Clinical trial NCT04312841
Conditions: B-Cell Prolymphocytic Leukemia Chronic Lymphocytic Leukemia Peripheral T-Cell Lymphoma Primary Cutaneous T-Cell Non-Hodgkin Lymphoma Sezary Syndrome T-Cell Prolymphocytic Leukemia
Sponsor: Ohio State University Comprehensive Cancer Center
Start date: 2020-09-15; Completion date: 2024-04-09
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well letermovir works for the prevention of cytomegalovirus reactivation in patients with hematological malignancies treated with alemtuzumab. Patients receiving treatment with alemtuzumab may experience cytomegalovirus reactivation. Letermovir may block cytomegalovirus replication and prevent infection.

Detailed description:
PRIMARY OBJECTIVE:

I. To estimate the rate of cytomegalovirus (CMV) reactivation in patients treated with letermovir at 3 months after completion of alemtuzumab therapy.

SECONDARY OBJECTIVES:

I. To evaluate the tolerability of letermovir in combination with alemtuzumab.

II. To evaluate the efficacy of letermovir for the prevention of clinically significant CMV disease.

III. To estimate the progression free survival of patients in the study population.

IV. To estimate the overall survival of patients in the study population.

EXPLORATORY OBJECTIVE:

I. To evaluate mechanisms of antiviral resistance in letermovir prophylaxis failures.

OUTLINE:

Beginning within 7 days of the first administration of standard alemtuzumab, patients receive letermovir orally (PO) (or intravenously \[IV\] over 1 hour if patient is unable to take PO for an extended period of time) daily on days 1-28. Cycles repeat every 28 days for up to 3 months after the last dose of alemtuzumab in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: Beginning within 7 days of the first administration of standard alemtuzumab, patients receive letermovir PO (or IV over 1 hour if patient is unable to take PO for an extended period of time) daily on days 1-28. Cycles repeat every 28 days for up to 3 months after the last dose of alemtuzumab in the absence of unacceptable toxicity.
Interventions: intervention 1: Letermovir
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
Protocol: OSU-19289 
Version Date: 09June2022 
IRB Approved: 23Feb2023 
Page 1 of 57 
 
PROTOCOL 
TITLE: 
Letermovir for cytomegalovirus prophylaxis in patients with 
hematological malignancies treated with alemtuzumab 
STUDY NUMBER: 
OSU-19289 
IND NUMBER: 
147864 
TEST PRODUCTS: 
NA 
COMMERICAL PRODUCTS: 
Letermovir 
INDICATION: 
Hematologic malignancies treated with alemtuzumab 
INVESTIGATOR: 
John C. Reneau, MD, PhD 
320 West 10th Avenue 
A350A Starling Loving Hall  
Telephone: 614-688-7942 
Fax: 614-293-7526 
E-mail: john.reneau@osumc.edu 
Statistician 
Ying Huang, MSc 
320 West 10th Avenue  
Telephone: 614-688-7591 
Fax: 614-293-7526 
Email: ying.huang@osumc.edu 
SUPPORT PROVIDED BY: 
The Ohio State University  
Merck 
 
1 
CONFIDENTIAL 
2 
This is an Ohio State University document that contains confidential information. It is intended 
3 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party. This 
4 
material may be used only for evaluating or conducting clinical investigations; any other 
5 
proposed use requires written consent from Ohio State University. 
6 
 
 
7 


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8 
TABLE OF CONTENTS 
9 
Trial Summary............................................................................................................................ 5 
10 
1 
Background and Rationale .................................................................................................. 7 
11 
1.1 
Mature T-cell Lymphomas ............................................................................................ 7 
12 
1.1.1 
Peripheral T-cell Lymphoma ................................................................................. 7 
13 
1.1.2 
Cutaneous T-cell Lymphoma ................................................................................ 7 
14 
1.1.3 
T-cell Prolymphocytic Leukemia ........................................................................... 7 
15 
1.2 
Alemtuzumab ............................................................................................................... 8 
16 
1.3 
Cytomegalovirus .......................................................................................................... 8 
17 
1.4 
Letermovir ...................................................................................................................10 
18 
2 
Objectives and Endpoints ..................................................................................................11 
19 
2.1 
Objectives ...................................................................................................................11 
20 
2.1.1 
Primary Objective ................................................................................................11 
21 
2.1.2 
Secondary Objectives ..........................................................................................11 
22 
2.1.3 
Exploratory Objectives .........................................................................................11 
23 
2.2 
Endpoints ....................................................................................................................11 
24 
2.2.1 
Primary Endpoint .................................................................................................11 
25 
2.2.2 
Secondary Endpoints ...........................................................................................11 
26 
2.2.3 
Exploratory Endpoints ..........................................................................................11 
27 
3 
Patients and Methods ........................................................................................................11 
28 
3.1 
Inclusion Criteria .........................................................................................................11 
29 
3.2 
Exclusion Criteria ........................................................................................................13 
30 
3.3 
Screening Procedures ................................................................................................15 
31 
4 
Treatment Plan ..................................................................................................................15 
32 
4.1 
Premedication Administration .....................................................................................15 
33 
4.2 
Agent Administration ...................................................................................................15 
34 
4.3 
Rationale for Dose Selection .......................................................................................15 
35 
4.4 
Concomitant Medications and Supportive Care ..........................................................16 
36 
5 
Toxicities, Dose Delays, and Dose Modifications ...............................................................17 
37 
5.1 
Dose Delays and Modifications ...................................................................................17 
38 
5.2 
Protocol Therapy Discontinuation ...............................................................................17 
39 
6 
Study Evaluations ..............................................................................................................18 
40 
6.1 
Calendar of Events .....................................................................................................18 
41 


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6.2 
Biospecimen Studies and Procedures.........................................................................19 
42 
6.3 
Source and Timing of Biospecimen Collections ..........................................................19 
43 
6.4 
Storage of Biospecimens ............................................................................................19 
44 
7 
Criteria for Disease Evaluation ...........................................................................................19 
45 
8 
Letermovir Information .......................................................................................................19 
46 
8.1 
Letermovir Description and Mechanism of Action .......................................................19 
47 
8.2 
Clinical Pharmacology ................................................................................................20 
48 
8.3 
Pharmacokinetics and Drug Metabolism .....................................................................20 
49 
8.4 
Preparation, Storage, and Administration: Oral Formulation .......................................33 
50 
8.5 
Preparation, Storage, and Administration: Intravenous formulation .............................34 
51 
8.6 
Non Clinical Toxicology ...............................................................................................36 
52 
8.6.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility ..........................................36 
53 
8.6.2 
Animal Toxicology and Pharmacology .................................................................36 
54 
8.7 
Clinical Studies ...........................................................................................................36 
55 
8.8 
Adverse Events ...........................................................................................................41 
56 
9 
Regulatory and Reporting Requirements ...........................................................................43 
57 
9.1 
Adverse Events (AEs) .................................................................................................43 
58 
9.2 
Serious Adverse Events (SAEs) ..................................................................................44 
59 
9.3 
Noncompliance ...........................................................................................................44 
60 
9.4 
Serious Noncompliance ..............................................................................................45 
61 
9.5 
Reporting to the OSU IRB ...........................................................................................45 
62 
9.6 
Reporting to the sponsor .............................................................................................45 
63 
9.7 
Reporting to the FDA ..................................................................................................45 
64 
9.8 
Timeframe for Reporting Required Events ..................................................................46 
65 
9.9 
Overdose ....................................................................................................................47 
66 
9.10 
Pregnancies ................................................................................................................47 
67 
9.11 
Data and safety monitoring .........................................................................................47 
68 
9.11.1 
Data Submission ..................................................................................................48 
69 
9.11.2 
Auditing ................................................................................................................48 
70 
9.12 
Ethical Considerations ................................................................................................48 
71 
9.13 
Retention of records ....................................................................................................48 
72 
10 
Statistical Methods .........................................................................................................48 
73 
10.1 
Study Design and Sample Size Justification ...............................................................48 
74 
10.2 
Analysis of Primary Objective .....................................................................................49 
75 
10.3 
Analysis of Secondary Objectives ...............................................................................49 
76 


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10.4 
Analysis of Exploratory Objectives ..............................................................................50 
77 
11 
References .....................................................................................................................50 
78 
12 
Appendices ....................................................................................................................54 
79 
12.1 
CMV Disease Definitions Working Group of the Cytomegalovirus Drug Development 
80 
Forum 54 
81 
12.2 
Eastern Cooperative Oncology Group Performance Status Scale ...............................56 
82 
12.3 
Child-Pugh Classification of liver disease ....................................................................57 
83 
 
84 
 
 
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TRIAL SUMMARY 
86 
TITLE 
Letermovir for cytomegalovirus prophylaxis in patients with 
hematological malignancies treated with alemtuzumab 
PHASE 
II 
OBJECTIVES 
Primary Objective 
1. To estimate the rate of CMV reactivation in patients treated with 
letermovir at 3 months after completion of alemtuzumab therapy.  
 
Secondary Objectives 
1. To evaluate the tolerability of letermovir in combination with 
alemtuzumab. 
2. To evaluate the efficacy of letermovir for the prevention of clinically 
significant CMV disease. 
4. To estimate the overall survival of patients in the study population 
STUDY DESIGN 
Single center, single arm, non-randomized 
KEY ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
1. Confirmed diagnosis of any lymphoid malignancy including, but not 
limited to, T- or B-PLL, CLL, PTCL, CTCL, Sézary syndrome, or 
LGLL. 
2. Intent to treat with alemtuzumab (monotherapy or in combination 
with chemotherapy).  
3. Confirmed seropositivity for CMV IgG  
4. Confirmed lack of active CMV infection as evidenced by CMV DNA 
PCR ≤ 200 IU/mL and no clinical evidence of CMV disease within 14 
days of first letermovir dose. 
5. Age ≥18 years old 
6. Able to provide informed consent  
7. Life expectancy >4 months 
8. ECOG performance status ≤3 
9. Highly unlikely to become pregnant or impregnate a partner (post-
menopausal, sterile, abstinence, or adequate contraceptive method) 
 
Exclusion Criteria 
1. History of confirmed CMV disease within 1 year of study entry. 
2. History of prior allogeneic hematopoietic stem cell transplant within 
6 months of enrollment. Allogeneic transplant more than 6  months 
prior to enrollment is allowed as long as the subject is off 
immunosuppression without active GVHD. 
3. End stage renal disease with creatinine clearance < 10 mL/min  
4. Severe hepatic impairment defined as Child-Pugh class C OR AST 
or ALT > 5 x ULN OR serum total bilirubin > 2.5 x ULN. 
5. Both moderate hepatic insufficiency AND moderate renal 
insufficiency defined as Child Pugh Class B AND creatinine clearance 
less than 50 mL/min 
6. Cytopenias are NOT an exclusion criteria  
7. Received antiviral medications with activity against CMV or 
contraindicated medication within specified windows (see Section 3.2 
for details) 
8. Received cidofovir, CMV hyper-immune globulin, or an 
investigational anti CMV agent within 30 days.  


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9. Infection or underlying disease necessitating ongoing use of 
prohibited medications (Section 4.4).  
10. Suspected or known hypersensitivity to active or inactive 
ingredients of letermovir formulations 
11. Active HIV, hepatitis B, or hepatitis C infection (see section 3.2 for 
exceptions) 
12. Pregnant, breastfeeding, or expecting to conceive. 
13. Expecting to donate eggs or sperm  
14. Current or recent participation in a study with an unapproved 
investigational compound. 
15. Previous participation in a study using letermovir.  
16. Any condition which might interfere with subjects participation as 
judged by investigator. 
STATISTICS 
The primary objective of this single center, single arm phase II study 
is to determine the efficacy of letermovir prophylaxis in PLL, CLL, 
PTCL or CTCL patients treated with alemtuzumab. The efficacy will 
be measured through the CMV reactivation rate during letermovir 
prophylaxis (3 months after completion of alemtuzumab therapy). All 
eligible patients who receive any letermovir will be included in the 
tolerability analysis, and all patients who receive ≥90% of planned 
letermovir doses are evaluable for the efficacy analysis. 
Fleming’s two-stage design will be used with the following 
parameters: 
• 
Null hypothesis: CMV reactivation rate of 30% or higher is not 
acceptable (70% safety rate) 
• 
Alternative hypothesis: CMV reactivation rate of 10% or less is 
acceptable (90% safety rate) 
With a one-sided type I error rate of 5% and 85% power, Fleming’s 
two-stage design allows a first-stage analysis after the first 14 
patients are enrolled and evaluated: 
• 
If ≥4 CMV reactivations, trial will terminate due to futility 
• 
If 0 CMV reactivations, trial will terminate due to efficacy 
• 
If 1-3 CMV reactivations, trial will accrue an additional 14 
patients. 
o If at least 24 of 28 enrolled patients are CMV free, we 
will conclude the regimen effective 
To account for the possibility that some patients will not be evaluable, 
we will allow a 5% over-accrual for a total target enrollment of 30.  
 
TOTAL NUMBER 
OF SUBJECTS 
14 to 30 depending upon results of interim analysis. 
ESTIMATED 
ENROLLMENT 
PERIOD 
Stage 1: 10 months from first patient enrolled 
Stage 2: 20 months from first patient enrolled 
ESTIMATED STUDY 
DURATION 
Stage 1: 17 months from first patient enrolled 
Stage 2: 27 months from first patient enrolled 
 
 
87 


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1 
BACKGROUND AND RATIONALE 
88 
1.1 Mature T-cell Lymphomas 
89 
Approximately 10-15% of non-Hodgkin lymphomas (NHL) are derived from mature (i.e. post-
90 
thymic) T lymphocytes [1]. The heterogeneity of these lymphomas and poor understanding of 
91 
their pathogenesis continue to impede their classification and the development of novel 
92 
therapeutic strategies.  
93 
1.1.1 Peripheral T-cell Lymphoma 
94 
The most common subtype of peripheral T-cell lymphoma (PTCL) lacks any distinguishing 
95 
characteristics and is designated by the World Health Organization as “PTCL, not otherwise 
96 
specified (PTCL, NOS)” [1, 2]. While the development of combination immunochemotherapy 
97 
(e.g. “R-CHOP”) has led to significant survival benefits in B-cell NHL, the PTCLs are associated 
98 
with inferior responses to therapy and overall survival [3]. In fact, the vast majority of PTCL 
99 
patients will ultimately succumb to their disease, most within a few years of diagnosis [1, 2, 4]. 
100 
Novel therapeutic strategies are needed if improved outcomes are to be achieved. The 
101 
observation that PTCL incidence rates are increasing faster than almost any other subgroup of 
102 
NHL further heightens this sense of urgency [5, 6]. 
103 
1.1.2 Cutaneous T-cell Lymphoma 
104 
Primary cutaneous T-cell lymphoma (CTCL), of which the two most common forms are mycosis 
105 
fungoides (MF) and Sézary syndrome (SS), predominantly involves the skin. Most CTCL 
106 
patients present with limited-stage disease that is confined to the skin (i.e. patches or plaques) 
107 
and are managed with topical therapies. In contrast, patients with advanced-stage disease with 
108 
significant blood, nodal or visceral organ involvement are managed with systemic therapies [7]. 
109 
A variety of single agent or combination chemotherapy regimens are utilized, as there is no 
110 
standard of care for these patients. Therefore, the National Comprehensive Cancer Network 
111 
(NCCN) guidelines endorse these agents or participation in a clinical trial as first-line therapy in 
112 
these patients. Median overall survival for patients with stage IV disease ranges from 1.4-3.8 
113 
years, depending upon the extent of blood, nodal or visceral organ involvement [8]. Five FDA 
114 
approved agents are currently available for CTCL patients failing at least one prior therapy, 
115 
including bexarotene, vorinostat, romidepsin, brentuximab vedotin (for CD30 positive disease), 
116 
and mogamulizumab. These agents are associated with overall response rates of 28-56% [9-15] 
117 
with generally short duration of response. Despite the use of these novel agents, the long term 
118 
outlook for most CTCL patients remains grim. 
119 
1.1.3 T-cell Prolymphocytic Leukemia 
120 
T-cell prolymphocytic leukemia (T-PLL) is a rare T-cell malignancy most often presenting in 
121 
adult males[16]. While most presentations of this disease are acute, a minority of patients will 
122 
not require treatment immediately. There is a limited response to conventional chemotherapy 
123 
with alkylating agents or anthracyclines, with a median overall survival (OS) of 7 months in 
124 
historical series [16, 17]. In the absence of a clinical trials, patients should be offered 
125 
alemtuzumab as front line therapy. Alemtuzumab has a high overall response rate >80% in the 
126 
front line setting [18] and 51-76% in the relapsed setting [19-22]. Even with high response rates, 
127 
relapse is common in the absence of consolidative therapy. Allogeneic hematopoietic stem cell 
128 


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transplantation is frequently recommended as consolidation therapy with resulted prolongation 
129 
of overall survival and cure in a minority of cases [23-26] 
130 
1.2 Alemtuzumab 
131 
Alemtuzumab is a humanized IgG1 kappa monoclonal antibody directed against the CD52 
132 
antigen, which is mostly expressed by B- and T-lymphocytes. Clinical activity of alemtuzumab 
133 
has been evaluated in multiple lymphoid malignancies including peripheral T cell lymphoma 
134 
(PTCL), mycosis fungoides (MF), Sézary syndrome (SS), T-cell prolymphocytic leukemia (T-
135 
PLL), and chronic lymphocytic leukemia (CLL)[27].  
136 
In the relapsed setting, alemtuzumab monotherapy results in 36% overall response rate (ORR) 
137 
with 21% complete response rate (CRR) in PTCL [28]. Patients with MF/SS have an ORR 
138 
ranging from 55% to 100% with an average ORR of 65% [29]. Patients with erythrodermic MF or 
139 
SS have significantly better responses (ORR 85-100%) even with lower doses of alemtuzumab 
140 
therapy[30, 31]. Alemtuzumab is considered standard front line therapy for symptomatic T-PLL 
141 
(NCCN guidelines) with ORR of 51-76% and CRR of 40-60% [21, 22]. Alemtuzumab has also 
142 
been used in combination with various chemotherapeutic agents in the front line and relapsed 
143 
setting in these diseases including CHOP (cyclophosphamide, doxorubicin, vincristine, and 
144 
prednisone), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), 
145 
and pentostatin [32-34]. Efficacy is improved with these combinations, but also results in 
146 
cumulative toxicities.  
147 
In general, therapy with alemtuzumab is well tolerated, but cytomegalovirus (CMV) reactivation 
148 
and other infectious complications remain a significant barrier to more widespread clinical use. 
149 
In clinical trials where data is available, reported rates of CMV reactivation average 30% (see 
150 
Table 1). 
151 
1.3 Cytomegalovirus  
152 
Infection with human cytomegalovirus (CMV) is relatively frequent in the human population with 
153 
a seroprevalence ranging from 45-100% [35]. Following initial exposure, the virus establishes a 
154 
lifelong latent infection that can periodically reactivate with shedding of infectious virus, although 
155 
this rarely results in a clinically significant infection in healthy individuals. In contrast, 
156 
reactivation is responsible for significant mortality and morbidity in immunocompromised 
157 
patients [35]. CMV replication involves the cleaving of concatameric genomic viral DNA and the 
158 
packaging of each genome into preformed viral capsids. This process is mediated by the CMV-
159 
terminase complex (UL51, UL56, and UL89) [36].  
160 
Risk factors associated with CMV reactivation include seropositivity of the recipient while 
161 
undergoing therapy immunosuppressive therapy with autologous or allogeneic transplant or 
162 
drugs like high dose steroids or alemtuzumab. Clinical manifestations include interstitial 
163 
pneumonitis, encephalitis, retinitis, fevers, hepatitis, hemorrhagic cystitis and diarrhea [37]. 
164 
Current management focuses on reduction in immunosuppression and initiation of antiviral 
165 
therapies including ganciclovir, cidofovir, foscarnet, and valganciclovir [37, 38]. Use of these 
166 
agents, while necessary, carries significant side effect profiles including marrow suppression 
167 
and nephrotoxicity. Furthermore, the development of antiviral resistance via mutations to CMV 
168 
UL97 or UL54 genes limits the available agents effective against CMV [38].  Antiviral drug 
169 
resistance should be suspected in patients who fail to improve (i.e., >1 log10 increase in CMV 
170 


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DNA levels in blood or serum) after 2 weeks of appropriately dosed antiviral therapy [38]. 
171 
Although the incidence of drug resistant CMV remains low (0-8%)[39, 40], it can still pose 
172 
significant challenges to treatment when it occurs. Therefore, novel therapies to reduce the risk 
173 
of CMV reactivation are needed in order to avoid serious side effects of antiviral therapies and 
174 
to avoid drug resistance to these agents.  
175 
A review of published studies using alemtuzumab in the target patient population for this trial is 
176 
summarized in Table 1. This shows that the CMV reactivation rate in this patient population is 
177 
~30%.  
178 
Table 1: Reported rates of CMV reactivation with alemtuzumab in target patient 
179 
population 
180 
Ref 
Population 
CMV 
Reactivation 
(n) 
Total 
Patients 
(n) 
Reactivation 
Rate 
CMV 
Prophy* 
Chemo 
Combination 
Front 
Line 
Therapy 
Relapsed 
Therapy 
[34] 
PTCL, T-
PLL, T-LGL, 
T-ALL, MF 
9 
24 
38% 
Y 
Y 
Y 
Y 
[41] 
HTLV+ 
ATLL 
29 
29 
100% 
Y 
N 
Y 
Y 
[42] 
PTCL 
5 
20 
25% 
N 
Y 
Y 
N 
[43] 
PTCL 
5 
41 
12% 
N 
Y 
Y 
N 
[32] 
PTCL 
7 
20 
35% 
N 
Y 
Y 
N 
[44] 
PTCL 
12 
38 
32% 
N 
Y 
Y 
Y 
[33] 
PTCL 
16 
31 
52% 
N 
Y 
Y 
N 
[45] 
T-PLL 
13 
21 
62% 
N 
Y 
Y 
N 
[46] 
PTCL, T-
ALL 
6 
13 
46% 
N 
Y 
Y 
Y 
[47] 
PTCL 
8 
15 
53% 
N 
Y 
Y 
N 
[48] 
PTCL 
8 
24 
33% 
N 
Y 
N 
Y 
[49] 
SS 
3 
5 
60% 
N 
Y 
N 
Y 
[30] 
SS 
3 
14 
21% 
N 
N 
Y 
Y 
[50] 
CTCL 
10 
39 
26% 
N 
N 
Y 
Y 
[51] 
T-LGL 
6 
13 
46% 
N 
N 
Y 
Y 
[20] 
CLL, PLL, 
CTCL, 
PTCL, T-
LGL, MCL, 
HCL 
15 
78 
19% 
N 
N 
Y 
Y 
[52] 
SS 
2 
5 
40% 
N 
N 
Y 
Y 
[21] 
T-PLL 
3 
76 
4% 
N 
N 
Y 
Y 
[28] 
PTCL 
6 
14 
43% 
N 
N 
N 
Y 
[53] 
CLL, PLL 
5 
34 
15% 
N 
N 
N 
Y 
[54] 
MF, SS 
0 
10 
0% 
N 
N 
N 
Y 
[55] 
PTCL, CTCL 
1 
10 
10% 
N 
N 
N 
Y 
[56] 
MF, SS 
1 
8 
13% 
N 
N 
N 
Y 
[57] 
MF, SS 
4 
22 
18% 
N 
N 
N 
Y 
[58] 
MF, SS 
0 
18 
0% 
N 
N 
N 
Y 


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Ref 
Population 
CMV 
Reactivation 
(n) 
Total 
Patients 
(n) 
Reactivation 
Rate 
CMV 
Prophy* 
Chemo 
Combination 
Front 
Line 
Therapy 
Relapsed 
Therapy 
[59] 
SS 
3 
6 
50% 
N 
N 
N 
Y 
[60] 
PTCL 
10 
20 
50% 
NR 
Y 
Y 
N 
[61] 
PTCL 
5 
16 
31% 
NR 
Y 
N 
Y 
[62] 
PTCL 
1 
10 
10% 
NR 
Y 
N 
Y 
[18] 
T-PLL 
2 
9 
22% 
NR 
N 
Y 
N 
[22] 
T-PLL 
1 
39 
3% 
NR 
N 
Y 
Y 
[19] 
T-PLL 
1 
15 
7% 
NR 
N 
N 
Y 
[63] 
SS 
6 
13 
46% 
NR 
N 
N 
Y 
[64] 
SS 
1 
1 
100% 
NR 
N 
N 
Y 
[65] 
SS 
3 
6 
50% 
NR 
N 
NR 
NR 
[66] 
NHL, PTCL, 
AML, ALL, 
MDS, AA 
66 
180 
37% 
Variable 
Y 
Y 
Y 
  
  
  
  
  
  
  
  
  
  
TOTAL 
276 
937 
29% 
  
  
  
  
  
  
  
  
  
  
  
  
  
*CMV prophylaxis defined as planned routine use of: ganciclovir (any dose), valganciclovir (any dose), foscarnet (any dose), 
acyclovir (>3200 mg by mouth per day or >25 mg/kg IV per day), valacyclovir (>3000 mg by mouth per day), or famciclovir 
(>1500 mg by mouth daily). 
 
Abbreviations: AA = aplastic anemia, ALL = T-cell acute lymphoblastic leukemia, AML = acute myeloid leukemia, ATLL = 
adult T-cell leukemia/lymphoma, CLL = chronic lymphocytic leukemia, CMV = cytomegalovirus, CTCL = cutaneous T-cell 
lymphoma, HCL = hairy cell leukemia, HTLV = human T-lymphotropic virus, MCL = mantle cell lymphoma, MDS = 
myelodysplastic syndrome, MF = mycosis fungoides, N = no, NHL = non-Hodgkin lymphoma, NR = not reported, PLL = 
prolymphocytic leukemia, Prophy = prophylaxis, PTCL = peripheral T cell lymphoma, SS = Sézary syndrome,  T-LGL = T-cell 
large granular lymphocytic leukemia, Y = yes 
1.4 Letermovir 
181 
Letermovir is a highly potent anti-CMV agent recently FDA approved for anti-CMV prophylaxis 
182 
post-transplant based on the results of a recent randomized phase 3 trial [67]. Letermovir 
183 
inhibits CMV replication by binding components of the terminase complex resulting in impaired 
184 
cleavage and packaging of viral DNA into capsids [68, 69]. 
185 
In the trial leading to FDA approval, 565 CMV seropositive patients without detectable CMV 
186 
DNA at baseline undergoing allogeneic hematopoietic stem cell transplantation were 
187 
randomized to receive letermovir prophylaxis or placebo through week 14 after transplantation. 
188 
Patients treated with letermovir experienced a statistically significant decrease in clinically 
189 
significant CMV infection compared to placebo (37.5% vs 60.6%, P<0.001). Additionally, the 
190 
frequency and severity of adverse events were statistically similar between the two groups 
191 
overall. Patients in the letermovir group may have experienced slightly higher rates of nausea 
192 
and vomiting, peripheral edema, and atrial fibrillation. Importantly, the use of letermovir 
193 
prophylaxis was associated with a trend toward lower all-cause mortality compared to placebo 
194 
in this trial and this was confirmed in a post hoc analysis of survival [70].  
195 


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Based on these data and the high rate of CMV reactivation following alemtuzumab therapy, we 
196 
propose the following phase 2 clinical trial of letermovir prophylaxis in patients with hematologic 
197 
malignancies receiving alemtuzumab. 
198 
2 
OBJECTIVES AND ENDPOINTS 
199 
2.1 Objectives 
200 
2.1.1 Primary Objective 
201 
1. To estimate the rate of CMV reactivation in patients treated with letermovir at 3 months 
202 
after completion of alemtuzumab therapy.  
203 
2.1.2 Secondary Objectives 
204 
1. To evaluate the tolerability of letermovir in combination with alemtuzumab 
205 
2. To evaluate the efficacy of letermovir for the prevention of clinically significant CMV 
206 
disease 
207 
3. To estimate the overall survival of patients in the study population 
208 
2.1.3 Exploratory Objectives 
209 
1. To evaluate mechanisms of antiviral resistance in letermovir prophylaxis failures.   
210 
2.2 Endpoints 
211 
2.2.1 Primary Endpoint 
212 
1. CMV reactivation as defined in section 10.2. 
213 
2.2.2 Secondary Endpoints 
214 
1. Adverse events (AEs) using NCI Common Terminology Criteria for Adverse Events 
215 
(CTCAE) version 5. 
216 
2. Development of CMV disease per the Disease Definitions Working Group of the 
217 
Cytomegalovirus Drug Development Forum [71] (Appendix 12.1) 
218 
3. Overall survival as defined in section 10.3 
219 
2.2.3 Exploratory Endpoints 
220 
1. Genotyping to evaluate mutations in CMV terminase complex genes (UL51, UL56, 
221 
UL89) [72-79] 
222 
3 
PATIENTS AND METHODS 
223 
3.1 Inclusion Criteria 
224 
1. Confirmed diagnosis of any lymphoid malignancy including, but not limited to, T-cell or 
225 
B-cell prolymphocytic leukemia, chronic lymphocytic leukemia, peripheral T-cell 
226 
lymphoma, cutaneous T-cell lymphoma, Sézary syndrome, or large granular lymphocytic 
227 
leukemia. 
228 


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2. Intent to treat with alemtuzumab. Monotherapy or combination with chemotherapy is 
229 
allowed. 
230 
3. Confirmed seropositivity for CMV IgG (≥0.7 U/mL) within 1 year of first letermovir dose. 
231 
4. Confirmed lack of active CMV infection as evidenced by CMV DNA PCR ≤ 200 IU/mL 
232 
and no clinical evidence of CMV disease within 14 days of first letermovir dose. 
233 
5. Age ≥18 years old 
234 
6. Able to provide informed consent. 
235 
7. Life expectancy >4 months 
236 
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤3 (Appendix 12.2) 
237 
9. Highly unlikely to become pregnant or impregnate a partner by meeting at least one of 
238 
the following: 
239 
a. A female subject who is not of reproductive potential is eligible without requiring 
240 
the use of contraception. A female subject who is not of reproductive potential is 
241 
defined as one who: 
242 
i. has reached natural menopause (defined as 6 months of spontaneous 
243 
amenorrhea with serum follicle-stimulating hormone [FSH] levels in the 
244 
postmenopausal range as determined by the local laboratory, or 12 
245 
months of spontaneous amenorrhea) 
246 
OR 
247 
ii. is 6 weeks post-surgical bilateral oophorectomy with or without 
248 
hysterectomy 
249 
OR 
250 
iii. has undergone bilateral tubal ligation. Spontaneous amenorrhea does not 
251 
include cases for which there is an underlying disease that causes 
252 
amenorrhea (e.g., anorexia nervosa). 
253 
b. A male subject who is not of reproductive potential is eligible without requiring the 
254 
use of contraception. A male subject who is not of reproductive potential is 
255 
defined as one whom has undergone a successful defined as:  
256 
i. microscopic documentation of azoospermia 
257 
OR 
258 
ii. a vasectomy more than 2 years ago with no resultant pregnancy despite 
259 
sexual activity post-vasectomy 
260 
c. A male or female subject who is of reproductive potential agrees to true 
261 
abstinence or to use (or have their partner use) an acceptable method of birth 
262 
control starting from the time of consent through 90 days after the last dose of 
263 
study therapy. True abstinence is defined as abstinence in line with the preferred 
264 
and usual lifestyle of the subject. Periodic abstinence (e.g., abstinence only on 
265 
certain calendar days, abstinence only during ovulation period, use of 
266 
symptothermal method, use of post-ovulation methods) and withdrawal are not 
267 
acceptable methods of contraception. Acceptable methods of birth control are: 
268 
i. intrauterine device (IUD), diaphragm with spermicide, contraceptive 
269 
sponge, condom, and vasectomy OR use of appropriate double barrier 
270 


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contraception. Hormonal contraceptives (e.g., birth control pills, 
271 
transdermal patch, or injectables) are also acceptable. 
272 
3.2 Exclusion Criteria 
273 
1. History of confirmed CMV disease within 1 year of study entry. 
274 
2. History of prior allogeneic hematopoietic stem cell transplant within 6 months of trial 
275 
enrollment. Subjects who have undergone allogeneic transplant more than 6 months 
276 
prior to enrollment are eligible as long as the subject is off immunosuppression without 
277 
active GVHD. 
278 
3. End stage renal disease with creatinine clearance < 10 mL/min as defined by Cockcroft-
279 
Gault equation using serum creatinine within 7 days of enrollment 
280 
a. Creatinine clearance (males) = 
(Weight in kg)(140−age)
(72)(creatinine in mg/dL) 
281 
b. Creatinine clearance (females) = 
(Weight in kg)(140−age)
(72)(creatinine in mg/dL) ∗0.85 
282 
4. Severe hepatic impairment defined as: 
283 
a.  Child-Pugh class C (see appendix 12.2) within 7 days of enrollment 
284 
b. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 
285 
times the upper limit of normal (ULN) or serum total bilirubin > 2.5 x ULN. 
286 
Note: Subjects who meet this exclusion criterion may, at the discretion of the 
287 
investigator, have one repeat testing done. If the repeat value does not meet this 
288 
criterion, they may continue in the screening process. Only the specific out of 
289 
range value should be repeated (not the entire panel). 
290 
5. Both moderate hepatic insufficiency AND moderate renal insufficiency: 
291 
a. Moderate hepatic insufficiency is defined as Child Pugh Class B (see Appendix 
292 
12.2) 
293 
b. Moderate renal insufficiency is defined as a creatinine clearance less than 50 
294 
mL/min, as calculated by the Cockcroft-Gault equation (as above) 
295 
6. Cytopenias are NOT an exclusion criteria in this trial as cytopenias are common in this 
296 
patient population and letermovir has no known adverse effects on blood counts. 
297 
Patients will be treated per institutional standard of care with as needed transfusions and 
298 
growth factor support. 
299 
7. Received any of the following drugs within 7 days of enrollment or plans to receive any 
300 
of the following during the study: 
301 
a. ganciclovir 
302 
b. valganciclovir 
303 
c. foscarnet 
304 
d. acyclovir (at doses > 3200 mg PO per day or > 25 mg/kg IV per day) 
305 
e. valacyclovir (at doses > 3000 mg PO per day) 
306 
f. famciclovir (at doses > 1500 mg PO per day) 
307 
g. Cyclosporine A 
308 


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h. Pimozide 
309 
i. 
Ergot alkaloids (ergotamine and dihydroergotamine) 
310 
j. 
Atorvastatin at doses greater than 20 mg daily (see Table 5) 
311 
8. Received any of the following within 30 days prior to enrollment 
312 
a. cidofovir 
313 
b. CMV hyper-immune globulin 
314 
c. Any investigational CMV antiviral agent/biologic therapy 
315 
9. Infection or underlying disease necessitating ongoing use of prohibited medications 
316 
(Section 4.3).  
317 
10. Suspected or known hypersensitivity to active or inactive ingredients of letermovir 
318 
formulations 
319 
11. Positive at the time of screening for: 
320 
a. HIV with CD4 count <350. If HIV positive, must remain on antiretroviral therapy 
321 
that is not anticipated to interact with letermovir throughout study. 
322 
b. Hepatitis B surface antigen or core antibody positivity associated with detectable 
323 
viral load. For any patient with serologic evidence of prior infection but 
324 
undetectable viral load, viral load and surface antigen will be monitored every 2 
325 
weeks. Those with evidence of reactivation (detectable viral load) will be treated 
326 
with entecavir or lamivudine. Upon resolution of detectable viral load, the patient 
327 
will be allowed to continue on trial assuming adequate liver function as defined 
328 
above. Alternatively, patients may be put on prophylactic entecavir or lamivudine 
329 
to prevent hepatitis B reactivation at the investigators discretion.  
330 
c. Hepatitis C if no prior or current curative antiviral therapy. For those currently on 
331 
curative antiviral therapy, they will be allowed on trial if HCV quantitation is below 
332 
the limit of detection and adequate liver function as above. 
333 
12. Pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time 
334 
of consent through 90 days after the last dose of study therapy. 
335 
13. Expecting to donate eggs or sperm starting from the time of consent through 90 days 
336 
after the last dose of study therapy. 
337 
14. Currently participating or has participated in a study with an unapproved investigational 
338 
compound or device within 28 days, or 5X half-life of the investigational compound 
339 
(excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. 
340 
Subjects previously treated with a monoclonal antibody will be eligible to participate after 
341 
a 28-day washout period. 
342 
15. Previous participation in a study using letermovir.  
343 
16. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
344 
circumstance that might confound the results of the study, interfere with the subject's 
345 
participation for the full duration of the study, or would be put at undue risk as judged by 
346 
the investigator, such that it is not in the best interest of the subject to participate in this 
347 
study 
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3.3 Screening Procedures 
349 
Patients may be screened for study entry when the determination has been made by the 
350 
treating physician that they need therapy with alemtuzumab. Application to receive 
351 
alemtuzumab for compassionate use would be started by the treating physician team, as per 
352 
standard of care, while patient is being screened for trial. Application for compassionate use of 
353 
alemtuzumab can be accessed here: https://www.campathproviderportal.com.  
354 
4 
TREATMENT PLAN 
355 
4.1 Premedication Administration 
356 
No premedication is necessary for letermovir.  
357 
4.2 Agent Administration 
358 
Letermovir will be administered at 480 mg by mouth daily starting up to two weeks after the first 
359 
administration of alemtuzumab. Treatment will continue for 3 months after the last dose of 
360 
alemtuzumab is given.  
361 
If for any reason, the subject is unable to take the oral formulation of letermovir for an extended 
362 
period of time, the intravenous (IV) formulation of letermovir may be use. Simultaneous use of 
363 
IV and oral study therapy is not allowed. The IV formulation should be switched to oral study 
364 
therapy (i.e., at the next planned dose) as soon as such subjects are able to swallow and/or the 
365 
condition necessitating the use of the IV formulation resolve. 
366 
Study therapy with letermovir may begin as early as the first day of alemtuzumab infusion to no 
367 
later than 14 days after the first alemtuzumab infusion, once the subject is determined to be 
368 
negative for active CMV infection as outlined in the inclusion criteria. Letermovir should continue 
369 
through 90 days after the final planned alemtuzumab infusion. 
370 
Study therapy should be administered at the same time each day. Tablets are to be swallowed 
371 
whole (i.e., no crushing or chewing the tablet is allowed). Study therapy may be administered 
372 
with or without food.  
373 
If a subject misses a dose, the missed dose should be given as soon as possible during the 
374 
same day. If more than 18 hours have gone by after the regular dosing time, then the missed 
375 
dose should be skipped and the normal dosing schedule should be resumed. The next dose 
376 
should not be doubled in order to “make up” what has been missed. 
377 
Study therapy can be administered with or without food. Subjects must avoid consumption of 
378 
grapefruit, Seville oranges or their respective juices, and other quinine-containing drinks or food 
379 
during the trial from 2 weeks prior to study drug administration until 72 hours after the final 
380 
administration of study drug. 
381 
4.3 Rationale for Dose Selection 
382 
Please refer to the letermovir package insert for further details of preclinical data and study 
383 
results in humans.  
384 


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Letermovir belongs to a new class of anti-CMV agents which have a different mechanism of 
385 
action compared to currently available drugs for the treatment of CMV infection. By inhibiting the 
386 
viral terminase complex, the drug plays a key role in cleavage and packaging of genomic virus 
387 
DNA into provirions.  
388 
Letermovir is anticipated to be efficacious based on both the in vitro potency of letermovir as 
389 
well as its in vivo efficacy for CMV prophylaxis in a Phase III trial in allogeneic hematopoietic 
390 
stem cell transplantation (HSCT) recipients [67]. In this trial, 565 CMV seropositive patients 
391 
without detectable CMV DNA at baseline undergoing allogeneic HSCT were randomized to 
392 
receive letermovir prophylaxis (480 mg daily or 240 mg daily or patients concomitantly receiving 
393 
CsA) or placebo through week 14 after transplantation. Patients treated with letermovir 
394 
experienced a statistically significant decrease in clinically significant CMV infection compared 
395 
to placebo (37.5% vs 60.6%, P<0.001). Additionally, the frequency and severity of adverse 
396 
events were statistically similar between the two groups overall. Patients in the letermovir group 
397 
may have experienced slightly higher rates of nausea and vomiting, peripheral edema, and 
398 
atrial fibrillation. 
399 
Based on all available safety data, letermovir efficacy in the Phase II and III studies, and the 
400 
exposure-response data, this study will use a dose of 480 mg daily. Patients who have had 
401 
allogeneic transplant within 6 months prior to trial enrollment and patients receiving cyclosporine 
402 
A (CsA) are excluded; phase I studies have demonstrated that co-administration of letermovir 
403 
with CsA increases letermovir exposure ~3 fold. Patients who have undergone allogeneic 
404 
transplant more than 6 months prior to enrollment are eligible as long as the subject is off 
405 
immunosuppression without active GVHD. 
406 
4.4 Concomitant Medications and Supportive Care 
407 
Allowed Medications/Therapies  
408 
The following medications/therapies are allowed in this study: 
409 
• 
Standard antimicrobial prophylaxis (e.g., levofloxacin for bacteria, fluconazole/ 
410 
voriconazole/posaconazole for fungi)  
411 
• 
Acyclovir, valacyclovir, or famciclovir for prophylaxis of herpes simplex virus (HSV) or 
412 
varicella zoster virus (VZV) infections at doses no greater than prohibited doses of these 
413 
medications (see below)  
414 
Prohibited Medications/Therapies  
415 
The following medications/therapies are prohibited in this study: 
416 
Antiviral drugs or therapies for prevention/treatment of CMV, including but not limited to:  
417 
• 
ganciclovir  
418 
• 
valganciclovir 
419 
• 
foscarnet 
420 
• 
cidofovir 
421 
• 
acyclovir (at doses > 3200 mg PO per day or > 25 mg/kg IV per day) 
422 


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• 
valacyclovir (at doses > 3000 mg PO per day) 
423 
• 
famciclovir (at doses > 1500 mg PO per day) 
424 
• 
CMV hyper-immune globulin 
425 
• 
any investigational CMV antiviral agent/biologic therapy 
426 
• 
CMV vaccine  
427 
Investigational Agents  
428 
Investigational agents are not permitted with the following exceptions: (1) Investigational 
429 
chemotherapy regimens involving approved agents and (2) investigational antimicrobial 
430 
regimens involving approved antibacterial/antifungal/antiviral agents. 
431 
Other Agents: 
432 
• 
Cyclosporine A 
433 
• 
Pimozide 
434 
• 
Ergot alkaloids (ergotamine and dihydroergotamine) 
435 
• 
Atorvastatin at doses greater than 20 mg daily (see Table 5) 
436 
Medications/Therapies to be Administered with Caution  
437 
Preclinical studies suggest MK-8228 acts as a weak to moderate inhibitor of cytochrome 
438 
(CYP)3A4, CYP2C8, CYP2B6 and the transporters OATP1B1 and OATP1B3. It is therefore 
439 
possible that MK-8228 may increase the exposure of co-administered drugs whose primary 
440 
route of clearance involves these enzymes or transporters. Please see Table 5 (section 8.3) 
441 
for a list of potentially clinically significant drug interactions.  
442 
5 
TOXICITIES, DOSE DELAYS, AND DOSE MODIFICATIONS 
443 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
444 
adverse events.  
445 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
446 
before and at regular intervals during their participation in this study as specified in Study 
447 
Calendar & Evaluations. 
448 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
449 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
450 
Evaluations (section 6).  
451 
5.1 Dose Delays and Modifications 
452 
Dose modifications are not allowed on trial. 
453 
5.2 Protocol Therapy Discontinuation 
454 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
455 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
456 


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withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
457 
plan is violated, or for administrative and/or other safety reasons. 
458 
A subject must be discontinued from the trial for any of the following reasons: 
459 
• 
CMV reactivation as defined in section 10.2 at any time during the study period, study 
460 
therapy will be discontinued and the subject may be treated according to the local 
461 
standard of care (outside the context of the study). In this setting, any of the prohibited 
462 
anti-CMV medications (outlined in section 4.4) may be used. 
463 
• 
The subject becomes pregnant during the study 
464 
• 
The subject’s investigator feels it is in the best interest of the subject to discontinue. 
465 
A subject may be discontinued from therapy for any of the following reasons: 
466 
• 
Any AE/SAE assessed by the physician investigator as possibly or probably related to 
467 
study therapy. Investigator may continue the subject in the trial if it is deemed to be in the 
468 
best interest of the subject to stay on study therapy. 
469 
• 
Failure to comply with the dosing, evaluations, or other requirements of the trial. 
470 
• 
The subject has a medical condition or personal circumstance which, in the opinion of the 
471 
investigator and/or Sponsor, places the subject at unnecessary risk through continued 
472 
participation in the trial or does not allow the subject to adhere to the requirements of the 
473 
protocol. 
474 
6 
STUDY EVALUATIONS 
475 
6.1 Calendar of Events 
476 
Cycle = 28 days 
Screen (-28 
days) 
On 
Treatment1 
At CMV 
reactivation2 
AE follow 
up3 
REQUIRED ASSESSMENTS 
Review of eligibility criteria, informed 
consent  
X 
 
 
 
Medical history 
X 
 
 
 
ECOG PS4 
X 
 
 
 
Physical exam, vital signs5 
X 
X 
X 
X 
AEs, concomitant medications 
X 
X 
X 
X 
Drug diary 
 
X 
X 
 
Assessment of contraception method6 
X 
 
 
 
CMV disease assessment7 
 
 
X 
X 
LABORATORY ASSESSMENTS 
Complete blood cell count with differential 
(CBC) 
X 
X 
X 
X 
Comprehensive metabolic profile (CMP)8 
X 
X 
X 
X 
Prothrombin time (INR) 
X 
 
 
 
Urine pregnancy test in WOCBP 
X 
X 
X 
X 
HIV, hepatitis B, and hepatitis C screen9 
X 
 
 
 


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CMV IgG10 
X 
 
 
 
CMV viral load11 (at least every other 
week, weekly preferred) 
X 
X 
X 
X 
CORRELATIVE STUDIES (SPECIMEN COLLECTION) 
CMV Genotyping 
 
 
X 
 
1. 
On study visits will occur every 28 days (+/- 7 days). Treatment with letermovir should be continued for 90 after the last dose of 
alemtuzumab. 
2. 
CMV reactivation defined as CMV DNA by real time polymerase chain reaction >500 IU/mL 
3. 
AE follow up to occur 30 days (+/- 7 days) from last dose of letermovir therapy. If patients have any ongoing toxicity related to 
letermovir, investigator should continue to monitor and provide appropriate supportive care. If patient has active CMV infection or 
reactivation, investigator should continue to monitor and provide appropriate treatment including antiviral therapy.  
4. 
See Appendix 12.2 
5. 
Vital signs include height, weight, blood pressure, heart rate, respiratory rate, temperature 
6. 
See section 3.1 for acceptable methods of contraception 
7. 
CMV disease assessment is a focused history and physical exam guided by known manifestations of CMV disease (see Appendix 
12.1). CMV disease assessment is to be performed if reactivation occurs as defined in Section 10.2. 
8. 
CMP should include at least the following: sodium, potassium, chloride, creatinine, glucose, calcium, phosphorus, total bilirubin, 
AST, ALT, alkaline phosphatase, albumin. 
9. 
Screening to be completed with: HIV antibody, hepatitis B surface antibody, hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis C antibody. If hepatitis B surface antigen or core antibody is positive, hepatitis B viral load quantification with PCR should 
be ordered; if hepatitis C antibody is positive, viral load quantification by PCR should be ordered. 
10. CMV IgG seropositivity may be confirmed up to 1 year prior to starting letermovir.  
11. CMV viral load testing by PCR will be completed at least every other week while on therapy with letermovir. Weekly monitoring is 
preferred but can be reduced to every 2 weeks at the investigator’s discretion. Window for screening is within 2 weeks of first dose 
of letermovir. 
 
6.2 Biospecimen Studies and Procedures 
477 
The correlative studies will include genotyping to evaluate mutations in CMV terminase complex 
478 
genes (UL51, UL56, UL89) through Viracor.  
479 
6.3 Source and Timing of Biospecimen Collections 
480 
Peripheral blood of approximately 10 ml in EDTA (lavender top) tube will be inverted to mix anti-
481 
coagulant and then kept at room temperature until transport to the OSU Leukemia Tissue Bank 
482 
(LTB). Plasma and PBMCs will be separated and cryopreserved by standard methods. Samples 
483 
will be labeled with the study time point, collection date and protocol number as well as study 
484 
participant number. Frozen plasma samples would be batch analyzed after the completion of 
485 
the study for CMV genotyping studies.  
486 
6.4 Storage of Biospecimens 
487 
Samples will be stored in OSU LTB. 
488 
7 
CRITERIA FOR DISEASE EVALUATION 
489 
CMV reactivation is defined in section 10.2. CMV disease will be defined as in Disease 
490 
Definitions Working Group of the Cytomegalovirus Drug Development Forum [71] (Appendix 
491 
12.1). 
492 
8 
LETERMOVIR INFORMATION  
493 
8.1 Letermovir Description and Mechanism of Action 
494 
Letermovir inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89) which is 
495 
required for viral DNA processing and packaging. Biochemical characterization and electron 
496 


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microscopy demonstrated that letermovir affects the production of proper unit length genomes 
497 
and interferes with virion maturation. Genotypic characterization of virus resistant to letermovir 
498 
confirmed that letermovir targets the terminase complex. 
499 
The median EC50 value of letermovir against a collection of clinical CMV isolates in a cell-
500 
culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no 
501 
significant difference in EC50 value by CMV gB genotype (gB1=29; gB2=27; gB3=11; and 
502 
gB4=3). No antagonism of the antiviral activity was seen when letermovir was combined with 
503 
CMV DNA polymerase inhibitors (cidofovir, foscarnet, or ganciclovir). 
504 
8.2 Clinical Pharmacology 
505 
Letermovir has a molecular formula of C29H28F4N4O4 and a molecular weight of 572.55. The 
506 
chemical name for letermovir is (4S)-2-[8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-
507 
methoxy-5(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl] acetic acid. Letermovir is very 
508 
slightly soluble in water. 
509 
The chemical structure of letermovir is: 
510 
 
511 
 
512 
8.3 Pharmacokinetics and Drug Metabolism 
513 
The pharmacokinetic properties of letermovir are displayed in Table 2.  
514 
Table 2: Absorption, Distribution, Metabolism, Elimination (ADME), and Pharmacokinetic 
515 
Properties of letermovir 
516 
Pharmacokinetics in HSCT Recipients 
Treatment Regimen 
Steady-state median (90% prediction interval) 
AUC (ng•hr/mL) of letermovir 
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 
letermovir 
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 letermovir 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 letermovir without 
cyclosporine: 94% at an oral dose range of 240 
mg to 480 mg 
HSCT recipients administered letermovir without 
cyclosporine: 35% with 480 mg oral once daily 
HSCT recipients administered letermovir 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 IV administration in HSCT 
recipients 
% 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 letermovir 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. 
 
 
517 
Specific Populations 
518 
Pediatric Population 
519 
The pharmacokinetics of letermovir in patients less than 18 years of age have not been 
520 
evaluated. 
521 
Age, Gender, Race, and Weight 
522 
Age (18 to 78 years), gender, race (White vs. non-White), and body weight (up to 100 kg) did 
523 
not have a clinically significant effect on the pharmacokinetics of letermovir. 
524 
Renal Impairment 
525 
Letermovir AUC was approximately 1.9-and 1.4-fold higher in subjects with moderate (eGFR 
526 
greater than or equal to 30 to 59 mL/min/1.73m2) and severe (eGFR less than 30 
527 
mL/min/1.73m2) renal impairment, respectively, compared to healthy subjects. 
528 
Hydroxypropyl betadex present in the intravenous letermovir formulation is mainly eliminated by 
529 
glomerular filtration. Decreased elimination of hydroxypropyl betadex has been reported in the 
530 
literature in patients with severe renal impairment. 
531 
Hepatic Impairment 
532 
Letermovir AUC was approximately 1.6-and 3.8-fold higher in subjects with moderate (Child-
533 
Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) 
534 
hepatic impairment, respectively, compared to healthy subjects. 
535 
Drug Interaction Studies  
536 
Drug interaction studies were performed in healthy subjects with letermovir and drugs likely to 
537 
be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see  
538 


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Table 3 and  
 
539 


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Table 4). 
540 
In vitro results indicate that letermovir is a substrate of drug metabolizing enzymes CYP3A, 
541 
CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp. Oxidative 
542 
metabolism is considered to be a minor elimination pathway based on in vivo human data. 
543 
Inhibitors of OATP1B1/3 may result in increases in letermovir plasma concentrations. Changes 
544 
in letermovir plasma concentrations due to inhibition of P-gp or UGTs are not anticipated to be 
545 
clinically relevant. 
546 
Based on in vitro studies, the metabolism of letermovir is not mediated by CYP1A2, CYP2A6, 
547 
CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP4A11, UGT1A4, UGT1A6, 
548 
UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, or UGT2B17. The 
549 
transport of letermovir is not mediated by OATP2B1, OCT1, OAT1, BCRP, or MRP2 in vitro. 
550 
Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of 
551 
letermovir with midazolam resulted in increased exposure of midazolam, indicating that the net 
552 
effect of letermovir on CYP3A is moderate inhibition (see  
 
553 


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Table 4). Based on these results, co-administration of letermovir with CYP3A substrates may 
554 
increase the plasma concentrations of the CYP3A substrates (see  
 
555 


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Table 4). Letermovir is a reversible inhibitor of CYP2C8 in vitro. When co-administered with 
556 
letermovir, plasma concentrations of CYP2C8 substrates are predicted to be increased (see  
557 


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Table 4). Co-administration of letermovir reduced the exposure of voriconazole, most likely due 
558 
to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-
559 
administration of letermovir with CYP2C9 and CYP2C19 substrates may decrease the plasma 
560 
concentrations of the CYP2C9 and CYP2C19 substrates (see Table 5). Letermovir is an inducer 
561 
of CYP2B6 in vitro; the clinical relevance is unknown. 
562 
Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt 
563 
export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic 
564 
uptake transporter OATP1B1/3 in vitro. Co-administration of letermovir with substrates of 
565 
OATP1B1/3 transporters (e.g. atorvastatin, a known substrate of CYP3A, OATP1B1/3, and 
566 
potentially BCRP) may result in a clinically relevant increase in plasma concentrations of 
567 
OATP1B1/3 substrates (see Table 5). There were no clinically relevant changes in plasma 
568 
concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-
569 
administration with letermovir in clinical studies (see 
 
570 


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Table 4). The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in 
571 
clinical studies; the clinical relevance is unknown. 
572 
Based on in vitro results letermovir is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, 
573 
CYP2D6, CYP2E1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and is not an inducer of CYP1A2. 
574 
Letermovir is not an inhibitor of MRP2, OATP2B1, BSEP, OCT1, OCT2, or OAT1 in vitro. 
575 
 
 
576 


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Table 3: Drug Interactions: Changes in Pharmacokinetics of Letermovir in the Presence 
577 
of Co-administered Drug 
578 
Co-   
administered 
Drug 
Regimen of 
Co-   
administered 
Drug 
Letermovir 
Regimen 
Geometric Mean Ratio [90% CI] of 
Letermovir PK with/without 
Co-administered Drug 
(No Effect=1.00) 
AUC 
Cmax 
C24hr* 
Immunosuppressants 
cyclosporine 
200 mg single 
dose PO 
240 mg 
once daily 
PO 
2.11 
(1.97, 2.26) 
1.48 
(1.33, 1.65) 
2.06 
(1.81, 2.35) 
mycophenolate 
mofetil 
1 g single 
dose PO 
480 mg 
once daily 
PO 
1.18 
(1.04, 1.32) 
1.11 
(0.93, 1.34) 
1.39 
(1.12, 1.74) 
tacrolimus 
5 mg single 
dose PO 
80 mg 
twice daily 
PO 
1.02 
(0.97, 1.07) 
0.92 
(0.84, 1.00) 
1.02 
(0.93, 1.12) 
Abbreviations: PO= oral 
* C12hr for tacrolimus 
 
579 
 
 
580 


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Table 4: Drug Interactions: Changes in Pharmacokinetics for Co-administered Drug in the 
581 
Presence of Letermovir 
582 
Co-   
administered 
Drug 
Regimen of 
Co-   
administered 
Drug 
Letermovir 
Regimen 
Geometric Mean Ratio 
[90% CI] of Co-administered Drug PK 
with/without Letermovir 
(No Effect=1.00) 
AUC 
Cmax 
C24hr* 
CYP3A Substrates 
midazolam 
1 mg single 
dose IV 
240 mg once 
daily PO 
1.47 
(1.37, 1.58) 
1.05 
(0.94, 1.17) 
2.74 
(2.16, 3.49) 
midazolam 
2 mg single 
dose PO 
240 mg once 
daily PO 
2.25 
(2.04, 2.49) 
1.72 
(1.54, 1.92) 
Not available 
P-gp Substrates 
digoxin 
0.5 mg single 
dose PO 
240 mg twice 
daily PO 
0.88 
(0.80, 0.96) 
0.75 
(0.63, 0.89) 
0.90 
(0.84, 0.96) 
Immunosuppressants 
cyclosporine 
50 mg single 
dose PO 
240 mg once 
daily PO 
1.66 
(1.51, 1.82) 
1.08 
(0.97, 1.19) 
2.19 
(1.80, 2.66) 
mycophenolate 
mofetil 
1 g single dose 
PO 
480 mg once 
daily PO 
1.08 
(0.97, 1.20) 
0.96 
(0.82, 1.12) 
1.04 
(0.86, 1.27) 
tacrolimus 
5 mg single 
dose PO 
480 mg once 
daily PO 
2.42 
(2.04, 2.88) 
1.57 
(1.32, 1.86) 
2.53 
(2.12, 3.03) 
sirolimus 
2 mg single 
dose PO 
480 mg once 
daily PO 
3.40 
(3.01, 3.85) 
2.76 
(2.48, 3.06) 
3.15 
(2.80, 3.55) 
Antifungals and Antivirals 
acyclovir 
400 mg single 
dose PO 
480 mg once 
daily PO 
1.02 
(0.87, 1.2) 
0.82 
(0.71, 0.93) 
1.13 
(0.94, 1.36) 
posaconazole 
300 mg single 
dose PO 
480 mg once 
daily PO 
0.98 
(0.82, 1.17) 
1.11 
(0.95, 1.29) 
1.10 
(0.94, 1.30) 
voriconazole 
200 mg twice 
daily PO 
480 mg once 
daily PO 
0.56 
(0.51, 0.62) 
0.61 
(0.53, 0.71) 
0.49 
(0.42, 0.57) 
HMG-CoA Reductase Inhibitors 
atorvastatin 
20 mg single 
dose PO 
480 mg once 
daily PO 
3.29 
(2.84, 3.82) 
2.17 
(1.76, 2.67) 
3.62 
(2.87, 4.55) 
Oral Contraceptives 
ethinyl estradiol 
(EE) 
/levonorgestrel 
(LNG) 
0.03 mg EE 
single dose PO 
480 mg once 
daily PO 
1.42 
(1.32, 1.52) 
0.89 
(0.83, 0.96) 
1.57 
(1.45, 1.70) 
0.15 mg LNG 
single dose PO 
1.36 
(1.30, 1.43) 
0.95 
(0.86, 1.04) 
1.38 
(1.32, 1.46) 
Abbreviations: PO=oral 
* C12hr reported for voriconazole. 
 
583 


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Table 5: Potentially Significant Drug Interactions: Alteration in Dose May Be 
584 
Recommended Based on Results from Drug Interaction Studies or Predicted 
585 
Interactions* (Information in the Table Applies to Co-administration of Letermovir and the 
586 
Concomitant Drug without Cyclosporine, Unless Otherwise Indicated) 
587 
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 
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 


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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§. 


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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§. 
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 letermovir 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 [see Package Insert: Clinical Pharmacology (12.3)]. 
§ Refer to the respective prescribing information. 
 
588 
8.4 Preparation, Storage, and Administration: Oral Formulation 
589 
Letermovir tablets are supplied in two formulations: 
590 
• 
Letermovir 240 mg tablet: yellow oval tablet with “591” on one side and Merck logo on the 
591 
other side. 
592 
• 
Letermovir 480 mg tablet: pink oval, bi-convex tablet with “595” on one side and Merck 
593 
logo on the other side. 
594 


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Letermovir tablets contain either 240 mg or 480 mg of letermovir and the following inactive 
595 
ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, 
596 
microcrystalline cellulose, povidone 25, and film-coated with a coating material containing the 
597 
following inactive ingredients: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron 
598 
oxide yellow, lactose monohydrate, titanium dioxide, and triacetin, Carnauba wax is added as a 
599 
polishing agent. 
600 
Tablets should be swallowed whole with or without food.  
601 
Store letermovir tablets in the original package until use. 
602 
Store letermovir tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
603 
(59°F to 86°F) 
604 
8.5 Preparation, Storage, and Administration: Intravenous formulation 
605 
Letermovir injection is supplied in 30 mL single-dose vials containing either 240 mg/12 mL per 
606 
vial (20 mg/mL) or 480 mg/24 mL per vial (20 mg/mL). The preparation and administration 
607 
instructions are the same for either dose. 
608 
Letermovir vials are for single use only. Discard any unused portion.  
609 
Preparation and Administration Instructions 
610 
• 
Letermovir must be diluted prior to intravenous (IV) use. 
611 
• 
Inspect vial contents for discoloration and particulate matter prior to dilution. Letermovir 
612 
injection is a clear colorless solution. Do not use the vial if the solution is discolored or 
613 
contains visible particles. 
614 
• 
Do not shake letermovir vial. 
615 
• 
Add one single-dose vial of letermovir injection into a 250 mL pre-filled IV bag containing 
616 
either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and mix bag 
617 
gently. Do not shake. Only 0.9% Sodium Chloride and 5% Dextrose are chemically and 
618 
physically compatible with letermovir injection. 
619 
• 
Use compatible IV bags and infusion set materials. Letermovir injection is compatible with 
620 
the following IV bags and infusion set materials. Letermovir injection is not recommended 
621 
with any IV bags or infusion set materials not listed below (note that letermovir injection is 
622 
not recommended for use with polyurethane-containing IV administration set tubing). 
623 
IV Bags Materials: 
624 
Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and 
625 
polyethylene) 
626 
Infusion Sets Materials: 
627 
PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene 
628 
copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS) 
629 
Plasticizers: 
630 


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Diethylhexyl phthalate (DEHP), tris (2-ethylhexyl) trimellitate (TOTM), benzyl butyl 
631 
phthalate (BBP) 
632 
Catheters: 
633 
Radiopaque polyurethane 
634 
• 
Once diluted, the solution of letermovir is clear, and ranges from colorless to yellow. 
635 
Variations of color within this range do not affect the quality of the product. Parenteral 
636 
drug products should be inspected visually for particulate matter and discoloration prior to 
637 
administration, whenever solution and container permit. Discard if discoloration or visible 
638 
particles are observed. 
639 
• 
The diluted solution is stable for up to 24 hours at room temperature or up to 48 hours 
640 
under refrigeration at 2°C to 8°C (36°F to 46°F) (this time includes storage of the diluted 
641 
solution in the intravenous bag through the duration of infusion). 
642 
• 
Administer the entire contents of the intravenous bag by intravenous infusion via a 
643 
peripheral catheter or central venous line at a constant rate over 1 hour. Do not 
644 
administer as an IV bolus injection. 
645 
Compatible Drug Products: 
646 
The physical compatibility of letermovir injection with selected injectable drug products was 
647 
evaluated in two commonly available diluents. Letermovir should not be co-administered 
648 
through the same intravenous line (or cannula) with other drug products and diluent 
649 
combinations except those listed below. Refer to the respective prescribing information of the 
650 
co-administered drug(s) to confirm compatibility of simultaneous co-administration. 
651 
List of Compatible Drug Products when letermovir and Drug Products are Prepared in 0.9% 
652 
Sodium Chloride Injection, USP: 
653 
Ampicillin sodium, ampicillin sodium/sulbactam sodium, anti-thymocyte globulin, 
654 
caspofungin, daptomycin, fentanyl citrate, fluconazole, furosemide, human insulin, 
655 
magnesium sulfate, methotrexate, micafungin. 
656 
List of Compatible Drug Products when letermovir and Drug Products are Prepared in 5% 
657 
Dextrose Injection, USP: 
658 
Amphotericin B (lipid complex)*, anidulafungin, cefazolin sodium, ceftaroline, ceftriaxone 
659 
sodium, doripenem, famotidine, folic acid, ganciclovir sodium, hydrocortisone sodium 
660 
succinate, morphine sulfate, norepinephrine bitartrate, pantoprazole sodium, potassium 
661 
chloride, potassium phosphate, tacrolimus, telavancin, tigecycline. 
662 
*Amphotericin B (lipid complex) is compatible with letermovir. However, Amphotericin B 
663 
(liposomal) is incompatible (see below) 
664 
Incompatible Drug Products 
665 
Letermovir injection is physically incompatible with amiodarone hydrochloride, amphotericin B 
666 
(liposomal), aztreonam, cefepime hydrochloride, ciprofloxacin, cyclosporine, diltiazem 
667 
hydrochloride, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, 
668 
mycophenolate mofetil hydrochloride, ondansetron, palonosetron. 
669 


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Storage 
670 
Store letermovir injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 
671 
30°C (59°F to 86°F). 
672 
Store in the original carton to protect from exposure to light. 
673 
8.6 Non Clinical Toxicology 
674 
8.6.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
675 
Carcinogenesis and Mutagenesis 
676 
Letermovir was not genotoxic in in vitro or in vivo assays, including microbial mutagenesis 
677 
assays, chromosomal aberration in Chinese hamster ovary cells, and in an in vivo mouse 
678 
micronucleus study. 
679 
Carcinogenicity studies with letermovir have not been conducted.  
680 
Impairment of Fertility 
681 
In a fertility and early embryonic development study in rats, no effects of letermovir on female 
682 
fertility were observed at letermovir exposures (AUC) approximately 5 times higher than human 
683 
exposure at the RHD. 
684 
In male rat fertility studies, decreased fertility associated with irreversible testicular toxicity was 
685 
observed at 
686 
≥180 mg/kg/day (greater than or equal to 3 times the human exposure at the RHD). No fertility 
687 
or testicular effects were observed at dose levels resulting in letermovir exposures (AUC) similar 
688 
to human exposure at the RHD [see Nonclinical Toxicology (13.2)]. 
689 
8.6.2 Animal Toxicology and Pharmacology 
690 
Testicular toxicity in rats observed at ≥180 mg/kg/day (greater than or equal to 3 times the 
691 
human exposure at the RHD) was characterized by decreased testis weight, bilateral 
692 
seminiferous tubular degeneration, decreased sperm count and motility, and resultant 
693 
decreased male fertility. Male reproductive system toxicities were not observed in either a 
694 
monkey testicular toxicity study up to 240 mg/kg/day (approximately 2 times higher than human 
695 
exposure at the RHD), or a general toxicology study in mice up to 250 mg/kg/day 
696 
(approximately 3 times higher than human exposure at the RHD). 
697 
8.7 Clinical Studies 
698 
To evaluate letermovir prophylaxis as a preventive strategy for CMV infection or disease in 
699 
transplant recipients at high risk for CMV reactivation, the efficacy of letermovir was assessed in 
700 
a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult 
701 
CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). 
702 
Subjects were randomized (2:1) to receive either letermovir at a dose of 480 mg once daily 
703 
adjusted to 240 mg when co-administered with cyclosporine, or placebo. Randomization was 
704 
stratified by investigational site and risk level for CMV reactivation at the time of study entry. 
705 
Study drug was initiated after HSCT (at any time from Day 0 to Day 28 post-transplant) and 
706 
continued through Week 14 post-transplant. Study drug was administered either orally or 
707 


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intravenously; the dose of letermovir was the same regardless of the route of administration. 
708 
Subjects received CMV DNA monitoring weekly until post-transplant Week 14 and then bi-
709 
weekly until post- transplant Week 24, with initiation of standard-of-care CMV pre-emptive 
710 
therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up 
711 
through Week 48 post-transplant. 
712 
Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study 
713 
drug initiation and were therefore excluded from the efficacy analyses. The efficacy population 
714 
consisted of 325 subjects who received letermovir (including 91 subjects who received at least 
715 
one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV 
716 
dose). The IV formulation of letermovir was used at investigators’ discretion in subjects who 
717 
were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to 
718 
starting study drug was 8 days after transplantation. Thirty-four percent (34%) of subjects were 
719 
engrafted at baseline. The median age was 55 years (range: 18 to 76 years); 57% were male; 
720 
84% were White; 9% were Asian; 2% were Black or African American; and 7% were Hispanic or 
721 
Latino. 
722 
At baseline, 30% of all subjects had one or more of the following factors associated with 
723 
increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related 
724 
donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; 
725 
haploidentical donor; unrelated donor with at least one mismatch at one of the following four 
726 
HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use 
727 
of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft- Versus-Host Disease (GVHD) 
728 
requiring systemic corticosteroids. The remaining 70% of subjects did not meet any of these 
729 
high risk stratum criteria and were therefore included in the low risk stratum. Additionally, 48% 
730 
of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were 
731 
receiving tacrolimus. The most common primary reasons for transplant were acute myeloid 
732 
leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%). 
733 
Clinically Significant CMV Infection 
734 
The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV 
735 
infection through Week 24 post-transplant (prophylaxis failure). Clinically significant CMV 
736 
infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-
737 
CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche 
738 
COBAS® AmpliPrep/COBAS TaqMan® assay, LLoQ is 137 IU/mL, which is approximately 150 
739 
copies/mL) and the clinical condition of the subject. The protocol- 
740 
specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period 
741 
was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, 
742 
respectively. From Week 14 through Week 24, the threshold was >300 copies/mL for both high 
743 
and low risk strata subjects. The Non- Completer=Failure (NC=F) approach was used, where 
744 
subjects who discontinued from the trial prior to Week 24 post-transplant or had a missing 
745 
outcome at Week 24 post-transplant were counted as failures. 
746 
Efficacy results from Trial P001 are shown in . 
 
747 


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Table 6. 
 
748 


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Table 6: Trial P001 Efficacy Results in HSCT Recipients (NC=F Approach, FAS 
749 
Population) Through Week 24 
750 
Parameter 
Letermovir 
(N=325) 
Placebo 
(N=170) 
Proportion of subjects who failed prophylaxis 
Reasons for failures* 
38% 
61% 
Clinically significant CMV infection by Week 24† 
18% 
42% 
Initiation of PET based on documented CMV 
viremia 
16% 
40% 
CMV end-organ disease 
2% 
2% 
Discontinued from study before Week 24‡ 
17% 
16% 
Missing outcome in Week 24 visit window 
Stratum-adjusted treatment difference 
(Letermovir-Placebo)§ 
Difference (95% CI) 
3% 
-23.5 (-32.5, -14.6)¶ 
3% 
* The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed. 
† Through Week 14, 8% of subjects in the letermovir group and 39% of subjects in the placebo group experienced clinically 
significant CMV infection. 
‡ Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, and withdrawal by subject. 
§ 95% CI and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel 
method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk). 
¶ p-value <0.0001. 
Note: FAS=Full analysis set; FAS includes randomized subjects who received at least one dose of study medication, and 
excludes subjects with detectable CMV DNA at baseline. Approach to handling missing values: Non-Completer=Failure 
(NC=F) approach. With NC=F approach, failure was defined as all subjects who developed clinically significant CMV infection 
or prematurely discontinued from the study or had a missing outcome through Week 24 post-transplant visit window. 
 
751 
Efficacy results were consistent across high and low risk strata for CMV reactivation. The time 
752 
to clinically significant CMV infection is shown in  
 
753 


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Figure 1. 
754 
 
 
755 


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Figure 1: P001: Kaplan-Meier Plot of Time to Onset of Clinically Significant CMV Infection 
756 
Through Week 24 Post-Transplant in HSCT Recipients (FAS Population) 
757 
 
758 
Post-hoc analysis demonstrated that among letermovir-treated subjects, inclusion in the high 
759 
risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time 
760 
after randomization may be associated with the development of clinically significant CMV 
761 
infection between Week 14 and Week 24 post-transplant. 
762 
Mortality 
763 
The Kaplan-Meier event rate for all-cause mortality in the letermovir vs. placebo groups was 
764 
12% vs. 17% at Week 24 post-transplant, and 24% vs. 28% at Week 48 post-transplant. 
765 
8.8 Adverse Events 
766 
Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT 
767 
The safety of letermovir was evaluated in one Phase 3 randomized, double-blind, placebo-
768 
controlled trial (P001) in which 565 subjects were randomized and treated with letermovir 
769 
(N=373) or placebo (N=192) through Week 14 post-transplant. Adverse events were those 
770 
reported while subjects were on study medication or within two weeks of study medication 
771 
completion/discontinuation. The mean time for reporting adverse events and laboratory 
772 
abnormalities was approximately 22% longer in the letermovir arm compared to the placebo 
773 
arm. 
774 


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Cardiac Adverse Events: 
775 
The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in 
776 
subjects receiving letermovir (13%) compared to subjects receiving placebo (6%). The most 
777 
common cardiac adverse events were tachycardia (reported in 4% of letermovir subjects and in 
778 
2% of placebo subjects) and atrial fibrillation (reported in 3% of letermovir subjects and in 1% of 
779 
placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 
780 
85% of letermovir and 92% of placebo subjects had events reported as mild or moderate in 
781 
severity. 
782 
Common Adverse Events 
783 
The rate of adverse events occurring in at least 10% of subjects in the letermovir group and at a 
784 
frequency at least 2% greater than placebo are outlined in Table 7.  
785 
Table 7: Trial P001 All Grade Adverse Events Reported in ≥ 10% of Letermovir-Treated 
786 
HSCT Recipients at a Frequency at least 2% Greater than Placebo 
787 
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% 
 
788 
Overall, similar proportions of subjects in each group discontinued study medication due to an 
789 
adverse event (13% of letermovir subjects vs. 12% of placebo subjects). The most frequently 
790 
reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of 
791 
letermovir subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated 
792 
moderate dyspnea, occurred in one subject following the first infusion of IV letermovir after 
793 
switching from oral letermovir, leading to treatment discontinuation. 
794 
Laboratory Abnormalities 
795 
Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping 
796 
treatment are presented in Table 8. 
797 
Table 8: Trial P001 Selected Laboratory Abnormalities 
798 
Letermovir 
N=373 
Placebo 
N=192 
Absolute neutrophil count (cells/μL) 
 
 
< 500 
19% 
19% 


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500 – < 750 
4% 
7% 
750 – < 1000 
8% 
9% 
Hemoglobin (g/dL) 
 
 
< 6.5 
2% 
1% 
6.5 – < 8.0 
14% 
15% 
8.0 – < 9.5 
41% 
43% 
Platelets (cells/μL) 
 
< 25000 
27% 
21% 
25000 – < 50000 
17% 
18% 
50000 – < 100000 
20% 
30% 
Serum creatinine (mg/dL) 
 
 
> 2.5 
2% 
3% 
> 1.5 – 2.5 
17% 
20% 
 
799 
The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 
800 
consecutive days after transplantation) was 19 days in the letermovir group and 18 days in the 
801 
placebo group. 
802 
9 
REGULATORY AND REPORTING REQUIREMENTS 
803 
9.1 Adverse Events (AEs) 
804 
Definition: any unfavorable medical occurrence in a human subject including any abnormal sign, 
805 
symptom, or disease. 
806 
For the purposes if this study, “Adverse Event” or “AE” shall mean any untoward medical 
807 
occurrence iin a Study subject who is administered the Study Drug (letermovir) regardless 
808 
of whether or not a causal relationship with the Study Drug exists. By way of example and 
809 
without limitation, an AE can be any unfavorable and unintended sign (for example, an 
810 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
811 
the Study Drug. 
812 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
813 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. A copy 
814 
of the CTCAE version 5.0 can be downloaded from the CTEP website. 
815 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms listed 
816 
that should be used are those provided by the Department of Health and Human Services’ 
817 
Office for Human Research Protections (OHRP). A copy of this guidance can be found on 
818 
OHRP’s website: 
819 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
820 


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Unanticipated Problems Definition: 
821 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
822 
that are described in the protocol-related documents, such as the IRB- approved 
823 
research protocol and informed consent document; and (b) the characteristics of the 
824 
subject population being studied; 
825 
• 
related or possibly related to participation in the research (“possibly related” means there 
826 
is a reasonable possibility that the incident, experience, or outcome may have been 
827 
caused by the procedures involved in the research); 
828 
• 
Suggests that the research places subjects or others at a greater risk of harm (including 
829 
physical, psychological, economic, or social harm) than was previously known or 
830 
recognized. 
831 
9.2 Serious Adverse Events (SAEs) 
832 
“Serious Adverse Event” or “SAE” shall mean any untoward medical occurrence in a Study 
833 
subject who is administered the Study Drug (letermovir) which meets one or more of the 
834 
seriousness criteria outlined below. 
835 
An adverse event should be classified as a serious adverse event if the following seriousness 
836 
criteria are met: 
837 
• 
It results in death (i.e., the adverse event actually causes or leads to death) 
838 
• 
It is life threatening (i.e., the adverse event, in the view of the investigator, places the 
839 
subject at immediate risk of death. It does not include an adverse event that, had it 
840 
occurred in a more severe form, might have caused death.). 
841 
• 
It requires or prolongs inpatient hospitalization. 
842 
• 
It results in persistent or significant disability/incapacity (i.e., the adverse event results in 
843 
substantial disruption of the subject’s ability to conduct normal life functions). 
844 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
845 
exposed to the IMP. 
846 
• 
It is considered a significant medical event by the investigator based on medical 
847 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to 
848 
prevent one of the outcomes listed above). 
849 
“Suspected Unexpected Serious Adverse Reaction” or “SUSAR” shall mean any Serious 
850 
Adverse Event, the nature, severity or frequency of which is not consistent with information in 
851 
the most current Summary of Product Characteristics (SPC) or Package Insert. 
852 
9.3 Noncompliance 
853 
Definition: failure to follow any applicable regulation or institutional policies that govern human 
854 
subjects research or failure to follow the determinations of the IRB. Noncompliance may occur 
855 
due to lack of knowledge or due to deliberate choice to ignore regulations, institutional policies, 
856 
or determinations of the IRB. 
857 


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9.4 Serious Noncompliance 
858 
Definition: noncompliance that materially increases risks, that results in substantial harm to 
859 
subjects or others, or that materially compromises the rights or welfare of participants. 
860 
9.5 Reporting to the OSU IRB 
861 
The OSU PI is required to promptly notify the IRB of the following events: 
862 
• 
Any unanticipated problems involving risks to participants or others which occur at OSU, 
863 
or that impacts participants or the conduct of the study. 
864 
• 
Noncompliance with federal regulations or the requirements or determinations of the IRB. 
865 
• 
Receipt of new information that may impact the willingness of participants to participate 
866 
or continue participation in the research study. 
867 
These events must be reported to the IRB within the time frames outlined in the IRB policy. 
868 
9.6 Reporting to the sponsor 
869 
Principal investigator shall forward to Merck’s Global Pharmacovigilance (“Merck GPV”) group, 
870 
any SAE or SUSAR, including, but not limited to, all initial and follow up information involving 
871 
any study subject in the study. Notification shall be in the form of a completed CIOMS 
872 
I/MedWatch (or other mutually agreed upon format) within two (2) business days of but not 
873 
longer than three (3) calendar days of receipt of this information. This information shall be 
874 
transmitted to Merck GPV using the contact information provided below or such other modified 
875 
contact information as provided by Merck in writing. All information shall be transmitted in the 
876 
English language and contain the reporter’s name and the study subject identifier code. SUSAR 
877 
information will be reported unblinded if the study drug has been blinded in the study. 
878 
Randomization codes for all other SAEs will be provided to Merck GPV at end of study if the 
879 
Study Drug has been blinded in the study. 
880 
SAE reports and any other relevant safety information are to be forwarded to Merck GPV 
881 
facsimile number: 215-661-6229. 
882 
9.7 Reporting to the FDA 
883 
The conduct of the study will comply with all FDA safety reporting requirements. PLEASE 
884 
NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM REPORTING 
885 
REQUIREMENTS FOR THE IRB. It is the responsibility of the investigator to report any 
886 
unanticipated problem to the FDA as follows: 
887 
• 
Report any unexpected fatal or life-threatening adverse experiences associated with use 
888 
of the drug (i.e., there is a reasonable possibility that the experience may have been 
889 
caused by the drug) by telephone or fax no later than 7 calendar days after initial receipt 
890 
of the information. A life-threatening adverse experience is defined as any adverse drug 
891 
experience that places the subject (in the view of the investigator) at immediate risk of 
892 
death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
893 
occurred in a more severe form, might have caused death. 
894 


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• 
Report any serious, unexpected adverse experiences, as well as results from animal 
895 
studies that suggest significant clinical risk within 15 calendar days after initial receipt of 
896 
this information. A serious adverse drug experience is defined as any adverse drug 
897 
experience occurring at any dose that results in any of the following outcomes: 
898 
o Death 
899 
o A life-threatening adverse drug experience 
900 
o Inpatient hospitalization or prolongation of existing hospitalization 
901 
o A persistent or significant disability/incapacity (i.e., a substantial disruption of a 
902 
person’s ability to conduct normal life functions) 
903 
o A congenital anomaly/birth defect 
904 
o Any other experience which, based upon appropriate medical judgment, may 
905 
jeopardize the subject and may require medical or surgical intervention to 
906 
prevent one of the outcomes listed above 
907 
An unexpected adverse drug experience is defined as any adverse drug experience, the 
908 
specificity or severity of which is not consistent with the current investigator brochure (or risk 
909 
information, if an IB is not required or available). 
910 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA (refer to 
911 
the FDA website to obtain the current address and fax number for the Center for Drug 
912 
Evaluation and Research Division of Oncology Drug Products). 
913 
9.8 Timeframe for Reporting Required Events 
914 
Reportable adverse events will be tracked for 30 days following the last day of study treatment. 
915 
Deaths 
Any reportable death while on study or 
within 30 days of study 
Immediately, within 24 hours, to PI and the 
IRB 
Any reportable death while off study 
Immediately, within 24 hours, to PI and the 
IRB 
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described 
in Sections 9.1 and 9.2 (other than death) 
and 9.9 
Immediately, within 24 hours to PI and 
within required time frame to the IRB (per 
local policy) and within 7 or 15 calendar 
days to the FDA 
All adverse events regardless of grade and 
attribution should be submitted cumulatively 
Include in DSM report 
Noncompliance and Serious Noncompliance 


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All noncompliance and serious 
noncompliance as described in Sections 9.3 
and 9.4 
Immediately, within 24 hours, to PI and 
within required time frame to the IRB (per 
local policy) 
 
916 
9.9 Overdose 
917 
In this trial, an overdose is any dose higher than two times the dose specified in section 4.  
918 
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product, the 
919 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
920 
are met. If a dose of Sponsor's product meeting the protocol definition of overdose is taken 
921 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
922 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
923 
intentional overdose without adverse effect.” All reports of overdose with and without an adverse 
924 
event must be reported within 24 hours to the Sponsor either by electronic media or paper.  
925 
There is no specific antidote for overdose with letermovir. In case of overdose, it is 
926 
recommended that the patient be monitored for adverse reactions and appropriate symptomatic 
927 
treatment be instituted. 
928 
 
929 
It is unknown whether dialysis will result in meaningful removal of letermovir from systemic 
930 
circulation. 
931 
9.10 Pregnancies 
932 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
933 
or disease state) of a woman occurring while on study or within 28 days of her last dose of study 
934 
drug are considered immediately reportable events. Protocol therapy is to be discontinued 
935 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
936 
within 24 hours. 
937 
All subjects who become pregnant must be followed to the completion/termination of the 
938 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
939 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
940 
as serious events (Important Medical Events). CRFs will be used to report pregnancies and 
941 
pregnancy outcomes. 
942 
9.11 Data and safety monitoring 
943 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
944 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
945 
the regular protocol review meeting at least monthly. The PI of the trial will review toxicities and 
946 
responses of the trial where applicable and determine if the risk/benefit ratio of the trial changes. 
947 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
948 
known about the agent/device from other sources; including published literature, scientific 
949 
meetings and discussions with sponsors, to determine if the trial should be terminated before 
950 
completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data 
951 


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and Safety Monitoring Committee (DSMC). The PI will also submit a progress report that will be 
952 
reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events (SAE) 
953 
will be reported to the IRB of record as per the policies of the IRB. 
954 
9.11.1 Data Submission 
955 
The study will be managed per OSU Clinical Trial Office. Data will be directly entered into the 
956 
OSU OnCore database. 
957 
9.11.2 Auditing 
958 
As the study sponsor, The Ohio State University Comprehensive Cancer Center (OSUCCC) will 
959 
audit the trial per OSU policies. Audits will be performed by the OSUCCC Clinical Research 
960 
Audit Team.  
961 
9.12 Ethical Considerations 
962 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
963 
Helsinki. Investigators and study staff will undergo training on Good Clinical Practice (GCP) 
964 
through the Collaborative Institutional Training Initiative (CITI). GCP training sets the standard 
965 
for the design, conduct, recording, and reporting of studies involving human subjects, ensuring 
966 
that study subjects rights, safety, and well-being are protected. The IRB will review all 
967 
appropriate study documentation in order to safeguard the rights, safety and wellbeing of the 
968 
patients. The study will only be conducted at sites where IRB approval has been obtained. The 
969 
protocol, informed consent form, written information given to the patients (including pill diaries), 
970 
safety updates, annual progress reports, and any revisions to these documents will be provided 
971 
to the IRB by the investigator, as allowable by local regulations. The principal investigator will 
972 
ensure that the study will be conducted according to the protocol and all applicable regulations. 
973 
The protection of each subject’s rights and welfare will be maintained. 
974 
9.13 Retention of records 
975 
FDA regulations (21 CFR § 312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of the 
976 
guideline) require that records and documents pertaining to the conduct of clinical trials and the 
977 
distribution of investigational drug, patient records, consent forms, laboratory test results, and 
978 
medication inventory records, must be retained for 2 years after the last marketing application 
979 
approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
980 
clinical development of the investigational product. All state and local laws for retention of 
981 
records also apply. 
982 
For studies conducted outside the United States under a U.S. IND, the Principal Investigator 
983 
must comply with the record retention requirements set forth in the FDA IND regulations and the 
984 
relevant national and local health authorities, whichever is longer. 
985 
10 STATISTICAL METHODS 
986 
10.1 Study Design and Sample Size Justification 
987 
The primary objective of this single center, single arm phase II study is to determine the efficacy 
988 
of letermovir prophylaxis in PLL, CLL, PTCL or CTCL patients treated with alemtuzumab. The 
989 
efficacy will be measured through the CMV reactivation rate during letermovir prophylaxis (3 
990 


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months after completion of alemtuzumab therapy). All eligible patients who receive any 
991 
letermovir will be included in the safety analysis, and all patients who receive ≥90% of planned 
992 
letermovir doses are evaluable for the efficacy analysis.  
993 
Fleming’s two-stage design[80] will be followed to conduct the study. Previous trials reported 
994 
CMV reactivation rate of 30% in a similar patient population, and our own institutional data 
995 
revealed a similar pattern.  Based on these data, we determined that a CMV reactivation rate of 
996 
30% or higher is not acceptable, which leads to our null hypothesis of a 70% safety rate. In a 
997 
pivotal phase 3 trial, letermovir prophylaxis resulted in a clinically significant 23.1% absolute 
998 
reduction (61.6% relative risk reduction) in CMV infection rate compared with placebo in 
999 
recipients of allogeneic hematopoietic stem cell transplantation without evidence of hematologic 
1000 
toxicity [67]. Therefore, we hypothesized that letermovir prophylaxis will reduce the CMV by 
1001 
20% in our patient population to a 10% reactivation rate, which translates to an alternative 
1002 
hypothesis of 90% safety rate.  
1003 
With a one-sided type I error rate of 5% and 85% power, Fleming’s two-stage design allows a 
1004 
first-stage analysis after the first 14 patients are enrolled and evaluated. If 4 or more patients 
1005 
have CMV reactivation during letermovir prophylaxis period, the regimen will be considered 
1006 
inefficacious, and the study will be terminated early due to futility. On the other hand, if none of 
1007 
the 14 patients experiences CMV reactivation, letermovir will be declared effective in preventing 
1008 
CMV reactivation, and the study will be ended early with rejection of the null hypothesis as the 
1009 
final conclusion. If CMV infection is observed in between 1 to 3 patients among the first 14, then 
1010 
the study will continue to accrue to a total of 28 patients. By the end of the study, if at least 24 
1011 
out of the 28 patients are CMV free, we will conclude the regimen effective to warrant further 
1012 
investigation.     
1013 
To account for the possibility that some patients might not be evaluable, we will allow a 5% 
1014 
over-accrual for a total target enrollment of 30 patients.  With an anticipated accrual rate of 1.5 
1015 
patients a month, the study is expected to complete enrolling for the first stage in 10 months. 
1016 
With another 7 months for the primary endpoint evaluation, the first stage will finish in about 17 
1017 
months. If the second stage were to continue, the whole study can last as long as 27 months.     
1018 
10.2 Analysis of Primary Objective 
1019 
1. For efficacy analysis, the CMV reactivation rate will be defined as the proportion of 
1020 
patients who experience CMV reactivation (CMV DNA by real time polymerase chain 
1021 
reaction >500 IU/mL) during prophylaxis period among all patients who receive ≥90% of 
1022 
planned letermovir doses.  The rate will be provided with 95% binomial confidence 
1023 
interval. 
1024 
10.3 Analysis of Secondary Objectives 
1025 
1. All eligible patients who receive any letermovir prophylaxis will be included in the 
1026 
tolerability analysis. Adverse event data will be described and graded per the NCI 
1027 
CTCAE v5.0 guidelines. The maximum grade for each type of toxicity will be recorded 
1028 
for each patient, and frequency tables will be reviewed to determine toxicity patterns, 
1029 
especially for grade 3 or above adverse events. To assess tolerability, we also capture 
1030 
the proportion of patients who require dose reduction as well as those who go off 
1031 
treatment due to adverse events. 
1032 


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2. Clinically significant CMV reactivation be determined per the Disease Definitions 
1033 
Working Group of the Cytomegalovirus Drug Development Forum [71] (Appendix 12.1). 
1034 
3. OS of patients treated with alemtuzumab after letermovir prophylaxis will be calculated 
1035 
from trial enrollment to the occurrence of (death due to any cause), censoring event-free 
1036 
patients at time of last follow-up. OS will be estimated with the method of Kaplan-Meier 
1037 
(KM), where KM curves will be drawn to aid with visualization and estimates provided 
1038 
with 95% confidence intervals.    
1039 
10.4 Analysis of Exploratory Objectives 
1040 
CMV DNA Sequence Analysis to be performed only in subjects with CMV reactivation. 
1041 
Resistance to letermovir will be monitored by retrospective genotypic analysis of the CMV 
1042 
terminase gene UL56 in CMV DNA extracts from selected plasma samples collected at the time 
1043 
of diagnosed CMV reactivation. Samples will be analyzed by standard population sequencing 
1044 
technology through an established contract laboratory with validated protocols in place. If no 
1045 
mutations are noted in UL56, then genotype testing will reflex to UL51 and UL89 (less frequent 
1046 
resistance mutations have been reported in these genes). 
1047 
11 REFERENCES 
1048 
 
1049 
1. 
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2. 
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Dearden, C.E., et al., High remission rate in T-cell prolymphocytic leukemia with 
1104 
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1105 
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1108 
24. 
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1109 
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1110 
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Guillaume, T., et al., Allogeneic hematopoietic stem cell transplantation for T-
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prolymphocytic leukemia: a report from the French society for stem cell transplantation 
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(SFGM-TC). Eur J Haematol, 2015. 94(3): p. 265-9. 
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26. 
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leukemia. Biol Blood Marrow Transplant, 2010. 16(4): p. 543-7. 
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27. 
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1118 
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28. 
Enblad, G., et al., A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) 
1120 
therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell 
1121 
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29. 
Stewart, J.R., et al., Alemtuzumab is an effective third-line treatment versus single-agent 
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1124 
Dermatol, 2018. 28(6): p. 764-774. 
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30. 
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syndrome: clinical and immunologic findings in 14 patients. Haematologica, 2007. 92(6): 
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diffuse erythema as a positive predictor of complete remission. JAMA Dermatol, 2014. 
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150(7): p. 776-9. 
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32. 
Kluin-Nelemans, H.C., et al., Intensified alemtuzumab-CHOP therapy for peripheral T-
1132 
cell lymphoma. Ann Oncol, 2011. 22(7): p. 1595-600. 
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33. 
Roswarski, J., et al., Phase 1/2 study of alemtuzumab with dose-adjusted EPOCH in 
1134 
untreated aggressive T and NK cell lymphomas. Leuk Lymphoma, 2019. 60(8): p. 2062-
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2066. 
1136 
34. 
Ravandi, F., et al., Phase II study of alemtuzumab in combination with pentostatin in 
1137 
patients with T-cell neoplasms. J Clin Oncol, 2009. 27(32): p. 5425-30. 
1138 
35. 
Cannon, M.J., D.S. Schmid, and T.B. Hyde, Review of cytomegalovirus seroprevalence 
1139 
and demographic characteristics associated with infection. Rev Med Virol, 2010. 20(4): 
1140 
p. 202-13. 
1141 
36. 
Borst, E.M., et al., The human cytomegalovirus UL51 protein is essential for viral 
1142 
genome cleavage-packaging and interacts with the terminase subunits pUL56 and 
1143 
pUL89. J Virol, 2013. 87(3): p. 1720-32. 
1144 
37. 
Boeckh, M., et al., Cytomegalovirus in hematopoietic stem cell transplant recipients: 
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Current status, known challenges, and future strategies. Biol Blood Marrow Transplant, 
1146 
2003. 9(9): p. 543-58. 
1147 
38. 
El Chaer, F., D.P. Shah, and R.F. Chemaly, How I treat resistant cytomegalovirus 
1148 
infection in hematopoietic cell transplantation recipients. Blood, 2016. 128(23): p. 2624-
1149 
2636. 
1150 
39. 
Allice, T., et al., Valganciclovir as pre-emptive therapy for cytomegalovirus infection post-
1151 
allogenic stem cell transplantation: implications for the emergence of drug-resistant 
1152 
cytomegalovirus. J Antimicrob Chemother, 2009. 63(3): p. 600-8. 
1153 
40. 
Hantz, S., et al., Drug-resistant cytomegalovirus in transplant recipients: a French cohort 
1154 
study. J Antimicrob Chemother, 2010. 65(12): p. 2628-40. 
1155 
41. 
Sharma, K., et al., Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-
1156 
1-Associated Adult T-cell Leukemia/lymphoma. Clin Cancer Res, 2017. 23(1): p. 35-42. 
1157 
42. 
Kim, J.G., et al., Alemtuzumab plus CHOP as front-line chemotherapy for patients with 
1158 
peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol, 2007. 
1159 
60(1): p. 129-34. 
1160 
43. 
Binder, C., et al., CHO(E)P-14 followed by alemtuzumab consolidation in untreated 
1161 
peripheral T cell lymphomas: final analysis of a prospective phase II trial. Ann Hematol, 
1162 
2013. 92(11): p. 1521-8. 
1163 
44. 
Weidmann, E., et al., A phase II study of alemtuzumab, fludarabine, cyclophosphamide, 
1164 
and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas. Leuk Lymphoma, 
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2010. 51(3): p. 447-55. 
1166 
45. 
Hopfinger, G., et al., Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and 
1167 
cyclophosphamide induction followed by alemtuzumab consolidation is effective in T-cell 
1168 
prolymphocytic leukemia. Cancer, 2013. 119(12): p. 2258-67. 
1169 
46. 
Kuan, J.W., et al., The Outcome of HyperCVAD Combined with Alemtuzumab for the 
1170 
Treatment of Aggressive T-Cell and NK-Cell Neoplasms. Indian J Hematol Blood 
1171 
Transfus, 2011. 27(3): p. 136-45. 
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47. 
Intragumtornchai, T., et al., Alemtuzumab in Combination with CHOP and ESHAP as 
1173 
First-Line Treatment in Peripheral T-Cell Lymphoma. Blood, 2006. 108(11): p. 4740-
1174 
4740. 
1175 
48. 
Kim, S.J., et al., Dose modification of alemtuzumab in combination with dexamethasone, 
1176 
cytarabine, and cisplatin in patients with relapsed or refractory peripheral T-cell 
1177 
lymphoma: analysis of efficacy and toxicity. Invest New Drugs, 2012. 30(1): p. 368-75. 
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49. 
Rupoli, S., et al., Alemtuzumab in Combination with Interferon-α or Gemcitabine in 
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Aggressive and Advanced Cutaneous T-Cell Lymphomas: Report of Preliminary Results. 
1180 
Blood, 2008. 112(11): p. 5000-5000. 
1181 
50. 
de Masson, A., et al., Long-term efficacy and safety of alemtuzumab in advanced 
1182 
primary cutaneous T-cell lymphomas. Br J Dermatol, 2014. 170(3): p. 720-4. 
1183 
51. 
Dumitriu, B., et al., Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim 
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results from a single-arm, open-label, phase 2 study. Lancet Haematol, 2016. 3(1): p. 
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e22-9. 
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52. 
Alinari, L., et al., Subcutaneous alemtuzumab for Sezary Syndrome in the very elderly. 
1187 
Leuk Res, 2008. 32(8): p. 1299-303. 
1188 
53. 
Nguyen, D.D., et al., Cytomegalovirus viremia during Campath-1H therapy for relapsed 
1189 
and refractory chronic lymphocytic leukemia and prolymphocytic leukemia. Clin 
1190 
Lymphoma, 2002. 3(2): p. 105-10. 
1191 
54. 
Querfeld, C., et al., Alemtuzumab for relapsed and refractory erythrodermic cutaneous 
1192 
T-cell lymphoma: a single institution experience from the Robert H. Lurie 
1193 
Comprehensive Cancer Center. Leuk Lymphoma, 2009. 50(12): p. 1969-76. 
1194 
55. 
Zinzani, P.L., et al., Preliminary observations of a phase II study of reduced-dose 
1195 
alemtuzumab treatment in patients with pretreated T-cell lymphoma. Haematologica, 
1196 
2005. 90(5): p. 702-3. 
1197 
56. 
Kennedy, G.A., et al., Treatment of patients with advanced mycosis fungoides and 
1198 
Sezary syndrome with alemtuzumab. Eur J Haematol, 2003. 71(4): p. 250-6. 
1199 
57. 
Lundin, J., et al., Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in 
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patients with advanced mycosis fungoides/Sezary syndrome. Blood, 2003. 101(11): p. 
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4267-72. 
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58. 
Clark, R.A., et al., Skin effector memory T cells do not recirculate and provide immune 
1203 
protection in alemtuzumab-treated CTCL patients. Sci Transl Med, 2012. 4(117): p. 
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117ra7. 
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experience. J Dermatolog Treat, 2016. 27(2): p. 179-81. 
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60. 
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1209 
Lymphoma Myeloma Leuk, 2016. 16(1): p. 18-28 e4. 
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61. 
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1211 
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1212 
2009. 20(2): p. 390-2. 
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62. 
Wulf, G.G., et al., Reduced intensity conditioning and allogeneic stem cell 
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transplantation after salvage therapy integrating alemtuzumab for patients with relapsed 
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peripheral T-cell non-Hodgkin's lymphoma. Bone Marrow Transplant, 2005. 36(3): p. 
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271-3. 
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63. 
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1218 
and Sezary Syndrome. Blood, 2007. 110(11): p. 3425-3425. 
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64. 
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1220 
dose subcutaneous alemtuzumab. Dermatol Online J, 2011. 17(11): p. 6. 
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1222 
predict the response of Sezary syndrome to alemtuzumab? J Am Acad Dermatol, 2012. 
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70. 
Ljungman, P., et al., A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus 
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87-91. 
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73. 
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1251 
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1260 
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1261 
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1262 
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80. 
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1265 
 
1266 
12 APPENDICES 
1267 
12.1 CMV Disease Definitions Working Group of the Cytomegalovirus Drug 
1268 
Development Forum 
1269 
CMV Disease 
Diagnostic criteria 
Notes 
Pneumonia 
Clinical symptoms and/or signs of 
pneumonia such as new infiltrates on 
imaging, hypoxia, tachypnea, and/or 
dyspnea  
AND 
• PCR may be too sensitive, so 
detection of CMV by PCR alone is 
insufficient for the diagnosis of 
CMV pneumonia. 


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CMV documented in BAL or lung 
tissue by virus isolation, rapid 
culture, histopathology, IHC, or DNA 
hybridization techniques 
• Detection of fungal co-pathogens 
like Aspergillus spp. + "halo" sign 
(radiology) indicates fungal, rather 
than CMV pneumonia. 
• Superinfection or coinfection with 
other pathogens may occur and 
should be noted when present. 
GI 
Upper and/or lower gastrointestinal 
(GI) symptoms 
AND 
macroscopic mucosal lesions  
AND 
CMV documented in tissue by 
histopathology, virus isolation, rapid 
culture, IHC, or DNA hybridization 
techniques. 
• PCR may be too sensitive, so 
detection of CMV by PCR alone is 
insufficient for the diagnosis of 
CMV GI disease 
• Studies should give information 
regarding the presence or 
absence of GI GVHD in HSCT 
recipients. 
 
Hepatitis 
Abnormal liver function tests 
AND 
CMV documented in tissue by 
histopathology, IHC, virus isolation, 
rapid culture, or DNA hybridization 
techniques  
AND 
Absence of other documented cause 
of hepatitis, including DILI 
• Studies should give information 
regarding the presence or 
absence of hepatic GVHD in 
HSCT recipients. 
 
CNS 
CNS symptoms 
AND 
Detection of CMV in CNS tissue by 
virus isolation, rapid culture, IHC, in 
situ hybridization, or (preferably) 
quantitative PCR. 
 
• Probable disease requires CNS 
symptoms plus detection of CMV 
in CSF without visible 
contamination of blood plus 
abnormal imaging results or 
evidence of encephalitis on 
electroencephalography. 
 
Retinitis 
Typical ophthalmological signs 
judged by an ophthalmologist 
experienced with the diagnosis of 
CMV retinitis 
OR 
CMV documented in vitreous fluid by 
NAT (for example PCR) 
 
Nephritis 
Renal dysfunction 
AND 
Detection of CMV by virus isolation, 
rapid culture, IHS, or in situ 
hybridization in a kidney biopsy 
specimen  
AND 
Identification of histologic features of 
CMV infection 
• The detection of CMV in urine by 
PCR or culture is not sufficient for 
the diagnosis of CMV nephritis as 
asymptomatic viral shedding in 
urine is common. 


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Cystitis 
Signs/symptoms of cystitis 
AND 
Detection of CMV by virus isolation, 
rapid culture, IHC, or in situ 
hybridization in a bladder biopsy 
specimen  
AND 
Histologic features of CMV infection. 
• The detection of CMV in urine by 
PCR or culture is not sufficient for 
the diagnosis of CMV cystitis as 
asymptomatic viral shedding in 
urine is common. 
Myocarditis 
Signs/symptoms of myocarditis 
AND 
Detection of CMV by virus isolation, 
rapid culture, IHC, or in situ 
hybridization in a myocardial biopsy 
specimen  
AND 
Histologic features of CMV infection. 
 
Pancreatitis 
Signs/symptoms of myocarditis 
AND 
Detection of CMV by virus isolation, 
rapid culture, IHC, or in situ 
hybridization in a pancreatic biopsy 
specimen  
AND 
Histologic features of CMV infection. 
 
Other 
Presence of compatible symptoms in 
other organs 
AND 
Detection of CMV by virus isolation, 
rapid culture, IHC, or in situ 
hybridization in a biopsy specimen  
 
Reference [71]. BAL= bronchoalveolar lavage; CMV = cytomegalovirus; CNS = central 
nervous system; DILI = drug induced liver injury; GI = gastrointestinal; GVHD = graft versus 
host disease; HSCT = hematopoietic stem cell transplant; IHC = immunohistochemistry; NAT 
= nucleic acid testing; PCR = polymerase chain reaction 
 
1270 
12.2 Eastern Cooperative Oncology Group Performance Status Scale 
1271 
ECOG 
Description 
0 
 Asymptomatic (Fully active, able to carry on all predisease activities without 
restriction) 
1 
Symptomatic but completely ambulatory (Restricted in physically strenuous 
activity but ambulatory and able to carry out work of a light or sedentary nature. 
For example, light housework, office work) 
2 
Symptomatic, <50% in bed during the day (Ambulatory and capable of all self-
care but unable to carry out any work activities. Up and about more than 50% of 
waking hours) 
3 
Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, 
confined to bed or chair 50% or more of waking hours) 
4 
Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair) 


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5 
Death 
 
1272 
12.3 Child-Pugh Classification of liver disease 
1273 
 
Scoring by Anomaly 
Signs or symptom 
1 point 
2 points 
3 points 
Hepatic encephalopathy1 
Absent 
Grade 1 or 2 
Grade 3 or 4 
Ascites 
Absent 
Mild 
Moderate 
Bilirubin (μmol/L) 
< 2 mg/dL 
2 – 3 mg/dL 
> 3 mg/dL 
Albumin (g/dL) 
> 3.5 g/dL 
2.8 – 3.5 g/dL 
< 2.8 g/dL 
Prothrombin time (INR) 
< 1.7 
1.7 – 2.3 
> 2.3 
1Hepatic encephalopathy grading:  
Grade 1: Altered mood/confusion  
Grade 2: Inappropriate behavior, impending stupor, somnolence  
Grade 3: Markedly confused, stuporous but arousable  
Grade 4: Comatose/unresponsive 
 
1274 
Child-Pugh Score interpretation 
5-6 points 
Child-Pugh Stage A (mild hepatic insufficiency) 
 
Child-Pugh Stage B (moderate hepatic insufficiency*) 
 
Child-Pugh Stage C (severe hepatic insufficiency) 
*If hypoalbuminemia is the only abnormality noted, the subject will need to have a score of ≥7 
to qualify for moderate hepatic insufficiency for this study 
 
1275 

ICF_000.pdf: 
CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 1 of 13 
Form date: 
05/17/2019 
 
The Ohio State University Combined Consent to Participate in 
Research and HIPAA Research Authorization 
 
Study Title: Letermovir for Cytomegalovirus Prophylaxis in Patients with 
Hematological Malignancies Treated with Alemtuzumab 
Principal Investigator: John Reneau, MD, PhD 
Sponsor: The Ohio State University 
 
• This is a consent form for research participation.  It contains important information 
about this study and what to expect if you decide to participate.  Please consider the 
information carefully. Feel free to discuss the study with your friends and family and 
to ask questions before making your decision whether or not to participate. 
• Your participation is voluntary.  You may refuse to participate in this study.  If you 
decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your 
usual benefits.  Your decision will not affect your future relationship with The Ohio 
State University.  If you are a student or employee at Ohio State, your decision will 
not affect your grades or employment status. 
• You may or may not benefit as a result of participating in this study.  Also, as 
explained below, your participation may result in unintended or harmful effects for 
you that may be minor or may be serious depending on the nature of the research. 
• You will be provided with any new information that develops during the study 
that may affect your decision whether or not to continue to participate.  If you 
decide to participate, you will be asked to sign this form and will receive a copy of the 
form.  You are being asked to consider participating in this study for the reasons 
explained below.   
 
Key Information About This Study 
The following is a short summary to help you decide whether or not to be a part of this study. 
More detailed information is listed later in this form.  
 
You are invited to take part in a clinical trial, a type of research study, because you have one 
of several types of blood cancers, you have not undergone an allogenic hematopoietic stem 
cell transplant (HSCT) in the last 6 months, your doctor intends to treat you with 
alemtuzumab, and you have been previously exposed to cytomegalovirus (CMV). Patients 
receiving this treatment can experience a reactivation of the CMV infection (when patients 
who had no symptoms of infection begin experiencing symptoms of active infection again), 
and this possibility prevents wider use of alemtuzumab, which is an otherwise well-tolerated 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 2 of 13 
Form date: 
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treatment. Successfully preventing a reactivation of CMV could allow doctors to offer more 
patients alemtuzumab. 
 
A drug called letermovir has been approved for preventing CMV reactivation in patients who 
have received HSCT. In this study, letermovir will be tested to determine if it is safe and 
effective in patients being treated with alemtuzumab and who have not received HSCT in the 
last 6 months.  
 
You will continue to take letermovir during your treatment with alemtuzumab, and for 3 
months after completing alemtuzumab. We will follow up with you once, about 30 days after 
your last dose of letermovir. You will undergo several medical procedures during this study, 
including: blood draws, physical exams, pregnancy tests, and taking the study medication. 
 
The most common side effects while taking letermovir are nausea, diarrhea, vomiting, 
swelling in your arms and legs, cough, headache, tiredness, and stomach (abdominal) pain. It 
is extremely important that you, any caregivers, and other healthcare providers have the 
correct study team contact information for safety and management of toxicities. To address 
this, Trial Alert Cards have been created to record study team phone numbers, with a 24-hour 
option, and come in a size that can be carried in your wallet. The cards include a note to 
healthcare providers asking them to contact your treating physician, in case you seek care 
with anyone unfamiliar with the trial. You will receive this card at your first/ next visit, please 
keep it with you at all times. 
 
You may or may not benefit from participating, but the information gained in this study may 
help doctors treat patients in the future.  
 
You do not have to take part in this clinical trial, and may still receive cancer care at The Ohio 
State University without taking part. 
 
1.   Why is this study being done? 
 
You are invited to take part in a clinical trial, a type of research study, because you have one 
of several types of blood cancers, and your doctor intends to treat you with alemtuzumab. The 
study doctors at Ohio State are testing a drug, letermovir, which will be given to you once a 
day during your normal treatment, and for 3 months after completing alemtuzumab.  
 
Merck is supporting this research study by providing the study drug, letermovir.  
 
The purpose of this research is to determine how safe and effective (how well something 
works) letermovir is in preventing reactivation of cytomegalovirus (CMV). This study will 
also be testing how effective letermovir is when taken with alemtuzumab.  
 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 3 of 13 
Form date: 
05/17/2019 
 
Letermovir is approved by the United States Food and Drug Administration (FDA) for the 
prevention of CMV reactivation in patients who have received an allogenic hematopoietic 
stem cell transplant (HSCT), but it has not been approved for non-transplant patients.  
 
This study is being done to determine if letermovir is effective in preventing CMV 
reactivation in non-HSCT patients treated with alemtuzumab.  
 
2.   How many people will take part in this study? 
 
At the Ohio State University, approximately 30 people will take part in this study. 
 
3.   What will happen if I take part in this study? 
 
If you decide to take part in this research study, you will first be asked to sign this consent 
form. 
 
Screening 
 
After signing the consent form, you will have tests and procedures completed to determine 
if you can participate in the study. Some of these may be completed as part of your 
standard medical care. They include: 
• Medical history:  A review of your complete medical history, lab results, including 
any medications/supplements you have used or are using now. 
• Pregnancy test (for females of childbearing potential only): A blood or urine 
sample will be taken, as part of your routine care, to see if you are pregnant.    
Additional details about contraception while participating in this study can be 
found in Section 6 (Pregnancy) of this informed consent form. 
• Physical exam: The doctor will do an overall review of your current health, which 
includes recording your vitals (blood pressure, heart rate, respiratory rate, 
temperature), height, weight, and ECOG performance status (a measure of how 
well you are feeling). Your doctor will also look for and ask you about common 
signs of CMV infection. 
• Blood will be collected for standard of care medical testing, as well as for HIV, 
Hepatitis, and CMV testing.  Blood tests will include the following: 
o CBC (complete blood cell count) with differential:  A test to measure the 
number of red blood cells, white blood cells, and platelets in the blood, 
including the different types of white blood cells (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils). 
o CMP (comprehensive metabolic panel):  A group of 14 tests that measures 
several different substances in your blood to give information about the 
current status of your body’s metabolism, including your blood sugar 
(glucose) levels, the balance of electrolytes and fluid in your body, and the 
health of your kidneys and liver. 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 4 of 13 
Form date: 
05/17/2019 
 
o Prothrombin time (PT-INR):  A test to measure how long it takes for a clot 
to form in a blood sample. An INR (international normalized ratio) is a 
type of calculation based on PT test results. 
• You will be assessed for any adverse symptoms you are experiencing at baseline 
before your first dose of letermovir.  
 
 
Treatment Procedures: (occur after you have been enrolled into the study) 
 
If you are eligible for this study and choose to participate, you will undergo the following 
procedures while you are undergoing alemtuzumab treatment.  
• Physical exam: The doctor will do an overall review of your current health, which 
includes recording your vitals, height, and weight. Your doctor will also look for 
and ask you about common signs of CMV infection. 
• Your doctor will review your lab results, and confirm any medications or 
supplements you have used or are using now. 
• Pregnancy test: A blood or urine sample will be taken, as part of your routine care, 
to see if you are pregnant (if you are a woman who is able to become pregnant). 
• Blood will be collected for standard of care medical testing and CMV testing.   
 
If you experience CMV reactivation while you are on study, all of these procedures will 
be repeated. At that time, you will also have additional blood drawn to look for any 
mutations in the CMV genes. 
• You will be assessed for any adverse events. 
 
 
Study Drug 
• Within  days of your treatment beginning, you will also receive your letermovir. It 
is an oval tablet that you will take once a day. You should swallow it whole, and 
you can take it with or without food.   
• You should take letermovir at the same time every day. If you miss a dose, take it 
as soon as you remember. If it is more than 18 hours late, skip that dose, and take 
your next dose at your regularly scheduled time. Do not double your dose to 
“make up” for the missed one.  
• While taking letermovir (from 2 weeks before treatment until 72 hours after your 
last dose), you must avoid eating grapefruit and Seville oranges or drinking their 
juices and other quinine-containing drinks or foods.  
• If for any reason, you are unable to take letermovir by mouth for an extended 
period of time, you will be able to receive it through your vein (intravenously).  
 
 
Follow-up 
 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 5 of 13 
Form date: 
05/17/2019 
 
About 30 days after your last dose of letermovir, you will be seen again by the study team, 
and you will have the following procedures: 
• Physical exam: The doctor will do an overall review of your current health, which 
includes recording your vitals, height, and weight. Your doctor will also look for 
and ask you about common signs of CMV infection. 
• Your doctor will review your lab results, and confirm any medications or 
supplements you have used or are using now. 
• Pregnancy test: A blood or urine sample will be taken, as part of your routine care, 
to see if you are pregnant (if you are a woman who is able to become pregnant). 
• Blood will be collected for standard of care medical testing and CMV testing.   
 
If you are having ongoing side effects, or you had CMV reactivation, your study doctor 
will continue to follow you and provide appropriate medical care until resolved.  
  
4.   How long will I be in the study? 
 
Your participation in this study begins once you sign this consent form, and will continue 
through 30 (+/- 7) days from the last dose of letermovir. The study team may continue to 
follow up with you after that time if you are having any side effects related to study 
treatment.  
 
You may have to discontinue treatment early if: 
• You experience intolerable or unacceptable side effects 
• You do not follow dosing instructions or other requirements of the trial  
• Your doctor feels that continuing on the study would place you in greater than 
necessary risk.  
 
You must discontinue study treatment if: 
• You experience a CMV reactivation  
• Your doctor feels it is in your best interests to discontinue 
• (Female patients) You become pregnant 
 
5. Can I stop being in the study? 
 
You may leave the study at any time.  If you decide to stop participating in the study, 
there will be no penalty to you, and you will not lose any benefits to which you are 
otherwise entitled.  Your decision will not affect your future relationship with The Ohio 
State University.  
 
6.   What risks, side effects or discomforts can I expect from being in the study? 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought. You should talk with your study doctor if you have any 
questions. 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 6 of 13 
Form date: 
05/17/2019 
 
 
Side Effects   
The most common side effects while taking letermovir are:  
• Nausea (27%)  
• Diarrhea (26%)  
• Vomiting (19%)  
• Swelling in your arms and legs (14%)  
• Cough (14%)  
• Headache (14%)  
• Tiredness (13%) 
• Stomach (abdominal) pain (12%)   
 
Other possible side effects while taking letermovir are: 
• Tachycardia (fast heart rate) (3%) 
• Atrial fibrillation (irregular heart rate) (3%) 
• Anemia (low hemoglobin) that is life-threatening or needs urgent treatment (2%) 
• Allergic reaction (<1%) 
  
Talk to your study doctor for medical advice about side effects.  
 
Pregnancy 
We do not know the risks associated with pregnancy while taking letermovir. For this 
reason, you should not become pregnant, breast-feed, or father a child while you are on 
this study. Women who can get pregnant and men with partners who can become pregnant 
will be asked to practice a highly effective method of birth control while participating in 
this study and for 90 days after the last study therapy.  
 
Highly effective birth control includes: 
• True abstinence 
• Intrauterine device (IUD)  
• Diaphragm with spermicide,  
• Contraceptive sponge,  
• Condom,  
• Vasectomy  
 
OR  
• Use of appropriate double barrier contraception.  
 
Also acceptable methods: 
• Hormonal (birth control pills, injections, implants) 
 
 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 7 of 13 
Form date: 
05/17/2019 
 
Personal Information 
Study doctors and the study team will take steps to ensure that information obtained about 
you for this study will be kept confidential to the extent required by U.S. or local law. 
However, there is still the potential risk of breach of confidentiality, patient identity, and 
privacy during the study.  
 
Other risks 
Obtaining blood samples may cause some discomfort, pain, bruising, and/or bleeding.  
You may feel lightheaded or faint, develop an infection with redness and irritation of the 
vein at the site where blood is drawn.   
 
Your study doctor will closely monitor your health through this study and will discuss 
with you any questions regarding risks, discomforts, and side effects.  If significant new 
findings are discovered during the study that could affect your willingness to continue to 
participate, this information will be reported to you as soon as possible. 
 
If you have any concerns about this study at any time you should contact your study 
doctor. 
 
7.   What benefits can I expect from being in the study? 
 
It is not possible to predict or guarantee that this treatment will benefit you. Even with 
letermovir treatment, you may still have a reactivation of CMV. This treatment may also 
be harmful to you. This study is an important step in developing a treatment and planning 
other studies that may help patients in the future. 
 
8.   What other choices do I have if I do not take part in the study? 
 
You do not have to take part in this research study. You may receive the standard medical 
care for prevention of CMV reactivation while receiving alemtuzumab, participate in 
another clinical trial for prevention of CMV reactivation, or go without treatment for 
prevention of CMV reactivation. 
 
You may choose not to participate without penalty or loss of benefits to which you are 
otherwise entitled. 
 
9. What are the costs of taking part in this study? 
 
The study drug Letermovir will be provided by Merck and not billed to you/your insurance 
company. In addition, you will not be charged for tests/procedures performed solely for 
research purposes.  
     


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 8 of 13 
Form date: 
05/17/2019 
 
The drug Alemtuzumab will be billed to you/your insurance, in the usual manner. Most of the 
care you receive on this study is considered routine for your condition, because you would 
receive it even if you were not participating in a clinical trial.  
 
Participating in this research study may lead to additional costs to you.  In some cases, it is 
possible that your insurance company will not pay for these costs because you are taking part 
in a research study. You and/or your insurance company will be billed for all tests or 
procedures that are considered to routine service for your condition. You will be responsible 
for any deductibles, coinsurance or co-payments required by your health plan.  Before 
participating in this trial, we recommend that you ask your health plan if there are any 
limitations or restrictions to your coverage.  Your study doctor or coordinator can tell you 
which costs are covered by the study. 
 
10. Will I be paid for taking part in this study? 
 
You will not be paid for taking part in this study. 
 
11. What happens if I am injured because I took part in this study? 
 
If you suffer an injury from participating in this study, you should notify the researcher or 
study doctor immediately, who will determine if you should obtain medical treatment at 
The Ohio State University Wexner Medical Center.   
 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
Ohio State University has no funds set aside for the payment of health care expenses for 
this study.  
 
12. What are my rights if I take part in this study? 
 
If you choose to participate in the study, you may discontinue participation at any time 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
legal rights you may have as a participant in this study. 
 
You will be provided with any new information that develops during the course of the 
research that may affect your decision whether or not to continue participation in the 
study. 
 
You may refuse to participate in this study without penalty or loss of benefits to which 
you are otherwise entitled.  
 
An Institutional Review Board responsible for human subjects’ research at The Ohio State 
University reviewed this research project and found it to be acceptable, according to 
applicable state and federal regulations and University policies designed to protect the 
rights and welfare of research participants. 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 9 of 13 
Form date: 
05/17/2019 
 
 
13. Will my de-identified information be used or shared for future research?   
 
Yes, they may be used or shared with other researchers without your additional informed 
consent.  
 
14. Will my study-related information be kept confidential? 
 
Efforts will be made to keep your study-related information confidential.  However, there 
may be circumstances where this information must be released.  For example, personal 
information regarding your participation in this study may be disclosed if required by state 
law.   
 
Also, your records may be reviewed by the following groups (as applicable to the 
research): 
• 
Office for Human Research Protections or other federal, state, or international 
regulatory agencies; 
• 
U.S. Food and Drug Administration; 
• 
The Ohio State University Institutional Review Board or Office of Responsible 
Research Practices; 
• 
The sponsor supporting the study, their agents or study monitors; and 
• 
Your insurance company (if charges are billed to insurance). 
 
If we find information that significantly impacts your health, we will share it with you.  If 
you have a CMV reactivation, your blood will be collected for CMV genotyping. Results 
of that will not significantly impact your health, but it may impact how your doctor wants 
to treat you, and they will discuss those findings with you if so.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search the website at 
any time.  
 
15. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
      RESEARCH PURPOSES  
 
I. What information may be used and given to others? 
 
• Past and present medical records; 
• Research records; 
• Records about phone calls made as part of this research; 
• Records about your study visits; 
• Information that includes personal identifiers, such as your name, or a number 
associated with you as an individual; 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 10 of 13 
Form date: 
05/17/2019 
 
• Information gathered for this research about: 
HIV / AIDS 
Hepatitis infection 
Other reportable infectious diseases 
Physical exams 
Laboratory, x-ray, and other test results 
Diaries and questionnaires 
• Records about any study drug you received; 
 
II. Who may use and give out information about you? 
 
Researchers and study staff.   
 
III. Who might get this information? 
 
• The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor; or  
• owned by the sponsor. 
• Authorized Ohio State University staff not involved in the study may be aware that 
you are participating in a research study and have access to your information; 
• If this study is related to your medical care, your study-related information may be 
placed in your permanent hospital, clinic, or physician’s office record; 
• Merck, who is providing letermovir for this study. 
 
IV. Your information may be given to: 
  
• The U.S. Food and Drug Administration (FDA), Department of Health and Human 
Services (DHHS) agencies, and other federal and state entities; 
• Governmental agencies in other countries; 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported; and  
• The Ohio State University units involved in managing and approving the research 
study including the Office of Research and the Office of Responsible Research 
Practices. 
 
V. Why will this information be used and/or given to others? 
 
• To do the research;  
• To study the results; and  
• To make sure that the research was done right.   
 
VI. When will my permission end? 
 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 11 of 13 
Form date: 
05/17/2019 
 
There is no date at which your permission ends. Your information will be used 
indefinitely. This is because the information used and created during the study may be 
analyzed for many years, and it is not possible to know when this will be complete. 
 
VII. May I withdraw or revoke (cancel) my permission? 
 
Yes. Your authorization will be good for the time period indicated above unless you 
change your mind and revoke it in writing. You may withdraw or take away your 
permission to use and disclose your health information at any time. You do this by 
sending written notice to the researchers. If you withdraw your permission, you will not 
be able to stay in this study. When you withdraw your permission, no new health 
information identifying you will be gathered after that date. Information that has already 
been gathered may still be used and given to others. 
 
VIII. What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to be in this research study and receive research-related 
treatment.  However, if you are being treated as a patient here, you will still be able to 
receive care. 
 
IX. Is my health information protected after it has been given to others? 
 
There is a risk that your information will be given to others without your permission. Any 
information that is shared may no longer be protected by federal privacy rules. 
 
X. May I review or copy my information? 
 
Signing this authorization also means that you may not be able to see or copy your study-
related information until the study is completed.   
 
 
16. Who can answer my questions about the study? 
 
For questions, concerns, or complaints about the study, or if you feel you have been 
harmed as a result of study participation, you may contact Dr. John Reneau at 614-293-
3196 (office hours) or 614-293-8000 (24 hours). 
 
For questions related to your privacy rights under HIPAA or related to this research 
authorization, please contact:   
HIPAA Privacy Manager 
The Ohio State University Medical Center 
600 Ackerman Road 
Suite E2140  


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 12 of 13 
Form date: 
05/17/2019 
 
Columbus, OH 43202  
614-293-4477 
 
For questions about your rights as a participant in this study or to discuss other study-
related concerns or complaints with someone who is not part of the research team, you 
may contact the Office of Responsible Research Practices at 1-800-678-6251. 
 
If you are injured as a result of participating in this study or for questions about a study-
related injury, you may contact Dr. John Reneau at 614-293-3196 (office hours) or 614-
293-8000 (24 hours). 
 


CONSENT & 
AUTHORIZATION 
 
 
 
IRB Protocol Number: 
2020C0070 
IRB Approval date:  18 Aug 2023 
Version:  14 Aug 2023  
 
 
Page 13 of 13 
Form date: 
05/17/2019 
 
Signing the consent form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this 
combined consent and HIPAA research authorization form. 
 
 
 
 
 
Printed name of participant 
 
Signature of participant 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for 
participant (when applicable) 
 
Signature of person authorized to consent for participant  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the participant 
 
Date and time 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
to the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time