480 mg tablets, injection 20 mg/ml 
b. Storage and Drug Accountability 

 
 
Trial product will be stored and dispensed by the Investigational Drug Service 
(IDS). IDS can develop protocol specific accountability logs or it can use the 
sponsor’s accountability logs. If the sponsor accountability logs do not have a 
running total, IDS will u  lize a secondary log for running totals of study drug. 
6) Treatment 
a. Rationale for Selection of Dose 
Selected dose follows the recommendations of the package insert. 
b. Study Drug Formulations 
240 mg and 480 mg tablets, injection 20 mg/ml 
c. Study Drug Administration 
LET will be administered at a dose of 480 mg orally or intravenously (IV) once 
daily. LET will be used IV only in patients unable to take oral therapy. Patients will 
be switched to oral LET as soon as they are able to take oral medications. It is 
anticipated that administration in the first 24-72h post-transplant will be IV, until 
extubation and clearance for oral intake. If oral or IV LET is co-administered with 
CsA, the dosage of LET will be decreased to 240 mg once daily. If CsA is initiated 
after starting LET, the next dose of LET will be decreased to 240 mg once daily. If 
CsA is discontinued after starting LET, the next dose of LET will be increased to 
480 mg once daily. If CsA dosing is interrupted due to high CsA levels, no dose 
adjustment of LET will be needed.  
7) Safety Measurements 
a. Definitions 
The patient population under study is complex. For this study, AEs will be 
reported only if study related or unexpected. For this study, a reportable adverse 
event is defined as: 
 Any clinically important untoward medical occurrence in a subject 
receiving study drug that is different from what is expected in the 
clinical course of a patient with a lung transplant (see appendix B for 
events considered to be part of the expected course of lung 
transplant) OR 

 
 
 Any clinically important, untoward medical occurrence that is 
thought to be related to the study drug, regardless of the 
“expectedness” of the event for the course of a patient with a lung 
transplant. Expected events for lung transplant are untoward clinical 
occurrences that are deemed by the investigator to occur with 
reasonable frequency in the day-to-day care of patients with a lung 
transplant (see appendix B for events considered to be part of the 
expected course of lung transplantation) 
 
b. Collection, Recording and Reporting of Serious Adverse Event 
(SAE/Safety/Suspected Unexpected Serious Adverse Reaction 
(SUSAR) 
All reportable AEs will be captured in the case report form. The following 
information will be collected: event description, time of onset, clinician’s 
assessment of severity, and time of resolution/stabilization of the event. 
Reportable AEs occurring while on study will be documented appropriately and 
will be followed to resolution or stabilization. The determination of seriousness 
and severity of an AE will be made by an investigator who is qualified (licensed) to 
diagnose AE information, provide a medical evaluation of AEs, and classify AEs 
based upon medical judgment. This is a small study in a critically ill population, 
therefore relationship of AEs to study product will not be assigned.  
Lung transplant recipients represent a critically ill population in whom a high rate 
of untoward medical events is commonly seen during the routine post-transplant 
course as part of their underlying medical condition, transplant surgery or 
postoperative state. In an effort to document only clinically-relevant untoward 
medical events that have a greater likelihood of being study-related, rather than 
the normal course of lung transplantation, study endpoints and certain pre-
specified expected events commonly seen in this population (see appendix B for 
list of expected events for lung transplant recipients) will not be reported as 
serious adverse events (SAEs) even if they meet serious event criteria. Reportable 
SAEs for this study will be adverse events that are serious and unexpected, i.e., 
not expected to occur with a reasonable frequency in the typical course of a 
patient following lung transplant (appendix B). Death will be recorded in the CRF 

 
 
although it will not be a reportable SAE unless it meets the study’s reportable 
criteria of related and/or unexpected (see appendix B for list of expected events 
for lung transplant recipients). Reportable SAEs will be recorded on appropriate 
CRF, followed through resolution by a study clinician, reviewed and evaluated by 
a study clinician.  
c. Pregnancy and Exposure During Breastfeeding  
No adequate human data are available to establish whether letermovir poses a 
risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal 
developmental toxicity (including fetal malformations) was observed in rats 
during the period of organogenesis at letermovir exposures (AUC) 11 times higher 
than human exposure at the recommended human dose. In rabbits, no embryo-
fetal developmental toxicity was noted at exposures that were not maternally 
toxic (up to letermovir exposures 2 times higher than human exposure at the 
recommended human dose). In a rat pre/post-natal development study, total 
litter loss was observed at maternal letermovir exposures approximately 2 times 
higher than human exposure at the recommended human dose.  
The background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the US general population, the estimated background 
risk of major birth defects and miscarriage in clinically recognized pregnancies is 
2-4% and 15-20%, respectively[11].  
Although pregnancy and infant exposure during breastfeeding are not considered 
adverse events, any pregnancy or infant exposure during breastfeeding in a 
participant while receiving LET or within 90 days of receipt of the last dose of LET, 
including the pregnancy of a male participant’s female partner, will be captured in 
the case report form. All reported pregnancies will be followed to the completion 
or termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, fetal death, intrauterine death, 
miscarriage, and stillbirth will be reported as serious events. If the pregnancy 
continues to term, the outcome will be captured.  
d. Safety Monitoring Plan 
The principal investigator will have oversight of the DSMP. The principal 
investigator, co-investigators, and primary research coordinator will meet monthly. 

 
 
Attendance by an investigator with expertise in Transplant Infectious Diseases will 
be mandatory. The following elements will be reviewed at the meetings:  
 
Overall study progress, including recruitment and retention 
 
Adverse events, unanticipated problems, and subject withdrawals. An 
assessment of any change to the anticipated benefit-to-risk ratio of study 
participation will be made and, based on that, it will be determined if the 
study should continue as originally designed, should be changed, or should 
be terminated.  
 
Assessment of new pertinent scientific literature or therapeutic 
developments that may have an impact on the safety of study participants 
or the ethics of this research protocol 
 
Breaches of confidentiality and procedures to protect the privacy of 
research subjects and confidentiality of research data 
Any unanticipated events or reportable adverse events will be reported to the 
University of Pittsburgh IRB as per its current policies. A summary of the DSMP 
meetings and its findings will be provided to the IRB yearly, at the time of study 
renewal.  
e. Complaint Handling 
Any concerns raised by participants will be answered by the investigators and, if 
not resolved, will be referred to the Human Subject Protection Advocate of the 
IRB Office, University of Pittsburgh.  
8) Sample Size and Statistical Methods 
a. Determination of Sample Size 
The incidence of CMV infection and disease in LTRs is approximately 30%. It is 
higher in IPF LTRs, particularly in those with short telomeres. Seventy percent of 
our IPF LTRs have short telomeres. This pilot, single arm, exploratory study will 
use a convenience sample to estimate the frequency of CMV infection and 
disease in the target population. A sample size of 10 to 30 is usually suggested for 
pilot studies and it is estimated that the UPMC transplant numbers will provide a 
sufficient sample size of n=15.  

 
 
Approximately 85 lung transplants are performed per year at UPMC. Thirty 
patients will be consented, of which we estimate 15 will undergo lung 
transplantation and receive LET prophylaxis.  
The results of this study will generate foundational data to examine the efficacy of 
LET in future studies with a larger sample size and more comprehensive protocols. 
b. Statistical and Analytical Plans 
This is an exploratory pilot study to generate preliminary data on the efficacy of 
LET prophylaxis in lung transplant recipients and support future hypothesis 
testing studies based on those data. As such, descriptive non-parametric statistics 
will be used to characterize the study population and outcomes, including means 
and medians for continuous measures, frequencies for count data, standard 
deviations, and interquartile ranges for variance. This analysis will be applied to 
both the LET prophylaxis and post-prophylaxis periods. Regression analysis will be 
used to find predictors of outcomes. Differences in proportions in the group 
receiving LET and historical controls will be compared with Fisher’s exact test.   
9) Ethical Considerations 
a. Informed Consent 
The process of obtaining informed consent will be documented in the medical 
records, clinic chart, and/or research chart. The consent form must be signed and 
dated by the study participant or legal guardian before participation in the study. 
A copy of the signed consent form must be provided to the study participant or 
legal guardian. Signed consent forms must remain in each study participants study 
file and must be available for verification at any time. Informed consent will be 
obtained by a physician.  
b. IRB Review 
This protocol will be reviewed by the University of Pittsburgh Institutional Review 
Board. 
10) 
Schedule of study procedures: 

 
 
Schedule of study procedures: R+ LTR 
  
Screening 
Pri
or 
to 
1st 
do
se 
of 
LET 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study 
week/month/y
ear 
Any time 
prior to 
transplant 
until 72h 
post-
transplant 
0 
Wk 
1 
W
k 
2 
W
k 
3 
W
k 
4 
W
k 
5 
W
k 
6 
W
k 
7 
W
k 
8 
W
k 
9 
W
k 
1
0 
W
k 
1
1 
W
k 
1
2 
W
k 
1
6 
W
k 
2
0 
Wk
24 
(EO
T) 
W
k 
2
5 
W
k 
2
6 
W
k 
2
7 
W
k 
2
8 
W
k 
2
9 
W
k 
3
0 
W
k 
3
1 
W
k 
3
2 
W
k 
3
3 
W
k 
3
4 
W
k 
3
5 
W
k 
3
6 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclus
ion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Current 
medications, 
therapies and 
procedures 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of CMV 
serology of 
donor and 
recipient 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Complete blood 
count 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Liver enzymes 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Pregnancy test 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
 
CMV PCR 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UL56 mutation 
detection 
  
  
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
  
  
  
  
  
  
  
  
  
  
  
  
CMV immune 
response assays 
  
  
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
X 
Adverse event 
assessment 
  
  
X 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Medications, 
therapies, and 
procedures 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Assessment of 
graft function 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Assessment of 
survival 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
a: only obtained once and if CMV PCR ≥ 1,000 IU/ml 
Bold: performed for study 
purposes only 

 
 
Schedule of study procedures: D+/R- LTR 
  
Scre
enin
g 
Pr
io
r 
to 
1s
t 
d
os
e 
of 
LE
T 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study 
week/mo
nth/year 
Any 
time 
prior 
to 
trans
plant 
until 
72h 
post-
trans
plant 
0 
W
k 
1 
W
k 
2 
W
k 
3 
W
k 
4 
W
k 
5 
W
k 
6 
W
k 
7 
W
k 
8 
W
k 
9 
W
k 
1
0 
W
k 
1
1 
W
k 
1
2 
W
k 
1
6 
W
k 
2
0 
W
k 
2
4 
M
o 
7 
M
o 
8 
M
o 
9 
M
o 
1
0 
M
o 
1
1 
M
o1
2 
(E
OT
) 
W
k 
5
3 
W
k 
5
4 
W
k 
5
5 
W
k 
5
6 
W
k 
5
7 
W
k 
5
8 
W
k 
5
9 
W
k 
6
0 
W
k 
6
1 
W
k 
6
2 
W
k 
6
3 
W
k 
6
4 
(1
5 
m
o) 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/
exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Current 
medicatio
ns, 
therapies 
and 
procedur
es 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of 
CMV 
serology 
of donor 
and 
recipient 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
 
Complete 
blood 
count 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Creatinin
e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Liver 
enzymes 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Pregnanc
y test 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CMV PCR 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UL56 
mutation 
detection 
  
  
Xa 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
X
a 
Xa 
  
  
  
  
  
  
  
  
  
  
  
  
CMV 
immune 
response 
assays 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
X 
Adverse 
event 
assessme
nt 
  
  
X 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Medicati
ons, 
therapies
, and 
procedur
es 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Assessme
nt of 
graft 
function 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Assessme
nt of 
survival 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
a: only obtained once and if CMV PCR ≥ 1,000 IU/ml 
Bold: performed for study 
purposes only 

 
 
 
11) 
Publications 
1. 
Avery RK, Silveira FP, Benedict K, et al. Cytomegalovirus infections in lung 
and hematopoietic cell transplant recipients in the Organ Transplant Infection 
Prevention and Detection Study: A multi-year, multicenter prospective cohort 
study. Transpl Infect Dis 2018; 20(3): e12877. 
2. 
Kerschner H, Jaksch P, Karigl G, Popow-Kraupp T, Klepetko W, 
Puchhammer-Stockl E. Cytomegalovirus DNA load patterns developing after lung 
transplantation are significantly correlated with long-term patient survival. 
Transplantation 2009; 87(11): 1720-6. 
3. 
Snyder LD, Finlen-Copeland CA, Turbyfill WJ, Howell D, Willner DA, Palmer 
SM. Cytomegalovirus pneumonitis is a risk for bronchiolitis obliterans syndrome in 
lung transplantation. Am J Respir Crit Care Med 2010; 181(12): 1391-6. 
4. 
Westall GP, Michaelides A, Williams TJ, Snell GI, Kotsimbos TC. Bronchiolitis 
obliterans syndrome and early human cytomegalovirus DNAaemia dynamics after 
lung transplantation. Transplantation 2003; 75(12): 2064-8. 
5. 
Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic 
Organ Transplant Registry of the International Society for Heart and Lung 
Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-
2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 
2019; 38(10): 1042-55. 
6. 
Popescu I, Mannem H, Winters SA, et al. Impaired Cytomegalovirus 
Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short 
Telomeres. Am J Respir Crit Care Med 2019; 199(3): 362-76. 
7. 
Minces LR, Nguyen MH, Mitsani D, et al. Ganciclovir-resistant 
cytomegalovirus infections among lung transplant recipients are associated with 
poor outcomes despite treatment with foscarnet-containing regimens. 
Antimicrob Agents Chemother 2014; 58(1): 128-35. 
8. 
Saullo JL FA, Eichenberger EM, Steinbrink JM, Baker AW, Bacchus M, 
Maziarz EK, Kakoullis S, Zaffiri L, Berry H, Reynolds JM, Wolfe CR. . Use of 
letermovir for cytomegalovirus management in thoraric organ transplantation 
[abstract]. Am J Transplant 2020; 20(suppl 3). 
9. 
Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus 
Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect 
Dis 2017; 64(1): 87-91. 

 
 
10. 
Hoji A, Popescu ID, Pipeling MR, Shah PD, Winters SA, McDyer JF. Early 
KLRG1(+) but Not CD57(+)CD8(+) T Cells in Primary Cytomegalovirus Infection 
Predict Effector Function and Viral Control. J Immunol 2019; 203(8): 2063-75. 
11. 
Prevymis Prescribing Information. Available at: 
https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_pi.pdf. 
Accessed March 2, 2021. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
APPENDIX A: POTENTIALLY SIGNIFICANT DRUG INTERACTIONS WITH CO-
ADMINISTRATION WITH LETERMOVIR AND RECOMMENDED MONITORING AS 
INDICATED IN THE PREVYMIS™ PRESCRIBING INFORMATION 
 
Concomitant Drug 
Effect on 
Concentration 
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 LET 
Antibiotics
Nafcillin 
↓ letermovir
Co-administration of LET and nafcillin is not recommended 
due to potential for loss of efficacy of LET 
Anticoagulants
Warfarin
↓ warfarin
When LET is co-administered with warfarin, frequently 
monitor International Normalized Ratio (INR) 
Anticonvulsants
Carbamazepine
↓ letermovir
Co-administration of LET and carbamazepine is not 
recommended due to potential for loss of efficacy of LET 
Phenobarbital
↓ letermovir
Co-administration of LET and phenobarbital is not 
recommended due to potential for loss of efficacy of LET 
Phenytoin
↓ letermovir                     
↓ phenytoin 
Co-administration of LET and phenytoin is not 
recommended due to potential for loss of efficacy of LET 
Antidiabetic agents
Glyburide, 
repaglinide, 
rosiglitazone 
↑ glyburide                       
↑ replaglinide                   
↑ rosiglitazone 
When LET is co-administered with glyburide, repaglinide, 
or rosiglitazone, frequently monitor glucose 
concentrations. When LET is co-administered with CsA, use 
of repaglinide is not recommended. 
Antifungals

 
 
Voriconazole
↓ voriconazole
If concomitant administration of voriconazole is necessary, 
closely monitor for reduced effectiveness of voriconazole.  
Antimycobacterials
Ribabutin
↓ letermovir
Co-administration of LET and rifabutin is not 
recommended due to potential for loss of efficacy of LET 
Rifampin
↓ letermovir
Co-administration of LET and rifampin is not 
recommended due to potential for loss of efficacy of LET 
Antipsychotics
Pimozide
↑ pimozide
Co-administration is contraindicated due to risk of QT 
prolongation and torsades de pointes.  
Thioridazine
↓ letermovir
Co-administration of LET and thioridazine is not 
recommended due to potential for loss of efficacy of LET 
Endothelin antagonists
Bosentan
↓ letermovir
Co-administration of LET and bosentan is not 
recommended due to potential for loss of efficacy of LET 
Ergot alkaloids
Ergotamine, 
dihydroergotamine
↑ ergotamine, 
dihydroergotamine 
Co-administration is contraindicated due to risk of 
ergotism 
Herbal products
St. John's wort
↓ letermovir
Co-administration of LET and St. John's wort is not 
recommended due to potential for loss of efficacy of LET 
HIV medications
Efavirenz
↓ letermovir
Co-administration of LET and efavirenz is not 
recommended due to potential for loss of efficacy of LET 

 
 
Etravirine
↓ letermovir
Co-administration of LET and etravirine is not 
recommended due to potential for loss of efficacy of LET 
Nevirapine
↓ letermovir
Co-administration of LET and nevirapine is not 
recommended due to potential for loss of efficacy of LET 
HMG-CoA reductase inhibitors
Atorvastatin
↑ atorvastaƟn
When LET is co-administered with atorvastatin, do not 
exceed an atorvastatin dosage of 20 mg daily. Closely 
monitor patients for myopathy and rhabdomyolysis. When 
LET is co-administered with CsA, use of atorvastatin is not 
recommended. 
Pitavastatin, 
simvastatin 
↑ HMG-CoA reductase 
inhibitors 
Co-administration of LET and pitavastatin or simvastatin is 
not recommended. When LET is co-administered with CsA, 
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 LET is co-administered with these statins, a statin 
dosage reduction may be necessary. Closely monitor 
patients for myopathy and rhabdomyolysis. When LET is 
co-administered with CsA, use of lovastatin is not 
recommended. When LET is co-administered with CsA, 
refer to the statin prescribing information for specific 
statin dosing recommendations.  
Immunosuppressants
Cyclosporine
↑ cyclosporine                  
↑ letermovir         
Decrease the dosage of LET to 240 mg once daily. 
Frequently monitor CsA whole blood concentrations 
during treatment and after discontinuation of LET and 
adjust the dose of CsA accordingly. 
Sirolimus
↑ sirolimus
When LET is co-administered with sirolimus, frequently 
monitor sirolimus whole blood concentrations during 
treatment and after discontinuation of LET and adjust the 
dose of sirolimus accordingly. When LET is co-administered 
with CsA 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 LET 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
Wakefulness-promoting agents
Modafinil
↓ letermovir
Co-administration of LET and modafinil is not 
recommended due to potential for loss of efficacy of LET 
CYP3A substrates
Alfentanil, 
fentanyl, 
midazolam, and 
quinidine 
↑ CYP3A substrate
When LET is co-administered with a CYP3A substrate, refer 
to the prescribing information for dosing of the CYP3A 
substrate with a moderate CYP3A inhibitor. When LET is 
co-administered with CsA, the combined effect on CYP3A 
substrates may be similar to a strong CYP3A inhibitor. 
Refer to the prescribing information for dosing of the 
CYP3A substrate with a strong CYP3A inhibitor. CYP3A 
substrates pimozide and ergot alkaloids are 
contraindicated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
APPENDIX B: EXPECTED EVENTS FOR LUNG TRANSPLANT RECIPIENTS 
 
The following events are expected to occur with a reasonable frequency in the 
typical/expected clinical course of a patient following lung transplant: 
 
 Pulmonary: acute lung injury, respiratory distress syndrome, aspiration, 
atelectasis, mucus plugging, respiratory failure, dyspnea, hypoxia, pneumonia, 
pleural effusion, pneumothorax, pulmonary edema, sinusitis, need for 
mechanical ventilation, intubation or reintubation, chest tube insertion, 
tracheostomy insertion, embolism, pulmonary hypertension, graft rejection, 
primary graft dysfunction, diffuse alveolar hemorrhage, need for ECMO 
 Surgical: anastomotic dehiscence, return to the operating room for surgery, 
subcutaneous emphysema, wound dehiscence, retransplantation, wound 
infection, fluid collection, seroma, hematoma 
 Gastrointestinal: vomiting, diarrhea, dyspepsia, abdominal distention or 
bloating, abdominal pain, anorexia, perforation, ischemic bowel, reflux 
gastritis, ascites, ileus, bowel obstruction, GI bleed 
 Neurologic: tremors, seizures, confusion, dizziness, hallucinations, delusion, 
psychosis, insomnia, somnolence, lethargy, depressed level of consciousness, 
agitation, amnesia, anxiety, emotional lability, vertigo, abnormal dreams, 
encephalopathy, posterior reversible encephalopathy syndrome, tacrolimus 
toxicity, neuropathy 
 Neuromuscular and skeletal: incoordination, leg cramps, nerve compression 
 Constitutional/systemic: fever, asthenia, failure to thrive, weight loss or weight 
gain, anasarca, embolism, multiorgan failure, malnutrition  
 Infection: fever, hypothermia, rigors, chills, systemic inflammatory response 
syndrome, infection (documented or suspected), sepsis, multisystem organ 
failure 
 Electrolyte and metabolic: acidosis or alkalosis, low albumin, dehydration, 
gout, increase or decrease in the levels of sodium, potassium, blood urea 
nitrogen, creatinine, glucose, calcium, magnesium, phosphate, uric acid, 
cholesterol, lipids, iron 
 Hematologic: anemia, blood loss, prolonged PT or PTT, abnormalities in 
coagulation, hematoma, hemorrhage, bleeding, venous thrombosis, 
thrombocytopenia/thrombocytosis, leukopenia/leukocytosis, thrombotic 
thrombocytopenic purpura, hemolytic uremic syndrome, pancytopenia 

 
 
 Cardiac: arrhythmias (will capture atrial fibrillation and use of amiodarone), 
prolonged QT interval, QRS or ST  segment abnormal, tachycardia, bradycardia, 
torsade de pointes, hypertension, hypotension, pulmonary hypertension, 
myocardial ischemia or infarction, syncope, postural hypotension, phlebitis, 
thrombosis 
 Renal: acute renal failure, albuminuria, nephropathy, hematuria, proteinuria, 
acute tubular necrosis, interstitial nephritis, hemorraghic cystitis 
 Genitourinary: bladder spasm, dysuria, nocturia, incontinence, urinary 
frequency, urinary retention 
 Malignancies: lymphoproliferative disorder, skin neoplasm 
 Dermatologic: edema at any body site, rash, ecchymosis, bruising, flushing, 
cellulitis, dermatitis, decubitus ulcer, photosensitivity, skin ulcer, impaired 
wound healing