A Multi-Site, Randomized Trial of Subject-Collected Dried Blood Spot CMV Testing With Mobile Technology Support to Optimize Preemptive Therapy Late After Allogeneic HCT
Phase: NA
Conditions: Cytomegalovirus Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol Number 16-0098 
 
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A MULTI-SITE, RANDOMIZED TRIAL OF  
SUBJECT-COLLECTED DRIED BLOOD SPOT CMV TESTING WITH 
MOBILE TECHNOLOGY SUPPORT TO OPTIMIZE PREEMPTIVE 
THERAPY LATE AFTER ALLOGENEIC HCT 
DMID Protocol Number: 16-0098  
DMID Funding Mechanism: Contract: HHSN272201600015C 
IDE Sponsor: Division of Microbiology and Infectious Diseases, 
National Institute of Allergy and Infectious Disease, 
National Institutes of Health 
Lead Principal Investigator: Michael Boeckh, MD 
DMID Clinical Project Managers: Walla Dempsey, PhD and 
 
 
                       Amber Linde, PhD 
 
DMID Medical Monitor: Tatiana Beresnev, MD 
 
Draft or Version Number: 5.0 
Day Month Year:  30 June 2022 
 
 

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STATEMENT OF COMPLIANCE 
This study will be carried out in compliance with the protocol and in accordance with Good 
Clinical Practice (GCP) and as required by the following: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects  
• Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50, 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical 
Investigators), 21 CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 
CFR Part 812 (Investigational Device Exemptions) 
• International Conference on Harmonization: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 
(NIAID) Clinical Terms of Award, as applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 
 

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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. I 
agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of subjects. 
 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Investigator Name 
Investigator Title 
 
 
 

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TABLE OF CONTENTS 
Statement of Compliance .................................................................................................................2 
Signature Page .................................................................................................................................3 
Table of Contents .............................................................................................................................4 
List of Abbreviations .......................................................................................................................8 
Protocol Summary .........................................................................................................................10 
1 
Key Roles ..............................................................................................................................12 
2 
Background Information and Scientific Rationale ...............................................................15 
 
Background Information ...........................................................................................15 
 CMV .............................................................................................................16 
 Importance and Risk Factors for Late CMV Disease after HCT ..................16 
 Outcome of Late CMV .................................................................................17 
 Approaches to Prevent Late CMV Disease ..................................................18 
 Dried Blood Spot CMV Testing ...................................................................20 
 Mobile Communication ................................................................................22 
 
Rationale ...................................................................................................................23 
 
Potential Risks and Benefits .....................................................................................23 
 Potential Risks ..............................................................................................23 
 Known Potential Benefits .............................................................................23 
3 
Objectives .............................................................................................................................24 
 
Study Objectives .......................................................................................................24 
 Primary Hypothesis .......................................................................................24 
 Primary Objective .........................................................................................24 
 Secondary Objectives....................................................................................24 
 Exploratory Objectives .................................................................................24 
 
Study Outcome Measures .........................................................................................25 
 Primary Outcome Measures ..........................................................................25 
 Secondary Outcome Measures ......................................................................25 
 Exploratory Outcome Measures ...................................................................25 
4 
Study Design .........................................................................................................................26 
 
Randomized Cohort ..................................................................................................28 
 
Observational Cohort ................................................................................................29 
5 
Study Enrollment and Withdrawal........................................................................................31 
 
Subject Inclusion Criteria .........................................................................................31 
 Randomized Cohort ......................................................................................31 
 Observational Cohort ....................................................................................33 
 
Subject Exclusion Criteria ........................................................................................34 

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 Randomized Study ........................................................................................34 
 Observational Cohort ....................................................................................34 
 
Treatment Assignment Procedures ...........................................................................35 
 Randomization Procedures ...........................................................................35 
 Masking Procedures ......................................................................................35 
 Reasons for Withdrawal ................................................................................35 
 Handling of Withdrawals ..............................................................................36 
6 
Study Intervention/Investigational Product ..........................................................................37 
 
Study Product Description ........................................................................................37 
 DBS Self-Collection Kit ...............................................................................37 
 CMV PCR .....................................................................................................37 
 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ......................................................................................................................38 
 
Concomitant Medications/Treatments ......................................................................38 
 Randomization ..............................................................................................38 
 Quarterly Follow-Up .....................................................................................39 
7 
Study Schedule......................................................................................................................40 
 
Screening...................................................................................................................40 
 
Enrollment/Baseline and Initial Study Visit .............................................................40 
 Enrollment and Initial Study Visit Procedures for Randomized DBS 
Arm ...............................................................................................................41 
 Enrollment Procedures for Randomized Standard of Care (SOC) Arm .......41 
 Enrollment Procedures for Observational Cohort.........................................41 
 
Weekly DBS Testing ................................................................................................41 
 
Questionnaires...........................................................................................................42 
 Subject Questionnaire ...................................................................................42 
 Provider Questionnaire .................................................................................42 
 
Follow-up (Quarterly, ± 2 weeks) .............................................................................43 
 
Final Study Visit .......................................................................................................43 
 
Hospitalizations.........................................................................................................44 
8 
Study Procedures/Evaluations ..............................................................................................45 
 
Laboratory Evaluations .............................................................................................45 
 Clinical Laboratory Evaluations ...................................................................45 
 Special Assays or Procedures .......................................................................45 
 Specimen Preparation, Handling, and Shipping ...........................................45 
9 
Assessment of Safety ............................................................................................................47 
 
Adverse Events .........................................................................................................47 
 
Serious Adverse Event of Special Interest (SAESI) .................................................47 

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Unanticipated Problems ............................................................................................48 
 
Type and Duration of Follow-up of Subjects after Adverse Events .........................49 
 
Safety Oversight........................................................................................................49 
 Data and Safety Monitoring Board (DSMB) ................................................49 
10 
Monitoring ............................................................................................................................51 
 
Study Kit Monitoring ................................................................................................51 
11 
Statistical Considerations ......................................................................................................52 
 
Study Outcome Measures .........................................................................................52 
 Primary Endpoint ..........................................................................................52 
 Secondary Endpoint ......................................................................................53 
 
Sample Size Considerations ......................................................................................53 
 
Participant Enrollment and Follow-Up .....................................................................55 
 
Randomization Scheme ............................................................................................55 
 
Analysis Plan ............................................................................................................55 
 Interim Safety Monitoring ............................................................................56 
12 
Source Documents and Access to Source Data/Documents .................................................57 
13 
Quality Control and Quality Assurance ................................................................................58 
14 
Ethics/Protection of Human Subjects ...................................................................................59 
 
Ethical Standard ........................................................................................................59 
 
Institutional Review Board .......................................................................................59 
 
Informed Consent Process ........................................................................................59 
 Informed Consent/Assent Process (in Case of a Minor) ...............................61 
 
Exclusion of Women, Minorities, and Children (Special Populations) ....................62 
 
Subject Confidentiality .............................................................................................62 
 
Future Use of Stored Specimens ...............................................................................63 
 
Disclosure of Individual Research Information ........................................................64 
15 
Data Handling and Record Keeping .....................................................................................65 
 
Data Management Responsibilities...........................................................................65 
 
Data Capture Methods ..............................................................................................65 
 
Types of Data ............................................................................................................65 
 
Timing/Reports .........................................................................................................65 
 
Study Records Retention...........................................................................................66 
 
Protocol Deviations ...................................................................................................66 
16 
IDE Reporting Requirements and Procedures ......................................................................67 
 
Reporting to FDA, investigators and IRBs for Study Conducted Under IDE ..........67 
 
Investigator required reporting .................................................................................67 
17 
Publication Policy .................................................................................................................68 
18 
Literature References ............................................................................................................69 

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Appendix A: DBS CMV PCR Assay Comparison ........................................................................74 
Appendix B: Definition of End-Organ CMV Disease .................................................................753 
Appendix C: Schedule of Events ...................................................................................................76 
Appendix D: Safety Reporting.....................................................................................................785 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ASBMT 
American Society for Blood and Marrow Transplantation 
CDC 
(U.S.) Centers for Disease Control and Prevention 
CDS 
Collaborative Data Services 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
CRF 
Case report form 
CRO 
Contract research organization 
DBS 
Dried blood spots 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
DMID-CROMS 
(NIAID) DMID, Clinical Research Operations and 
Management Support 
DSMB 
Data and Safety Monitoring Board 
EBMT 
European Society for Blood and Marrow Transplantation 
FDA 
(U.S.) Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GVHD 
Graft versus host disease 
HCT 
Hematopoietic cell transplantation 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
Human leukocyte antigen 
ICH 
International Conference on Harmonisation 
IDSA 
Infectious Disease Society of America 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-treat 
JAMA 
Journal of the American Medical Association 
LPS 
Lipopolysaccharide 
mITT 
Modified intent-to-treat 
MOP 
Manual of Operations 
N 
Number (typically refers to subjects) 
NEJM 
New England Journal of Medicine 

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NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, 
DHHS 
OHRP 
Office for Human Research Protections 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PTID 
Participant identification number 
qPCR 
Quantitative polymerase chain reaction 
SAE 
Serious adverse event 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Study Monitoring Committee 
SOP 
Standard operating procedures 
TNF-α 
Tumor necrosis factor alpha 
USPS 
United States Postal Services 
 
 

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PROTOCOL SUMMARY 
Title:    
A multi-site randomized trial of subject-collected CMV dried 
blood spot testing with mobile technology support to optimize 
preemptive therapy late after allogeneic HCT 
Population: 
150 allogeneic hematopoietic cell transplantation (HCT) 
recipients ≥15 years of age, who are considered by their 
transplant team to be at risk for late cytomegalovirus (CMV) 
disease and are recommended to continue CMV monitoring after 
day 100 post-transplant 
Number of Sites: 
4 
Study Duration: 
4.5 years 
Subject Participation 
Duration: 
6-10 months 
Description of Intervention: 
CMV polymerase chain reaction (PCR) testing of a Dried Blood 
Spot (DBS) Sample 
Objectives: 
 
Primary Objective: 
˗ 
To evaluate adherence to recommended CMV monitoring 
duration and interval during the first year after transplant 
upon enrollment using subject self-collected dried blood spot 
testing 
Secondary Objectives: 
Evaluate the mean difference between the recommended 
monitoring that each subject completes between the DBS 
and the control arm 
Compare the incidence of CMV disease between the DBS 
monitoring and standard of care arms 
Evaluate the safety of DBS monitoring 

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Description of Study Design: This is a randomized clinical trial to assess whether a subject 
centered, self-collection of DBS samples will improve 
compliance with the clinical recommendation of weekly CMV 
testing of HCT recipients who are at high risk for late CMV 
disease. Subjects will be randomized (2:1) to DBS monitoring or 
standard of care (per local institution) monitoring. Subjects in the 
DBS arm will receive training on the collection and shipment of 
the sample to a central laboratory for CMV PCR testing. 
Periodic whole blood samples also will be collected along with a 
DBS sample for plasma CMV PCR testing. Subjects in the 
standard monitoring arm will be followed per standard of care 
monitoring for their transplant center. Data from the CMV 
testing done at the local site will be collected from the subject’s 
chart. 
Estimated Time to Complete 
Enrollment: 
18-24 months 
 
 

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1 
KEY ROLES 
Individuals: 
Lead Principal Investigator:  
 
Michael Boeckh, MD 
Member and Head, Infectious Disease Sciences Program 
Vaccine and Infectious Disease Division, 
Fred Hutchinson Cancer Research Center 
Professor, Medicine (Infectious Diseases), 
University of Washington School of Medicine 
1100 Fairview Ave. N, E4-100, 
Seattle, WA  98109-1024 
 
DMID Clinical Project Managers and Scientific Leads: 
 
Walla Dempsey, PhD 
DMID/NIAID/NIH 
Virology Branch 
5601 Fishers Lane, Room 8E57 
Rockville, MD  20852-9825 
 
Amber Linde, PhD 
DMID/NIAID/NIH 
Virology Branch 
5601 Fishers Lane, Room 8E57 
Rockville, MD  20852-9825 
Medical Officer/Monitor: 
 
Tatiana Bresenev, MD 
Office of Clinical Research Affairs 
DMID/NIAID/NIH 
5601 Fishers Lane, Room 7E50 
Bethesda, MD  20892-9826 
 
 

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Institutions: 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, 
New York, NY  10065 
Genovefa Papanicolaou, MD 
Member, Infectious Disease Service, 
Memorial Sloan Kettering Cancer Center 
Professor, Medicine (Infectious Diseases), 
Weill Medical College of Cornell University 
University of Minnesota 
420 Delaware Street, SE, MMC 250, 
Minneapolis, MN  55455 
Jo-Anne Young, MD 
Professor, Medicine (Infectious Diseases and Internal Medicine), 
University of Minnesota Medical School 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave N, D5-290, 
Seattle, WA  98109 
Mary E. D. Flowers, MD 
Member, Clinical Research Division, 
Fred Hutchinson Cancer Research Center 
Professor, Medicine (Oncology), 
University of Washington School of Medicine 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Box 402, 
Houston, TX  77030 
Roy Chemaly, MD, MPH 
Professor, Department of Infectious Diseases, Infection Control 
and Employee Health, Division of Int. Medicine, 
University of Texas, MD Anderson Cancer Center 

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Study Device Assembly 
and Distribution 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave N, E4-100 
Seattle, WA  98109 
Central Laboratory 
University of Washington Molecular Virology Laboratory 
1616 Eastlake Ave E, Suite 320 
BOX 358115 
Seattle, WA  98102-3795 
Statistical Data 
Coordinating Center 
The Emmes Corporation 
400 N. Washington Street, Suite 700 
Rockville, MD  20850 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
Despite strong evidence that preemptive therapy is highly effective in preventing 
cytomegalovirus (CMV) end organ disease after HCT, CMV monitoring adherence decreases 
significantly after day 100, when patients typically leave the care of the transplant team. 
Preliminary data (section 2.1.4.) indicate that fewer than 50% of patients who are 
recommended to continue CMV testing do so throughout the recommended testing period; 
the drop-off starts as soon as two months after discharge. Consequently, the incidence of late 
CMV end organ disease (defined as disease occurring after day 100 after HCT) remains high 
at 8% in the current era with recommended surveillance testing and preemptive therapy. Half 
these cases are CMV pneumonia, which continues to carry a substantial risk of death (section 
2.1.3). In a recent multicenter randomized trial of prophylaxis compared to preemptive 
therapy for the prevention of late CMV disease the incidence of late CMV disease was only 
2% 1. During the trial, study coordinators were in close contact with study subjects, resulting 
in a CMV monitoring completion rate of 93%. Similarly, high rates of adherence are also 
routinely achieved during the first 3 months after HCT while patients are treated in 
specialized cancer centers, and these adherence rates correlate with CMV disease rates 
between 0 and 3%. However, outside of the clinical trial setting, the requirement for weekly 
blood draws is burdensome for patients late after HCT. In general, the frequency of CMV 
monitoring decreases as the frequency of doctor’s office visits decreases, resulting in missed 
opportunities for preemptive therapy. Finger-stick collected DBS CMV testing would allow 
subjects to collect their samples at home and mail the cards directly to the laboratory. This 
method of CMV PCR testing has been validated in transplant recipients and has sufficient 
sensitivity to detect viral loads appropriate for a preemptive therapy approach late after 
transplantation 2,3. 
In addition, mobile technology can be used to automate simple reminder and notification 
systems and to facilitate ongoing communication among the patient, their primary oncologist, 
and the transplant center. There is good evidence 4,5 that these types of reminders are 
efficacious for improving medication adherence; however, it has not yet been tested in the 
setting of post-transplant virologic monitoring. 
 

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 CMV 
CMV is a human herpesvirus known to infect 50-90% of US adults and is a major 
cause of morbidity and mortality in immunocompromised population. CMV infection 
can be acquired through multiple means, including: mother-to-child (in utero, breast 
milk), infected body fluids (saliva, genital secretions), blood transfusion, or organ 
transplant. The prevalence of CMV infection increases with age throughout life such 
that by age 90; ~90% of persons will have acquired CMV infection 6. In 
immunocompetent persons, following primary infection by any of the routes noted 
above, CMV is controlled by the immune system and establishes latency 
(“dormancy”) in multiple organs and cell-types for the life of the host. In particular, 
the lung represents one of the largest reservoirs of latent CMV in seropositive hosts, 
and may explain the propensity for CMV-associated pulmonary disease in 
predisposed hosts 7. During periods of immunosuppression (or as a result of specific 
stimuli such as TNF-α, LPS, or catecholamines that are commonly associated with 
critical illness and sepsis 8), CMV can reactivate from latency (preferentially in the 
lung) to produce active infection (viral replication). In persons with impaired cellular 
immunity, reactivation can progress to high-grade CMV replication, tissue injury, and 
clinically evident disease such as CMV pneumonia. Lower-grade CMV reactivation 
that is otherwise clinically silent (“subclinical”) can also be detected in apparently 
immunocompetent persons with critical illness using sensitive techniques such as 
PCR 1. In addition, even low-level, otherwise asymptomatic subclinical CMV 
reactivation can produce significant biologic effects both in vitro and in vivo, such as 
inflammation, fibrosis, and immunosuppression. These biological effects of CMV 
have been shown to occur through various mediators and other indirect means 
(reviewed in 9). Importantly, several important CMV-associated adverse clinical 
outcomes in transplant populations (e.g. allograft rejection, secondary infections) are 
not necessarily accompanied by overt CMV disease and can only be detected by 
relatively sensitive means of virus detection such as PCR 10–12. 
 Importance and Risk Factors for Late CMV Disease after HCT 
The phenomenon of late CMV disease was first recognized in the early 1990s when 
the first reports were published about effective prevention of early CMV disease, and, 
at the same time, cases of delayed onset CMV disease were observed 13. Since then, a 
substantial body of literature indicates that CMV disease can be prevented during the 
first 3 months after HCT when antiviral agents are given prophylactically at 
engraftment or pre-emptively for pp65 antigenemia or detection of CMV DNA by 
PCR, with improved survival in selected high-risk patients 14,15. However, once 

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prophylaxis is stopped or the preemptive strategy is applied less rigorously, CMV 
disease incidence rises again. As a result, the majority of CMV disease now occurs 
after day 100, resulting in a much longer period of high risk 2,3,14,16–19. Late CMV 
disease (defined as disease presenting after day 100 after HCT) occurs primarily 
between day 100 and day 365 after transplant. Both late CMV infection and disease 
remain independent predictors for mortality after HCT, even though patients at 
highest risk for late CMV infection and disease can be identified by day 100 2. 
Without intervention, the incidence of late CMV disease ranges from about 10% to 
17% of CMV seropositive recipients who are alive at day 100 2. Mechanistically, 
lymphopenia and delayed reconstitution of CMV-specific T-cell responses are the 
immunologic defects that predispose patients to late CMV complications 2. In 
seronegative recipients with a positive donor (D+/R-), late CMV disease seems to 
occur almost exclusively in patients who had evidence of primary CMV infection 
during the first 100 days and the incidence of late CMV disease is similar to that 
observed in CMV seropositive recipients 3. 
Approximately 50% of patients with late CMV disease present with pneumonia, 
followed by gastrointestinal disease (40%) and other manifestations such as retinitis, 
encephalitis, and late graft failure 3. 
 Outcome of Late CMV  
The outcome of late disease remains poor, and late CMV disease is an independent 
risk factor for mortality in CMV seropositive recipients (adjusted hazard ratio 4.16 
[95% confidence interval 2.7-6.5]) 3. The outcome following pneumonia is worse 
than that following other manifestations of late CMV disease with 60% of patients 
dying within 6 months of late CMV pneumonia (Figure 1) 3,20. In a recent 
multivariate analysis, the outcome of CMV pneumonia occurring in the late period 
was not different from that early after HCT 20. 

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Figure 1. Kaplan-Meier plot of overall survival after late CMV disease, by 
disease type (n=117) 
 Approaches to Prevent Late CMV Disease 
Although preemptive therapy based on virologic monitoring is the most commonly 
used strategy to prevent CMV disease during the first 3 months after HCT 21, 
maintaining regular weekly monitoring is often difficult late after HCT. Indeed, 
preliminary data demonstrate that outside a clinical trial setting (during which 
surveillance can be reinforced by study personnel), adherence to recommended 
surveillance recommendations is poor (Figure 2). This poor adherence is associated 
with continued high rates of late CMV disease. 
There is compelling data from both cohort studies and multicenter clinical trials, that 
preemptive therapy strategies are highly effective when administered properly (Table 
1). Moreover, a recent study showed excellent performance for PCR-based 
preemptive therapy (started at a plasma viral load ≥1000 IU/mL) 22. In this study, the 
CMV disease incidence was similar to what has been accomplished in other recent 
multicenter randomized trials early after HCT (Table 1).  This represents the first 
documentation in a randomized trial that preemptive therapy in the late setting can be 
highly effective if virologic monitoring is performed at >90% of expected time 
points. This rate contrasts starkly with what has been achieved with patients outside 
the clinical trial setting and provides the rationale for the key hypothesis of this 
proposal that home-based, mobile technology supported virologic monitoring will 

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result in adherence rates associated with effective preemptive treatment strategies (see 
Table 1). 
 
Figure 2. Proportion of expected CMV monitoring tests performed by week after day 
100 (14 weeks) post-transplant in patients for whom extended monitoring is 
recommended (review of 1246 HCT recipients at risk of CMV disease) 
Table 1. Effectiveness of preemptive therapy strategies in recent randomized trials 
with high viral monitoring adherence (placebo group) 22–25 
 
Author 
Journal 
Year 
N 
Period CMV Disease Incidence 
Marty et al. 
Lancet ID 
2011 227 
Early 
2.4% 
Marty et al. 
NEJM 
2014 
59 
Early 
3.0% 
Chemaly et al. 
NEJM 
2014 
33 
Early 
0% 
Boeckh et al. 
Ann Int Med 2014 
89 
Late 
2.0% 
Several novel CMV prevention strategies are or have recently been under 
investigation, including new drugs (e.g., letermovir, brincidofovir, and maribavir) and 
CMV vaccines 23–28. It is unclear whether the drugs will be efficacious or will be 
suitable for long-term use due to unknown long-term toxicities and cost. In addition, 
even if effective and non-toxic new anti CMV drugs become available, long term use 
of these therapies may delay CMV-specific immune reconstitution or promote 
resistance 29,30, or, in the case of the vaccine, may be less effective in the most 

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immunosuppressed patients 28. Thus, for years to come viral monitoring will likely be 
an essential part of preemptive therapy strategies. 
 Dried Blood Spot CMV Testing 
DBS testing has been increasingly utilized to detect CMV in studies of congenital 
CMV by using stored Guthrie cards 31–33. Self-collection of samples using swabs to 
examine the biology of herpesviruses (including CMV) is well established in healthy 
volunteers and HIV-infected subjects. It is not known whether giving subjects the 
ability to self-collect samples will improve compliance or whether CMV monitoring 
via DBS testing is sufficiently sensitive to detect re-emergence of late occurring 
CMV viremia. 
2.1.5.1 Dried Blood Spot Assay Design History 
The DBS PCR assay was initially developed in 2001 using two primer/probe pairs, one of 
which amplifies the gB region and one the IE region of the CMV genome. Over the last 
10 years, this PCR assay has been extensively used in clinical research to study CMV 
infections of immunocompromised patients at both the University of Washington (UW) 
and the Fred Hutchinson Cancer Research Center (Fred Hutch) and has proven to be a 
valuable tool for detection and monitoring of CMV reactivation and clinical disease. 
2.1.5.2 Summary of DBS Assay Performance vs Standard Plasma PCR Clinical Assay 
The performance of the current DBS PCR assay was compared to an ultrasensitive 
plasma PCR assay (lower level of quantitation 50 IU/mL) that is used clinically at the 
University of Washington Clinical Virology Laboratory to monitor patients for CMV 
infection.  The standard used in the clinical PCR assay is the WHO International 
Standard for human cytomegalovirus (HCMV).  Residual whole blood samples from 
specimens that were submitted for clinical plasma PCR testing were also examined by the 
DBS assay. The primary goal of the study was to determine whether the DBS assay 
detected CMV DNA in whole blood samples that were determined to be positive at the 
1000 (3.0 log 10) IU/mL level in the clinical PCR assay, a level that is commonly used to 
trigger preemptive treatment of patients in the late period after hematopoietic cell 
transplantation (HCT).  As a secondary goal, the study also examined the ability of the 
DBS to detect CMV DNA in whole blood samples that are positive at the 500 (3.0 log10) 
IU/mL level, a level also used by some sites to start preemptive therapy.  
Residual samples from patients who had plasma viral loads ≥150 (2.18 log10) IU/mL 
were spotted on to filter cards (50uL).  The residual blood sample was used with 24-72 

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hours after the sample had been drawn.   A total of 145 clinical samples from 69 persons 
were collected and tested.  From the 145 clinical samples, 22 had plasma CMV viral load 
≥1000 IU/mL; 48 had known plasma CMV viral load ≥500 IU/mL and 97 had viral loads 
≤ 500 IU/mL . The results of the comparisons at two different thresholds are summarized 
in the table below. 
Table 2. Summary of DBS assay evaluation 
Clinical plasma PCR and DBS PCR results with different thresholds 
N /Total 
Clinical Plasma CMV PCR ≥500 (2.7 log10) IU/mL 
48/145 
Clinical plasma CMV PCR ≥500 IU/mL (2.7 log10) and DBS positive 
44/145  
(Clinical PCR range: 510-36000 [2.7-4.6 log10] IU/mL) 
 
Clinical plasma CMV PCR <500 IU/mL (2.7 log10) and ≥150 (2.18 log10) 
IU/mL 
97/145  
Clinical plasma CMV PCR <500 IU/mL (2.7 log10) and DBS positive 
59/145 
(Clinical PCR range: 41-490 [1.6-2.7 log10] IU/mL) 
 
Clinical plasma CMV PCR ≥1000 (3.0 log10) IU/mL 
22/145 
Clinical plasma CMV PCR ≥1000 (2.7 log10) IU/mL and DBS positive  21/145  
(Clinical PCR range: 1000-36000 [3.0-4.6 log10] IU/mL) 
  
Clinical plasma CMV PCR <1000 (3.0 log10) IU/mL and ≥150 (2.18 log10) 
IU/mL 
123/145  
Clinical plasma CMV PCR <1000 (2.7 log10) IU/mL and DBS positive  82/145  
(Clinical PCR range: 41-970 [1.6-2.9 log10] IU/mL) 
  
Samples with a viral load ≥1000 
(2.7 log10) IU/mL were positive 
on the DBS assay 95% of the time 
(21/22 samples). Samples with 
viral loads between 150 (2.18 
log10) IU/mL and 1000 (2.7 log10) 
IU/mL were positive at a lower 
rate (67%).   
The proportion of DBS CMV 
PCR positive samples relative 
to plasma PCR positive 
samples in different plasma 
viral load ranges is visually 
depicted in Figure 3. 
Figure 3. Distribution of DBS CMV PCR result based on plasma CMV 
viral load across different viral load ranges (columns).    
150-249
250-499
500-999
1000-9999
>10000
DBS Neg
15
23
3
1
0
DBS Pos
14
45
23
19
2
0
10
20
30
40
50
60
70
80
Number of Samples
CMV Plasma Quant (IU/mL)
DBS Pos
DBS Neg

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2.1.5.3 Limit of Detection 
Based on a complementary log-log model, the rate of detection or sensitivity of the DBS 
assay at 2.99 log10 IU/mL CMV in plasma is above 95% (Figure 4. Thus, the limit of 
detection would be about 2.98 logs or 102.98 = 955 IU/ml (see the reference lines at x-axis 
of 2.99 and y-axis of 0.95). Similar results are obtained compared to these only the first 
sample date was used per person (69 samples), with a cut off of 2.91 on the log10 scale or 
812 IU/mL. Based on this model, the sensitivity at 500 (2.70 log10) IU/mL is 85%, and 
the sensitivity at 1000 (3.00 log10) IU/mL is 96%. 
 
Figure 4. Complementary log-log model to compare CMV viral load in plasma and the 
sensitivity of DBS 
Overall, the results of the most recent study shown above as well as prior clinical results 
using earlier versions of the assay suggest that the DBS assay reliably detects viral loads 
of >1000 (3.0 log10) IU/mL highly reliably and that the sensitivity is somewhat lower 
between 500 (2.7 log10) and 1000 (3.0 log10) IU/mL.  
 Mobile Communication 
The use of mobile technology to increase adherence to medical therapies has 
increased dramatically in recent years 5. In this study, mobile technology will be used 

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to remind HCT survivors to perform CMV monitoring using finger-stick collected 
DBS testing in their home setting or to visit their doctor’s office to perform the test. 
 
Rationale 
Given accumulating evidence that preemptive therapy is effective against CMV disease in 
the HCT setting with high (i.e., 90%+) adherence to the recommended CMV testing schedule 
22,24,25,35, a critical question is whether innovative easy-to-perform self-testing assisted by 
mobile technology reminders can improve monitoring frequency to the high rates needed in 
the late setting without the hands-on support that is available in the early post-transplant 
setting. This is a proof-of-concept, multi-site, randomized clinical trial to test whether 
subject-collected dried blood spot samples for CMV PCR testing can improve adherence to 
recommended CMV monitoring late after transplant compared to the standard of care. The 
study will enroll HCT recipients following their discharge from their transplant center who 
are, therefore, at risk for late CMV disease. Assessing adherence in this population to the 
recommended CMV testing schedule is critical to evaluating whether adopting DBS self-
collection can improve the efficacy of preemptive therapy strategies and, therefore, 
potentially reduce the morbidity and mortality associated with late CMV disease. 
 
Potential Risks and Benefits 
 Potential Risks 
There are few potential risks associated with this study. Risk is primarily derived 
from the needle stick. The following table presents risks based on experience with 
self-administered finger stick procedures. In theory, there is a risk of missing CMV 
cases due to the sensitivity limit of the DBS tests. This information will be 
communicated to subjects in the sample informed consent form. 
Table 3. Summary of potential risks 
Less common 
Pain and/or bruising at puncture site 
Uncommon or rare 
Missed CMV cases due to sensitivity limits of DBS test 
Uncommon or rare 
Infection at puncture site 
 Known Potential Benefits 
Study subjects may benefit from more frequent CMV monitoring and, as a result, 
more timely and effective initiation of preemptive therapy for CMV disease. It is also 
possible, though, that a study subject may not derive any benefit from participation in 
this trial. 

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3 
OBJECTIVES 
 
Study Objectives 
 Primary Hypothesis 
Home-based, mobile technology supported virologic monitoring will result in 
adherence rates associated with effective preemptive strategies against late CMV end 
organ disease 
 Primary Objective 
To evaluate adherence to recommended CMV monitoring duration and interval 
during the first year after HCT upon enrollment using subject collected dried blood 
spot testing 
 Secondary Objectives 
1. Evaluate the mean difference between the recommended monitoring that each 
subject completes between the DBS and the control arm 
2. Compare the incidence of CMV disease between the DBS monitoring and 
standard of care arms 
3. Evaluate the safety of DBS monitoring 
 Exploratory Objectives 
1. Evaluate the transit time from self-collection to arrival in the laboratory 
2. Assess the mechanism for non-compliance as defined by a missing DBS sample 
PCR result (e.g. mobile technology failure, sample collection failure, sample 
delivery failure, sample viability failure) 
3. Compare the performance characteristics of concurrently drawn DBS with plasma 
CMV PCR (e.g., sensitivity and specificity concordance)  
4. Determine if the randomized study population is representative of the population 
as a whole  
5. Obtain a population-based estimate of late CMV disease in observational and 
randomized cohorts  
6. Describe local provider CMV treatment algorithms  
7. Assess subject and provider satisfaction of DBS testing  

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Study Outcome Measures 
 Primary Outcome Measures 
The number of participants who have completed >90% of their recommended CMV 
monitoring tests at one year after HCT in the DBS and control arms 
 Secondary Outcome Measures 
1. The total number of recommended CMV monitoring tests that were completed 
per subject by 1 year after HCT 
2. Number of subjects in DBS and standard of care arms with end-organ CMV 
disease, possible and proven/probable36 by 1 year after HCT (Appendix  and 
MOP); CMV syndrome will not be used to define CMV disease 
3. Number of subjects with finger-stick procedure-related Grade 3 AEs at 1 year 
after HCT  
 Exploratory Outcome Measures 
1. Mean time from scheduled pick-up at subject residence (DBS tests) or blood draw 
facility (plasma sample) to arrival at the laboratory (hours) at all applicable test 
points throughout the study period  
2. Number of mobile technology failures, sample collection failures, sample delivery 
failures, and sample viability failures.  
3. Sensitivity, specificity and predictive values of CMV detection in DBS versus 
plasma testing 
4. Number and type of key transplant characteristics in randomized subjects and 
observational subjects (Section 5.1)  
5. Describe the baseline patient demographics of randomized cohort and 
observational cohort.  
6. Number of participants with end-organ CMV disease (possible and 
proven/possible) at 1 year after HCT in randomized subjects and observational 
subjects  
7. Describe local provider CMV treatment viral load treatment thresholds 
8. Describe local provider CMV monitoring interval recommendations 
9. Report composite scores of different variables of subject and provider 
satisfactions according to the 5-point Likert scale questionnaires. 

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4 
STUDY DESIGN 
This is a randomized clinical trial to assess whether self-collection of samples (DBS) that are 
mailed for testing to a central laboratory will improve the compliance with the clinical 
recommendation of weekly CMV testing of HCT recipients. 150 allogeneic HCT recipients 
≥15 years of age, who are considered by their transplant teams to be at risk for late CMV 
disease and who are clinically recommended to continue CMV monitoring after day 100 
post-transplant, will be randomized (2:1) to subject self-collected DBS CMV monitoring 
with mobile technology support or standard of care with office-based testing. Randomization 
will occur when discharge from the transplant service is imminent, generally near day 100 
post-transplant (enrollment window day 60-180 post-transplant). DBS self-collections will 
start the week after discharge. More than 85% of late CMV disease occurs within the first 
year after HCT 37. While most patients are discharged to long-term primary care providers 
approximately 100 days after HCT, some may be discharged earlier, and some may stay 
longer with the transplant team due to complications. These latter patients are often at 
particularly high risk for late CMV complications and thus are important candidates for 
participation in this trial. For this reason, study entry is allowed up to 180 days (~6 months) 
after HCT and the duration of study participation is anticipated to be within a range of 26 
weeks to 43 weeks. 
The transplant centers participating in this study have either a standard process where 
transplant recipients are offered to sign a consent to allow data from their charts to be 
accessed for retrospective trials or a waiver of additional consents for accessing charts for 
retrospective trials. This offers an opportunity to assess whether the study sample is 
representative of HCT population as a whole and to obtain a population-based estimate of 
later CMV disease. Therefore, clinical charts from an additional 450 HCT recipients 
(Observational Cohort) who meet eligibility criteria and have already consented for 
retrospective studies at the enrolling sites but are not participating in the DBS testing for 
CMV will be reviewed for the incidence and timing of CMV disease, morphologic relapse of 
the underlying disease, and death. Data from these subjects will be used to assess whether the 
randomized study sample is representative of the DBS study population and to obtain a 
population-based estimate of late CMV disease. 

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Figure 5. Schematic of Study Design 
 
 

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Randomized Cohort 
Following consent, subjects in the DBS arm of the study will be asked to perform weekly 
DBS collection starting the week after discharge, once appropriate training has been provided 
(collection can be performed by a caregiver as long as appropriate training has been 
completed). Weekly reminders will be sent either as email or text messages. DBS samples 
will be mailed directly to the central lab (University of Washington) via pre-paid overnight 
mail (pick-up can be scheduled via the website or by phone through website) by the subjects. 
Results will be transmitted via a secure server to participating site staffs. The research staff 
will then contact the subjects’ treating physicians via phone/fax notifying of positive results. 
The subjects will receive a notification via the study web portal when their positive CMV test 
results are available with a link to the secure website that can be used to access them. Text 
message reminders have been effective in randomized trials of medication adherence 5,38,39, 
but too frequent reminders may be counterproductive. The web/mobile technology employed 
in this trial allows subjects to select method of electronic reminders (email and/or text 
message) and day and time of weekly electronic reminders. At minimum, one reminder will 
be sent before the recommended test. 
In addition to the DBS Self-Collection Kits, subjects will be provided with Confirmatory 
Whole Blood Collection Kits for a plasma CMV PCR test (one 6 ml EDTA tube and a DBS 
self-collection kit with shipping material). When subjects are notified of a positive DBS 
result (a reminder will be provided with the notification of positive test results) they will take 
the Confirmatory Whole Blood Collection kit to their clinical blood draw facility and get 
their samples collected as soon as possible. The clinical laboratory staff will draw the 
additional blood and use the pre-paid FedEx shipping kit to send the sample to the University 
of Washington Molecular Virology Laboratory for testing. Decisions whether to administer 
preemptive treatment based on plasma viral load results will be made by the primary care 
provider of the subject. At the time of office-based blood draw for research confirmatory 
plasma CMV PCR, the subject will perform an additional DBS test, which will be sent 
together with the plasma sample to the central lab. These samples will provide additional 
virologic data to assess performance of the DBS assay. This method has been used 
successfully in a recently completed phase III trial 22. 
Training of participants on the DBS self-collection procedures will include three training 
sessions with a study coordinator. The first session will describe, observe, and provide 
guidance on DBS self-collection procedures and web/mobile technology. The second session 
will be a supervised session with the subject to observe and answer questions. It is preferable 
that supervised DBS trainings with a study coordinator are done in-person; however, if this is 

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not possible these supervised trainings may be completed remotely via video conferencing as 
an option (See MOP for details and instructions). The third session will be unsupervised with 
the subject performing the testing in their home or temporary residence nearby the transplant 
center This training session will be followed up with a phone call or in-person check-in and a 
questionnaire to assess understanding. At each session, the subject will have written 
instructions on performing the DBS testing and utilizing the web/mobile technology 
available for their reference. Each DBS training session requires the completion of a DBS 
collection. The study coordinator will be available to provide additional training session as 
needed. In addition, DBS collection instructional video is available on the study website. 
Prior to discharge from the transplant care team, study personnel must confirm that the 
subject demonstrates proficiency in DBS sample collection and use of the study website. 
The mobile technology will consist of a notification system that sends weekly reminders by 
email and/or text message determined by the subject’s preference to the subject to complete 
DBS self-collection procedures. The notifications are sent from a web-based, 21 CFR 11-
compliant electronic data capture system created and maintained by The Emmes Company. 
The subject will log into the system on a computer or mobile device with internet access to 
set up study reminders and record sample collection and shipment information. The system 
will also house IRB-approved training materials and the web address of the United States 
Postal Services (USPS) so that shipments may be scheduled. 
Subjects who are enrolled in the control arm of the randomized study will continue to receive 
their office-based CMV plasma testing as recommended by standard of care. 
Quarterly follow-up contacts will be made with the primary care physicians of all 
randomized subjects enrolled in the study to obtain each subject’s medical record. Data from 
each subject’s medical record on immunosuppression, CMV disease status, any interim use 
of antiviral therapy for CMV disease or plasma reactivation, clinically recommended CMV 
test interval, any hospitalization record, relapse, and survival status will be collected. 
 
Observational Cohort 
A parallel observational contemporary cohort will be established of up to 450 transplant 
recipients who are eligible for enrollment but declined participation as part of the randomized 
cohort and/or have consented at their site to have data from their charts abstracted for 
retrospective studies and meet entry criteria for the randomized trial. Selection of eligible 
subject charts will be based on similar criteria to the randomized study and will include 
subjects who qualified for the study but did not provide consent.  Eligible participants 
meeting those criteria will be included in an observational study. 

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To allow data extraction for this observational cohort, each participating site must have on 
record with their IRBs either:  
• 
A general consent for the review of medical records for retrospective studies that can 
be utilized for this activity, or 
A waiver of additional consent for the review of medical records for retrospective studies 
linked to this protocol. Data from each subject’s medical record on immunosuppression, 
steroid use, CMV disease status, any interim use of antiviral therapy for CMV disease or 
plasma reactivation, clinically recommended CMV test interval at time of discharge,  
morphological relapse, and survival status will be collected at approximately one year post 
transplant date. Data to be abstracted from the charts will cover an equivalent length of time 
as those subjects enrolled in the randomized study (i.e. until 1 year after HCT). 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Approximately, 150 allogeneic HCT recipients ≥15 years of age, who are considered by their 
transplant team to be at risk for late CMV disease as defined in the entry inclusion criteria 
and recommended to continue CMV monitoring after 100 days post-transplant, will be 
enrolled in the study. These individuals will be randomized (2:1) to subject collected DBS 
CMV monitoring with mobile technology support or standard care with office-based testing. 
Recruitment of subjects will follow local recruitment and enrollment policies and procedures. 
The study sites will request a waiver of informed consent and a waiver of HIPAA 
Authorization for pre-screening purposes (to determine CMV sero- and reactivation status) 
from their local Institutional Review Board (IRB). Upon approval of both waivers, research 
staff will review the electronic medical records to pre-screen subjects who will undergo or 
have undergone an allogeneic hematopoietic cell transplant (HCT). Pre-screening will be 
done by trained and experienced research staff who will review the electronic charts using a 
standardized screening tool. In addition, potential subjects may be identified by the attending 
physician (or team) based on the eligibility criteria approximately one month prior to 
anticipated discharge from the primary transplant team. If a subject is identified as meeting 
the inclusion/exclusion criteria, the PI or designee will explain the study and will seek 
informed consent to study participation. 
Retention efforts will focus on the interval between enrollment/randomization and discharge 
from the transplant team and start of diagnostic monitoring. Since adherence is a key study 
endpoint, direct contact between site personnel and study subjects will be kept as equal as 
possible between the two arms to avoid biasing the comparison of CMV monitoring 
adherence. 
 
Subject Inclusion Criteria  
 Randomized Cohort 
• Must be ≥15 years of age at the time of enrollment 
• Must be able to provide written consent and complete the informed consent  
• Must have received allogeneic hematopoietic cell transplantation within 60-180 
days prior to randomization 
• CMV seropositive or had a donor who was CMV positive 

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• One or both of the following: 
o CMV event1 within the first 100 days post-transplant requiring anti-viral 
treatment 
o Receipt of CMV prophylaxis2 (for at least 30 days) prior to randomization. 
Continuation of letermovir or acyclovir/valacyclovir (high and low dose) 
prophylaxis after day 100 per institutional standard of care is permitted.  
1 CMV event defined as DNA detection or disease 
2Anti-viral treatment or prophylaxis includes ganciclovir, valganciclovir, 
foscarnet, letermovir, maribavir or acyclovir/valacyclovir (high and low dose) 
• Direct availability to the internet either by a computer in the residence or a smart 
phone 
• Had at least one or more of these conditions: 
o HLA mismatch3 
o Umbilical cord blood source4 
o GVHD5  
o T-cell depletion6  
3Human leukocyte antigen (HLA)-related(sibling) donor with at least one mismatch at one of 
the following three HLA-gene loci: HLA-A, -B or -DR, Haploidentical donor, Unrelated 
donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C 
and -DRB1 
4Use of umbilical cord blood as stem cell source 
5Acute or chronic GVHD requiring topical steroid for GI GVHD and/or systemic steroid 
treatment (>1mg/kg/day of prednisone or equivalent dose of another corticosteroid) within 6 
weeks prior to enrollment  
6Subjects who have received partial or full T-cell depletion (with or without GVHD). T-cell 
depletion can be given as either ex-vivo or in-vivo for GVHD prophylaxis. T-cell depleting 
agents include, but are not limited to, anti-thymocyte globulin (ATG) and alemtuzumab.  

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 Observational Cohort 
• Must be ≥15 years of age at the time of enrollment 
• Must have one of the following:  
o Consented for retrospective studies at their transplant center, or 
o Be included under the auspices of the site’s IRB approved waiver of 
additional consent for retrospective studies 
• Must have received allogeneic hematopoietic cell transplantation  during or within 
1 year prior to the conduct of the randomized trial (defined as time during which 
randomization is done).  
• CMV seropositive or had a donor who was CMV positive 
• One or both of the following: 
o CMV event1 within the first 100 days post-transplant requiring anti-viral 
treatment. 
• Receipt of CMV prophylaxis2 (for at least 30 days) prior to 
registration. Continuation of letermovir prophylaxis or 
acyclovir/valacyclovir (high and low dose) after day 100 per 
institutional standard of care is permitted.  
1 CMV event defined as DNA detection or disease 
2Anti-viral treatment or prophylaxis includes ganciclovir, valganciclovir, 
foscarnet, letermovir, maribavir or acyclovir/valacyclovir (high and low dose) 
• Meet one or more criteria of the following: 
o HLA mismatch3 
o Umbilical cord blood source4 
o GVHD5  

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o T-cell depletion6  
3Human leukocyte antigen (HLA)-related(sibling) donor with at least one mismatch at one of 
the following three HLA-gene loci: HLA-A, -B or -DR, Haploidentical donor, Unrelated 
donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C 
and -DRB1 
4Use of umbilical cord blood as stem cell source 
5 Acute or chronic GVHD requiring topical steroid for GI GVHD and/or systemic steroid 
treatment (>1mg/kg/day of prednisone or equivalent dose of another corticosteroid) within 6 
weeks prior to enrollment  
6 Subjects who have received partial or full T-cell depletion (with or without GVHD). T-cell 
depletion can be given as either ex-vivo or in-vivo for GVHD prophylaxis. T-cell depleting 
agents include, but are not limited to, anti-thymocyte globulin (ATG) and alemtuzumab.   
 
 
Subject Exclusion Criteria 
 Randomized Study 
• Inability to fully comprehend the study website and study procedures 
• Any other condition, which in the opinion of the investigator would interfere with 
successful completion of this clinical trial  
• Morphological relapse (bone marrow or peripheral blood blast) prior to 
registration. 
  Observational Cohort  
• Did not meet all inclusion criteria 
• Morphological relapse (bone marrow or peripheral blood blast) prior to 
registration. 
 

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Treatment Assignment Procedures 
 Randomization Procedures 
Subjects will be randomized in a 2:1 ratio to subject-collected DBS CMV monitoring 
with mobile technology support (n=100) or standard care with office-based testing 
(n=50). Additional subjects will be enrolled as retrospective observational controls and 
will not be randomized (n=450). The list of randomized treatment assignments will be 
prepared by statisticians at The Emmes Corporation (Emmes) and included in the 
enrollment module of Emmes’ Internet Data Entry System (IDES). IDES will assign each 
subject a study arm from the list after demographic (date of birth, race/ethnicity, and sex) 
and eligibility data have been entered into the system. Randomization will be stratified by 
transplant site and subject’s perceived ease of access to blood draw facility. 
Observational cohort will be enrolled in IDES after the required demographic and 
eligibility information are entered. Instructions for use of the enrollment module are 
included in the IDES User’s Guide. Manual back-up randomization procedures are 
provided in the MOP for use in the event that the site temporarily loses access to the 
Internet or the online enrollment system is unavailable. 
Subject IDs will be assigned to potential subjects, who have documented informed 
consent by signing an Informed Consent form, as they are screened. The subject ID will 
be used for all communications with outside institutions to ensure confidentiality. 
Subjects who are randomized and drop out of the study prior to beginning follow-up (first 
scheduled test both arms) will be replaced. Over-enrollment is allowed to accommodate 
competitive enrollment and accommodate replacement subjects. 
 Masking Procedures 
None 
 Reasons for Withdrawal 
Any enrolled subject may withdraw or be withdrawn from the study for the following 
reasons: 
 The subject (guardian) withdraws consent 
 The study is terminated 
 Subject fails to demonstrate proficiency in DBS sample collection  

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 For any reasons that, in the opinion of the investigator, precludes the 
subject’s participation in the study 
 Subject has been enrolled inappropriately based on inclusion/exclusion 
criteria; these subjects may be replaced, or 
 Initiation of end of life care 
 If the subject has morphological relapse prior to the start of study related 
CMV surveillance testing.  
 
Subjects may withdraw from participation in the study at any time. If a subject withdraws 
or is withdrawn prior to completion of the study, the reason for this decision must be 
recorded in the case report forms (CRFs), although it is recognized that the subject can 
refuse to provide a reason.  If a randomized subject is withdrawn prior to the first 
scheduled study test (or prior to the start of late CMV surveillance) for any reason, they 
will be replaced; however, they will not be moved over to the observational cohort.  
For subjects who withdraw or are withdrawn prior to completion of the study, clinical 
information relevant to the secondary endpoint and the SAEs of special interest 
(proven/probable CMV disease) should continue to be obtained from the primary 
physicians’ office or medical records until the end of  the follow-up  unless the subject 
withdraws consent .  
The NIAID/DMID, the IRB and/or the FDA have the right to terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to the 
following: 
 Incidence of AE’s indicating a potential health hazard 
 Data recording is inaccurate or incomplete 
 The Investigators has not been adhering to the protocol or applicable 
regulatory guidelines in conducting the study. 
 Handling of Withdrawals 
Eligible subjects who withdraw from the study between randomization and the first 
scheduled study test  (or prior to the start of late CMV surveillance) may be replaced. 
Reasons for withdrawal will be recorded in the Consort diagram.  

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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
 
Study Product Description 
 DBS Self-Collection Kit 
The HTL Strefa Acti-Lance Safety 
Lancet (Universal) has been selected 
as the finger stick device for this trial. 
This lancet has a quick incision 
(0.002 seconds) and the 23-gauge 
needle penetrates 1.8mm, minimizing 
pain and bruising to the subject. This 
lancet has a closed design, which 
ensures that the needle remains inside 
the lancet before and after the 
puncture. DBS Self-Collection Kit 
will be assembled, packaged and 
distributed to each enrolling site by 
Fred Hutch (Table 4); the kit will be 
stored and shipped at room 
temperature. Each clinical site is 
responsible for supplying enrolled 
subjects with collection kits, which includes detailed instruction of use (refer to MOP). 
Biohazard sharps container will be provided with the initial supply to the subjects for 
disposal of lancets. Refer to MOP for detailed and updated instructions on study kits and 
supplies.  
 CMV PCR  
The DBS CMV assay consists of two major steps, an extraction to elute DNA from 
Whatman 903 Protein Saver Cards and purify it from other blood components on the 
DBS, followed by a real-time PCR to quantify the CMV present. The CMV PCR assay 
was initially developed in 2001 using two primer/probe pairs, one of which amplifies the 
gB region and one the IE region of the CMV genome. Over the last 10 years this PCR 
assay has been extensively used both clinically and to study CMV infections of 
immunocompromised patients at both at the University of Washington and the Fred 
Table 4. Contents of DBS Self-Collection Kit 
Item 
Quantity 
Lancet 
1 
Sterile Alcohol Prep Pad 
1 
Gauze Pad 
1 
Bandage 
1 
Whatman 903 Elute Card 
1 
Subject Label 
1 
Whatman FTA Multi-Barrier 
Pouch 
1 
Desiccant Pack 
1 
Biohazard Specimen Bag 
1 
Padded Envelope with 
Return Address Label 
1 
DBS Self-Collection Kit 
Instruction of Use 
1 

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Hutch. This assay has proven to be a valuable tool for detection and monitoring of CMV 
reactivation and clinical disease. 
The DBS testing has been increasingly utilized to detect CMV in studies of congenital 
CMV by using stored Guthrie cards 31–33. A critical element, which has a significant 
impact on the assay sensitivity, is the extraction method. A variety of extraction methods 
have been evaluated in the CAP/CLIA certified University of Washington Molecular 
Virology Laboratory to identify the method that gives maximum recovery of the virus 
from the filter paper but elutes the minimum amount of PCR-inhibiting polysaccharides. 
A study showed good correlation between the levels of CMV in plasma and DBS samples 
of 35 solid organ transplant patients, using a validated method of Whatman 903 Protein 
Saver Cards and a chemical extraction with Chelex developed at the University of 
Washington Molecular Virology Laboratory. The extraction method for the current DBS 
CMV Testing Device has been modified to use the extraction kit available on the 
Promega M16 MDx instrument, because of its ability to automate the extraction and to 
obtain an increased CMV yield. 
 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product 
Subject compliance will be measured by questionnaires as described in section 7.4. 
 
Concomitant Medications/Treatments 
 Randomization 
Any of the following medications, if applicable, that were administered within 14 days 
prior or ongoing at the time of randomization will be captured and reported to Advantage 
EDCSM: 
• 
Steroids, topical only for GI GVHD and systemic (within 6 weeks prior to 
randomization) 
• 
PUVA 
• 
Immunosuppressant for acute or chronic GVHD (within 14 days prior to 
randomization, collect only start and stop dates) 
• 
Preemptive or prophylactic antivirals (i.e. dosing of foscarnet, ganciclovir, 
valganciclovir, cidofovir, brincidofovir, letermovir, acyclovir/valacyclovir [high 

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and low dose], or any other investigational anti-CMV agent) (within 14 days prior 
to randomization). 
• 
T-cell depleting agents including, but not limited to, anti-thymocyte globulin 
(ATG), alemtuzumab, etc. (any time after conditioning) 
 Quarterly Follow-Up 
Following medications, if applicable, will be captured and reported to Advantage EDCSM 
during medical chart review at quarterly follow-up: 
• 
Antiviral used for CMV treatment 
• 
Steroids, topical only for GI GVHD and systemic 

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7 
STUDY SCHEDULE 
 
Screening  
Every inclusion and exclusion criteria will be assessed by reviewing medical records or 
databases by the study coordinators. These will then be confirmed by site principal investigators 
to proceed for an informed consent meeting. 
 
Enrollment/Baseline and Initial Study Visit 
Enrollment will occur when discharge from the transplant service is imminent, generally near 
day 100 post-transplant (enrollment window day 60-180 post-transplant). The schedule of 
procedures is summarized in Appendix C. 
At the enrollment visit, the following procedures will be performed for all study participants (e.g. 
DBS, Standard of Care, and Observational cohorts): 
• Confirm eligibility (if screening and enrollment is not done on the same day) 
• Confirm or obtain consent prior to proceeding with any study activities. (Refer to Section 4.2 
for Observational cohort enrollment) 
• Confirm recommended monitoring schedule. 
• Randomization (not applicable for observational cohort) 
• Counseling on the importance of adherence to the recommended CMV monitoring schedule 
(not applicable for Observational cohort) 
• Collection of baseline data from subject charts (see manual of procedures) 
o Age 
o Demographics 
o Medical history relating to: 
 Transplant 
 GVHD 
 CMV plasma reactivation or disease 
o Concomitant Medications 

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 Enrollment and Initial Study Visit Procedures for Randomized DBS Arm 
• Provision of DBS Self-Collection Kits (Refer to Section 6.1.1 and MOP) at each 
enrolling site (kits are assembled and distributed to each enrolling site by Fred 
Hutch) 
• Training in finger-stick DBS collection for subjects and/or caregivers and sample 
shipping (refer to MOP) 
• Training on the use of web and mobile technology tools with instructions 
provided in the manual of procedures from Emmes.  
Training includes: 
o Creation of login ID and password for website 
o Setting preferred communication method (SMS text or email) 
o Setting timeframe for receiving reminders and notifications 
o Using study website and mobile technology component 
• Provision of Confirmatory Whole Blood Collection Kit (each kit to include one 6 
mL EDTA tube with shipping box) at each enrolling site (kits are distributed to 
each enrolling site by Fred Hutch) 
• Confirmation of integrity of the initial supply of DBS and plasma kits 
• Instruction to provide plasma for central lab PCR testing at clinical blood draws 
 Enrollment Procedures for Randomized Standard of Care (SOC) Arm 
Subjects who meet all inclusion and exclusion criteria, signed DBS CMV protocol 
consent form to participate in the trial, and randomized into standard of care arm will 
provide the same baseline characteristics via review of medical records. All following 
study activities of SOC arm, other than DBS collection, will be the same as DBS arm. 
 Enrollment Procedures for Observational Cohort 
Subjects who meet all inclusion and exclusion criteria, declined DBS CMV protocol, but 
have signed medical records review consent at each participating transplant center will be 
enrolled in the control arm for retrospective chart review for CMV testing frequency at 
the time of discharge from transplant clinic, CMV disease, relapse, and mortality up to 1 
year after HCT. Refer to Section 4.2. 
 
Weekly DBS Testing 
Subjects randomized to the DBS arm are instructed to collect DBS on the same day and at 
approximately the same time each week (Sunday through Wednesday to avoid delays due to 
weekend shipping) following the provided instructions (refer to MOP). Subjects will start weekly 

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DBS collections the week after discharge and continue until approximately 1 year after HCT 
even following a positive result or initiation of preemptive therapy. If a DBS participant  is 
hospitalized, the participant should not collect weekly DBS samples  during hospitalization. The 
admitting hospital should monitor the DBS participant for CMV with at least weekly plasma 
CMV DNA PCR testing during hospitalization. Once discharged, the study team will remind the 
participants to resume  DBS collections according to their weekly schedules. The study team 
may provide a refresher DBS training if needed. If a subject’s DBS result is positive, and/or prior 
to any initiation of standard-of-care preemptive therapy, a 6ml whole blood (EDTA anti-
coagulant tube) will be collected for plasma CMV PCR analysis by the subject’s physician or 
referred collection site and an additional DBS sample at their scheduled laboratory visit with 
exemption to emergent hospital visit or hospitalization. Subjects will be provided with a pre-paid 
mailer with instructions to deliver to the collection center to assist with plasma CMV sample 
shipment to University of Washington Clinical Virology Laboratory on the day of collection. 
The subject will need to collect a DBS test at the time of the plasma collection. Subjects will be 
provided with a DBS kit to take with them to the physician’s office. USPS should be contacted 
from the physician’s office for pickup of the completed DBS kit. 
All test results will be transmitted via a secure server to the study sites from the laboratory. The 
research staff will then contact the subjects’ treating physicians via phone/fax. The subjects will 
receive a notification via the study web portal when their positive CMV test results are available 
with a link to a secure website that can be used to access them.  
 
Questionnaires 
 Subject Questionnaire 
Subjects who are enrolled and randomized into DBS arm will be asked to complete a 
questionnaire at three different time points throughout study participation: after the third 
training session, one month after discharge from transplant clinic, and at the end of study. 
The questionnaire will solicit user feedback on the utility and clarity of the DBS 
collection training, reminders, and shipping instructions. The questionnaire will be 
provided via web/mobile technology by Emmes. 
 Provider Questionnaire 
Primary care providers of subjects who are enrolled and randomized into DBS arm will 
be asked to complete a questionnaire at the end of subject’s study participation. The 
questionnaire will solicit the provider’s feedback on the utility and quality of the DBS 

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testing. The questionnaire will be provided via fax by study coordinators at the time of 
last quarterly follow up records request.  
 
Follow-up (Quarterly, ± 2 weeks) 
 
Quarterly follow-up contacts will be done on all randomized subjects while enrolled in the study 
regardless of the randomization status. Study sites will follow up with subjects’ primary care 
physicians to obtain the following records at each quarterly time point based on transplant date: 
• Current immunosuppression 
• Systemic steroid use 
• Recommended CMV test interval (i.e., testing frequency) 
• Office-based CMV test dates and results (i.e. PCR, IHC, histopathology, etc.) 
• Interim hospitalizations 
• CMV disease status 
• Interim use of preemptive therapy for late CMV disease 
• AEs 
• Date of morphological relapse 
• Survival status 
• Problems with DBS or plasma kit integrity 
 
If the scheduled quarterly visit is within 10 days of subject randomization, the corresponding 
quarterly visit will be waived.  
 
Final Study Visit 
At approximately 12 months after HCT (+4 months), study staff will conduct a closeout data 
collection of both randomized and observational cohorts by obtaining subject’s medical records. 
The following information should be recorded on the appropriate electronic case report form: 
• Current immunosuppression 
• Systemic steroid use 
• Recommended CMV test interval (i.e., testing frequency) 
• Office-based CMV test dates and results (i.e. PCR, IHC, histopathology, etc.) 
• Interim hospitalizations 
• CMV disease status 
• Interim use of preemptive therapy for late CMV disease 

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• AEs 
• Date of morphological relapse 
• Survival status 
• Problems with DBS or plasma kit integrity 
 
Hospitalizations 
If a study subject is hospitalized, both the clinical trial coordinating center (Fred Hutch) and local 
site should be informed by the study coordinator or admitting physician, respectively. Subjects 
will be provided a letter that includes information about the study (i.e., study synopsis), which 
should be given to the admitting physician (refer to MOP). Information includes a short 
description of the study, instructions for hospital monitoring for CMV during the hospitalization, 
and contact information (phone, fax, and email).  
If a DBS study participant is hospitalized, the participant should not collect weekly DBS, and 
local CMV monitoring with plasma CMV DNA PCR testing should be performed during the 
hospitalization. 

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8 
STUDY PROCEDURES/EVALUATIONS 
 
Laboratory Evaluations 
 Clinical Laboratory Evaluations 
8.1.1.1 Plasma CMV PCR Testing 
Subject plasma samples will be tested for CMV viral load at the University of 
Washington Molecular Virology Laboratory using a validated qPCR assay that targets 
two CMV genes (i.e., UL55 and UL123) simultaneously using TaqMan probes, standard 
primers, and a single FAM fluorophore 40,41. 
 Special Assays or Procedures 
8.1.2.1 CMV DBS PCR Testing 
Subject DBS samples will be tested for CMV viral load at the University of Washington 
Molecular Virology Laboratory using a slightly revised and optimized version of the 
assay described in Limaye, et al 34. In this assay, a single-use paper punch is used to 
punch a DBS from the Whatman 903 Protein Saver Card. DNA is extracted from the 
DBS (after washing) by adding 100µl of autoclave-sterilized 5% Chelax (Bio-Rad) and 
incubating at 95°C for 30 minutes (per manufacturer instructions). 20µl of eluted DNA 
are used for real-time TaqMan CMV PCR (as described in 40) of a 50µl PCR mixture 
containing 25µl of 2× QuantiText multiplex PCR master mix (Qiagen) a 415 nM 
concentration of each primer (gB and IE-Ex4), and 100 nM concentration of the probes 
(gB and IE-Ex4). 
 Specimen Preparation, Handling, and Shipping 
8.1.3.1 Specimen Collection and Transport to Processing Laboratory 
DBS specimen: 
Subjects are instructed to schedule same day or next morning (for evening DBS 
collection) mail carrier pick-up by website or phone or to deliver the envelope to the post 
office for overnight shipping with provided prepaid mailing envelopes. Subjects are to 
schedule pick up from Monday through Wednesday to avoid delays due to weekend 
shipping. 

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Plasma CMV PCR specimen: 
Subjects are instructed to have 6ml EDTA drawn at their primary oncologist’s office, 
primary transplant center, or blood draw facility, whichever is clinically scheduled, once 
their DBS is resulted positive or prior to initiation of preemptive therapy. The plasma 
sample will be sent from the collection center using the provided instructions and 
supplied prepaid mailing envelopes (which meet the biohazard shipping requirement) via 
overnight FedEx delivery. To ensure specimen’s viability, processing laboratory must 
receive the sample within 48 hours of collection. 
Detailed instruction regarding specimen collection and shipping will be provided to the 
subject at the time of training, prior to discharge from primary transplant clinic. All 
subjects will be provided with supplies with subject ID. 
All specimens (both DBS and plasma) will be shipped to University of Washington 
Clinical Virology Laboratory (1616 Eastlake Ave E, Suite 320, Seattle, WA 98109) for 
analysis. 
Specimen collection kits will be supplied by the coordinating center, Fred Hutch, to each 
site where they will be distributed to participating subjects. 
8.1.3.2 Specimen Processing and Storage 
Specimen processing and storage will occur at University of Washington Clinical 
Virology Laboratory. Samples will be labeled with date of collection, study protocol 
number, and subject ID. Leftover of plasma samples from EDTA tubes will be stored at  
-80 °C. 
 

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9 
ASSESSMENT OF SAFETY 
 
Adverse Events 
AEs will be elicited from subjects in the DBS arm at quarterly follow-up contacts and at the 
final closeout contact.  
For this trial, a reportable AE is defined as any clinically important untoward medical 
experience directly related to DBS collection, that is, the finger-stick procedure. The study 
source documents will include the assessment and evaluations of all AEs as defined above. 
Only those events that are considered “Severe” and “Related” to the DBS collection and 
finger stick procedure will be reported. See below for definition of “Severe” and “Related”: 
 Severe: Events interrupt a subject’s usual daily activity and require systemic drug therapy 
or other medically administered treatment. 
 Related: There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
AEs as defined above are reported on appropriate CRFs in the AdvantageEDCSM.  
If an AE is considered “Unexpected”, the appropriate CRF must be submitted within 10 
calendar days.  
 Unexpected: Event is not listed in study materials or is not listed at the specificity or 
severity that has been observed; or is not consistent with the risk information described in 
the general investigational plan. For example, under this definition, an infection requiring 
antibiotic treatment and causing a missed day of work may be considered Expected. An 
infection causing an extended absence from work or leading to necrosis may be 
considered Unexpected. 
DMID Medical Monitor will review adverse events and determine if additional reporting is 
applicable.  
 
Serious Adverse Event of Special Interest (SAESI) 
Breakthrough CMV disease events (mainly gastrointestinal disease) are expected to occur in 
both study arms at low frequency, however, in order to detect unusual patterns of 

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surveillance failure, breakthrough CMV disease will be considered a Serious Adverse Event 
of Special Interest. No other serious adverse events will be collected and reported in this trial. 
Breakthrough CMV disease (only proven/probable, as defined in 3.2.2) events after start of 
surveillance testing will be considered a serious adverse event of special interest and will be 
reported within one working day of site awareness on an SAE form to the DMID 
Pharmacovigilance Group. Fax forms to 1-800-275-7619 (US) or email to 
PVG@dmidcroms.com.  The DMID Pharmacovigilance Group may be reached at 1-800-
537-9979 (US), if needed.  
 
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible.  
The DMID Medical Monitor and DMID Clinical Project Manager will be notified of the 
SAESI by the DMID Pharmacovigilance Group. The DMID Medical Monitor will review 
and assess the SAESI for potential impact on study subject safety and protocol conduct.  
If the DMID Medical Monitor judges that there is a cluster of SAESI that represents a trend 
or suspicious pattern of SAESI, the DSMB will review those events in an ad-hoc meeting. 
In addition, following an evaluation of SAESIs of breakthrough CMV disease, DMID shall 
report the results of such evaluation to FDA and participating clinical site investigators 
within 10 working days after DMID first receives notice of SAESI evaluation from the 
DSMB. Clinical site investigators and Coordinating Center shall report to respective IRBs 
according to respective IRB guidelines. 
 
Unanticipated Problems 
Investigators must report Unanticipated Problems, regardless of severity, associated with 
self-administered finger-stick DBS collection or assay. This includes false positive or false 
negative assay results. An Unanticipated Problem is defined as: 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected, in terms of nature, severity, or frequency, given the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and the characteristics of the subject 
population being studied  

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• Related or possibly related to participation in the research, in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research 
The investigator shall submit to DMID and to its local IRB a report of any Unanticipated 
Problem occurring during an investigation as soon as possible, but in no later than 10 
working days or per local guidelines, respectively, after the investigator first learns of the 
effect. 
DMID as the sponsor shall immediately conduct an evaluation of any Unanticipated 
Problem. If an Unanticipated Problem presents an unreasonable risk to subjects, DMID shall 
terminate all investigations or parts of investigations presenting that risk as soon as possible. 
Termination shall occur no later than 5 working days after the sponsor makes this 
determination and no later than 15 working days after the sponsor first received notice of the 
effect. Resumption of any termination will not occur without FDA and IRB approval. (21 
CFR 812.46) 
If DMID conducts an evaluation of an Unanticipated Problem under 21 CFR 812.46 (b) then 
DMID will report the results of such evaluation to FDA and to all participating investigators 
no later than 15 working days after DMID first receives notice of the effect. Clinical site 
investigators and Coordinating Center shall report to IRBs per local guidelines after receipt 
of evaluation from DMID. Thereafter DMID will submit such additional reports concerning 
the effect as FDA requests. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
Information on finger-prick related adverse events will be obtained from the quarterly chart 
abstractions.  
 
Safety Oversight 
 Data and Safety Monitoring Board (DSMB) 
The DMID DSMB is convened by authority of DMID and is advisory to DMID and 
the study team. The DMID DSMB must consist of at least three voting members 
including a biostatistician experienced in statistical methods for clinical trials and a 
clinician with relevant expertise. Selection of DMID DSMB members should include 
consideration of clinical trials experience, relevant expertise, prior DSMB service, 
and absence of significant conflict of interest. DMID is responsible for deciding 
whether consultancies or the financial interests of the members materially affect their 

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objectivity. Members will notify DMID promptly if a change occurs that may create a 
potential conflict of interest. 
The DMID DSMB will operate under the rules of a DMID-approved charter that will 
be reviewed and finalized following the organizational meeting of the DSMB. The 
DMID DSMB Charter serves as the standard operating procedure and defines the 
primary responsibilities of the DSMB, its membership, the purpose and timing of its 
meetings, data to be reviewed, and procedures for ensuring confidentiality and proper 
communication. The following times are the proposed scheduled meetings of the 
DMID DSMB: 
• Organizational DMID DSMB meeting –The first meeting of the DMID DSMB 
will be primarily organizational and to review the study protocol, safety data 
shells, and frequency of scheduled meetings. This meeting will occur prior to the 
initiation of study enrollment.  
• Interim analysis data review meeting- Among the first 50 subjects enrolled on the 
DBS intervention arm and followed for at least a year, if the lower one-sided 90% 
confidence interval for the percent of subjects experiencing CMV disease by one-
year exceeds 8% (operationally 7 out of 50), a DSMB meeting will be convened. 
The DSMB will be charged with determining whether this exceptionally high rate 
of CMV disease has plausible clinical explanations related to the subject 
characteristics, or if it is the result of a failure in the monitoring system, and if so, 
what the source of the failure is (lack of compliance, failure of the system). 
Ultimately, they will make a recommendation to the PI as to whether any aspect 
of the study should be modified or terminated. 
• Ad Hoc meeting to review safety events such Unanticipated Problems or SAESIs 
(breakthrough CMV disease reports). 
• Final DMID DSMB meeting - 6 to 8 months after clinical database lock to review 
the cumulative safety data for the study. The data will be provided in a standard 
summary format. The DSMB may be asked to provide recommendations in 
response to questions posed by DMID. 
The DMID DSMB may also be convened for an ad hoc meeting, an unplanned 
meeting that is called for a specific purpose such as when a study halting rule is met. 
The meeting can be requested by any party with the responsibility of overseeing the 
trial (such as the PI, DSMB, DMID). In the case of an ad hoc meeting, the DMID 
DSMB may request special reports on an as-needed basis. 
If the study is discontinued, follow-up visits for safety would continue. 

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10 
MONITORING 
 Study Kit Monitoring  
The clinical sites are responsible for verifying the integrity of the study kit before supplying 
subjects with kits at enrollment and resupplies. Both the DBS and Confirmatory Whole Blood 
kits will be verified. The subject will be instructed to report problems with study kit integrity to 
the clinical site. If a problem is identified with study kit, the subject will contact the site, which 
will record problems on the appropriate eCRF. The subjects will submit resupply requests of 
additional study kit through the web/mobile technology.  
 
The SDCC will perform data logic checks and queries on the data entered into the data collection 
system. 
 

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11 
STATISTICAL CONSIDERATIONS 
 Study Outcome Measures 
 Primary Endpoint 
The primary endpoint will be the proportion of subjects who complete >90% of their 
recommended CMV monitoring tests by 1-year post-transplant. We will use logistic 
regression modeling to compare this proportion between subjects randomized to DBS 
testing versus standard office-based testing. Since randomization will be stratified by 
transplant site and subject’s perceived ease of access to blood draw facility, these factors 
will be used as adjustment factors in the models.  
For each subject, the number of CMV monitoring tests performed will be assessed and 
the percent of recommended tests will be calculated. Subjects with percent completion 
>90% will be considered a success with regard to the primary endpoint. The person-
specific denominator for the proportion, number of expected CMV monitoring tests, will 
be variable and dependent on subjects’ immunosuppression and hospitalizations during 
the study. For example, subjects in this study that are highly immunosuppressed a weekly 
monitoring schedule is generally recommended, often throughout the first year after 
transplantation. If such a subject were discharged from the primary transplant center at 
day 100, there would be 38 remaining tests until day 365 after HCT (if the subject is still 
alive at 1 year). We will assess the actual number of tests performed and calculate the 
percent of tests (e.g. 36/38 = 94.7%). Another scenario would be for a subject that 
stopped monitoring and was then re-started on high-dose steroids for treatment of GVHD 
with resumption of weekly testing, resulting in yet another denominator. Study 
participants in the DBS arm who are hospitalized during the study should not collect DBS 
samples while admitted. Rather, admitting hospitals should monitor participants for CMV 
with plasma CMV DNA PCR testing as recommended for their level of 
immunosuppression. Those inpatient testing timepoints will not be included in the 
person-specific denominator.  
The primary analysis will be an intent-to-treat (ITT) analysis of all subjects randomized. 
Another key analysis will be the modified intent to treat analysis of all subjects who had 
at least one test done after discharge from the primary transplant team. 

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 Secondary Endpoint 
As a secondary endpoint we will be comparing the incidence of late CMV disease by one 
year post HCT between the two randomized groups using competing risk regression with 
death treated as a competing risk event 42. Using similar methods, we will also compare 
the CMV disease incidence of trial participants compared to subjects who received HCTs 
at the clinical sites in the similar time period but did not participate in the trial. As 
expected, the planned trial would not be sufficiently powered to detect a difference in late 
CMV disease incidence from 8% (current standard care) to 2% (observed in clinical 
trial). A trial powered for that detectable effect size would require 330 subjects to have 
80% power (one-sided p values 0.05).  
To determine the rate of CMV disease at participating sites during the clinical trial we 
will collect concurrent retrospective baseline data as well as CMV disease and survival 
data from subjects that were eligible for randomization but decided not to participate (the 
majority of subjects return to the transplant center at one year). The purpose of this 
analysis is to determine whether the subjects who participated in the trial are 
representative of the population at risk for late CMV disease and whether the 
phenomenon of late CMV disease continues to occur throughout the study period.  
To assess the correlation of CMV viral load between DBS and plasma samples, we will 
use linear model. Other outcomes will be tabulated and compared between groups using 
Chi-Square, Fisher’s exact, and log rank tests, as appropriate.  
The relative contribution of mobile phone reminders, subject adherence to the device, and 
failures of the testing kit itself will be analyzed among subjects randomized to the DBS 
arm who did not reach the 90% adherence threshold.  
 Sample Size Considerations 
Power calculations utilized a binomial distribution to ascertain the number of subjects needed to 
detect a clinically meaningful difference in proportions of subjects meeting the primary endpoint 
43. Based on our preliminary data, we assumed the proportion of individuals completing >90% of 
their recommended surveillance tests in the standard office-based testing arm would be in the 
range of 50-55%. In our previously reported clinical trial, high rates of CMV monitoring 
completion resulted in the clinically relevant outcome of a low incidence of late CMV disease 22 
. To be successful, this proof of concept trial needs to demonstrate that similarly high rates of 
monitoring can be achieved with subject collected DBS monitoring. With 150 subjects, 
randomized 2:1, we will have 90-96% power to detect an absolute difference in testing rates of 
25-30% between subjects in the intervention (80% adherence) and control arms (50% adherence) 

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(Table 2). Although the 2:1 randomization does not result in increased statistical power, 
randomizations that favor the experimental arm (2:1 or 3:1) appear to increase the appeal to the 
potential study participant and have been used successfully in several recent multicenter CMV 
randomized trials 24,25,44.  
 
 

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Table 1 Power calculations for primary analysis 
Sample 
size 
Total 
Sample 
size 
DBS 
group 
Sample 
size 
Control 
Proportion of 
subjects with 
>90% Adherence 
rate 
DBS arm 
Proportion of 
subjects with 
>90% Adherence 
rate 
Control arm 
Sig. 
level 
Two-
sided 
Power 
150 
100 
50 
0.8 
0.5 
0.05 
96% 
150 
100 
50 
0.8 
0.55 
0.05 
89% 
150 
100 
50 
0.8 
0.58 
0.05 
80% 
 Participant Enrollment and Follow-Up 
Study is expected to enroll 150 allogeneic HCT recipients who meet inclusion criteria for 
randomized cohort and 450 allogeneic HCT recipients who meet inclusion criteria for 
observational cohort over period during which randomization is performed (and one year prior if 
needed) between four study sites. Follow-up for is described in the time and events schedule in 
Appendix C.  
 Randomization Scheme 
Randomization will be done by the SDCC online using the enrollment module of 
AdvantageEDCSM. Subjects will be stratified at the time of randomization according to transplant 
site and subject’s perceived ease of access to blood draw facility in order to prevent major 
imbalances within the study.  
 Analysis Plan 
As described under Primary Endpoint, the primary analysis will be a logistic regression analysis, 
comparing the study arms in an Intent-to-Treat analysis including all randomized subjects. Prior 
analyses will include careful checks of all key data elements (primary and secondary endpoints 
and subject characteristics) to ascertain implausible and missing values. Reports including all 
missing and implausible values will be generated and elements will be checked with source 
documents to attempt to correct or replace those values. If a data value is considered to be 
completely implausible and cannot be corrected with available information, its value will be 
considered “missing”. Once these edits have iterated until no further corrections can be made, 
each data element will be summarized by study arm, and percent of missing data evaluated. 
Ideally, missing data will be negligible in this study, but if that is not the case, we will determine 
the ideal method for handling this to avoid biased results (e.g. inverse probability weighting, 

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multiple imputation, etc.). Our final analysis plan will be reviewed prior to data lock and 
amended as needed before the start of analysis. 
The primary study period for subjects that have been withdrawn from the study will be from 
randomization to the day of withdrawal. A sensitivity analysis will be performed to estimate the 
impact of withdrawal on the primary endpoint using the maximum possible study period.  
The study statistician may provide an analysis of aggregate, uncleaned data from the 
observational cohort on the estimates of late CMV disease and on the sensitivity of CMV 
detection by PCR in DBS vs plasma samples to the investigators and sponsor for the purpose of 
abstract preparation or presentation or planning for future studies. While the results provided will 
not be used to make any decisions about the conduct of this study, they may be used to make 
decisions on activities external to this trial such as the design of other studies on CMV disease in 
transplant recipients or on CMV detection methodologies.  
 Interim Safety Monitoring 
Among the first 50 subjects enrolled on the DBS intervention arm and followed for at 
least a year, if the lower one-sided 90% confidence interval for the percent of subjects 
experiencing CMV disease by one-year exceeds 8% (operationally 7 out of 50), a DSMB 
meeting will be convened. The DSMB will be charged with determining whether this 
exceptionally high rate of CMV disease has plausible clinical explanations related to the 
subject characteristics, or if it is the result of a failure in the monitoring system, and if so, 
what the source of the failure is (lack of compliance, failure of the system). Ultimately, 
they will make a recommendation to the PI as to whether any aspect of the study should 
be modified or terminated. 
 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Data collection forms, most of which serve as source documents for this study, will be derived 
from the electronic CRF and provided by the SDCC to record and maintain data for each subject 
enrolled in the study. All data collection forms should be completed in a neat, legible manner to 
ensure accurate interpretation of data. Black or blue ink is required to ensure clarity of 
reproduced copies. When making a change or correction, cross out the original entry with a 
single line and initial and date the change. Do not erase, overwrite, or use correction fluid or tape 
on the original. 
Data reported in the eCRF derived from the data collection forms should be consistent with the 
source documents or the discrepancies should be explained. 
The sponsor will provide guidance to investigators on making corrections to the data collection 
forms and eCRFs. 
Each site will permit authorized representatives of the DMID, its designees, and appropriate 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits, monitoring, and evaluation of the study 
safety and progress. These representatives will be permitted access to all source data, which 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda, evaluation checklists, records of receipt, use or disposition of the device, records of 
each subject’s case history and exposure to the device, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files and 
records kept at the laboratories, and medico-technical departments involved in the clinical trial. 
Data collection forms used as source documents will be derived from the eCRFs and be provided 
by the SDCC. 
 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the investigational site is 
responsible for conducting routine quality assurance and quality control activities to internally 
monitor study progress and protocol compliance. The PI will provide direct access to all trial-
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
the sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentation is maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution.  
 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 Ethical Standard 
The site principal investigator (PI) will ensure that this study is conducted in full conformity with 
principles of The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research (National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research [April 18, 1979]) and codified in 45 CFR 46, 21 CFR 50 and 21 CFR 
56, as applicable. The PI will also ensure conformity with the ICH E6; 62 Good Clinical Practice 
and applicable federal regulations, guidance, and Guidelines for Good Clinical Practice and 
Clinical Trials with humans. 
 Institutional Review Board 
Prior to enrollment of subjects into this trial, the approved protocol and informed consent form 
will be reviewed and approved by the appropriate IRB listed on its FWA. 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to 
the start of this trial and a copy will be provided to DMID. The IRB FWA number will be 
provided to DMID. 
Should amendments to the protocol be required, the amendments will be written by the sponsor 
and provided to the site principal investigator for submission to the IRB. 
 Informed Consent Process 
Informed consent is a process that is initiated prior to an individual agreeing to participate in a 
trial and continuing throughout the individual’s trial participation. Before any study procedures 
are performed, informed consent will be obtained and documented. Subjects will receive a 
concise and focused presentation of key information about the clinical trial, verbally and with a 
written consent form. The explanation will be organized and presented in lay terminology and 
language that facilitates understanding why one might or might not want to participate. If an in-
person informed consent cannot be obtained, remote informed consenting via video 
teleconferencing is permissible under the site’s IRB approved remote consenting policy (See 
MOP for details and instructions).  
An investigator or designee will describe the protocol to potential subjects in person. The key 
information about the purpose of the study, the procedures and experimental aspects of the study, 

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the risks and discomforts, any expected benefits to the subject, and alternative treatment will be 
presented first to the subject. 
Subjects will also receive an explanation that the trial involves research and a detailed summary 
of the proposed study procedures and study interventions/products. This will include the aspects 
of the trial that are experimental, the probability for random assignment to treatment groups, any 
expected benefits, and all possible risks (including a statement that the particular treatment or 
procedure may involve risks to the subject that are currently unforeseeable). The expected 
duration of the subject’s participation in the trial, alternative procedures that may be available, 
and the important potential benefits and risks of these available alternative procedures will also 
be included in the detailed explanation. 
Subjects will be informed that they will be notified in a timely manner if information becomes 
available that may be relevant to their willingness to continue participation in the trial. Subjects 
will receive an explanation as to whether any compensation and any medical treatments are 
available if injury occurs, and, if so, what they consist of, or where further information may be 
obtained. Subjects will be informed of the anticipated financial expenses, if any, to the subject 
for participating in the trial, as well as any anticipated prorated payments, if any, to the subject 
for participating in the trial. They will be informed of whom to contact (e.g., the investigator) for 
answers to any questions relating to the research project. 
Information will also include the foreseeable circumstances and/or reasons under which the 
subject’s participation in the trial may be terminated. The subjects will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
The extent of the confidentiality of the subjects’ records will be defined, and subjects will be 
informed that applicable data protection legislation will be followed. Subjects will be informed 
that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be granted direct 
access to the subject’s original medical records for verification of clinical trial procedures and/or 
data without violating the confidentiality of the subject, to the extent permitted by the applicable 
laws and regulations, and that, by signing a written informed consent form, the subject is 
authorizing such access. 
Subjects will be informed that records identifying the subject will be kept confidential, and, to 
the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the subject’s identity will remain 
confidential. Subjects will be informed whether private information collected from this research 
and/or specimens will be used for additional research, even if identifiers are removed. 

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Subjects will be allowed sufficient time to consider participation in this research trial and have 
the opportunity to discuss this trial with their family, friends or legally authorized representative, 
or think about it prior to agreeing to participate. 
Informed Consent forms will be IRB-approved and subjects will be asked to read and review the 
consent form. Subjects must sign the informed consent form prior to starting any study 
procedures being done specifically for this trial. 
Once signed, a copy of the informed consent form will be given to the subjects for their records. 
The subjects may withdraw consent at any time throughout the course of the trial. The rights and 
welfare of the subjects will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
Study personnel may employ recruitment efforts prior to obtaining study consent if a subject-
specific screening consent is on record or if the IRB has agreed that chart review is allowed 
without a fully executed screening consent. In cases where there is not a subject-specific 
screening consent on record, site clinical staff may pre-screen via chart review and refer potential 
subjects to the Research staff. Research staff would obtain written consent per the standard 
informed consent process before conducting protocol-specific screening activities. 
New information will be communicated by the site principal investigator to subjects who consent 
to participate in this trial in accordance with IRB requirements. The informed consent document 
will be updated and subjects will be re-consented per IRB requirements, if necessary. Subjects 
will be given a copy of all informed consent forms that they sign. 
All subjects must sign an informed consent form that complies with the requirements of both 21 
CFR 50 and 45 CFR 46. 
Subjects will be allowed sufficient time to consider participation in the trial, after having the 
nature and risks of the trial explained to them. The consent form must not include any 
exculpatory statements. 
 Informed Consent/Assent Process (in Case of a Minor) 
Investigators will follow the site IRB/IEC requirements for enrollment of minors in this 
study. In most cases, investigators or designee will conduct the consent process with the 
minor and their parent(s)/legal guardian, who will be given an IRB/IEC-approved 
permission form, which may be referred to as a consent form, to read, review, and sign 
prior to any study procedures. The consent process will be conducted as outlined above in 
section 14.3, with both the minor subject and the parent(s)/legal guardian signing the 
consent form.  

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The investigator or designee will describe in simplified terms the details of the study 
intervention/product, study procedures, risks and discomforts, benefits, and other consent 
elements, as appropriate. 
No specific assent will be used in this study; subjects ≥15 and <18 years of age will sign 
consent together with his or her parent or guardian. When a minor subject who reaches 
the age of majority (18 years of age) during the study period, the subject will be re-
consented without a parent or guardian’s signature at the next visit prior to study 
procedures. When no further visits are planned but the subject’s participation is ongoing, 
requirements for reconsent will follow local IRB/IEC-approved processes. 
 Exclusion of Women, Minorities, and Children (Special Populations) 
This study will be inclusive of all adults who meet the inclusion/exclusion criteria, regardless of 
religion, sex, or ethnic background. Children between ≥15 and <18 years of age are also 
included. Children < 15 years of age are excluded because of requirements for self-reporting and 
self-administration of study procedures. 
 Subject Confidentiality 
This research is covered by a Certificate of Confidentiality from the NIH. Subject confidentiality 
is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their 
agents. This confidentiality includes documentation, investigation data, subject’s clinical 
information, and all other information generated during participation in the study. The 
investigators and their staff may not disclose or use information documents or biospecimens that 
may identify the subjects in any federal, state, or local civil, criminal, administrative, legislative 
or other action, or be used as evidence unless the subject has consented. This does not apply to 
requests for information from the NIH or its representatives that are needed to monitor or audit 
the study, or for information that must be disclosed in order to meet FDA requirements. 
At the clinical trial coordinating center, multiple mechanisms have been established to protect 
the confidentiality of specimens, medical records, and data. All personnel who work on this 
study must sign a pledge of confidentiality across all participating sites. Access to the database is 
controlled through secure password protection, and passwords must be changed quarterly. 
Access to the work site is controlled through passkeys and ID badges. Individuals who are not 
employees must be escorted at all times by an employee.  
Study sites employ site-specific confidentiality measures, including electronic and physical 
barriers. 

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Each participating subject will be assigned an identification number to be used for all subject 
data. Links to subject name and identifiers will be maintained and stored in files on computers 
protected by password and in locked office cabinets. All clinical data collected at individual sites 
will be entered into CRFs on a secure web-based system. 
Specimens will be coded with unique study identification numbers in order to ensure subject 
confidentiality. No identifying information of any kind may be released to persons or agencies 
without specific written permission. 
No information concerning the study or the data generated from the study will be released to any 
unauthorized third party without prior written approval of the DMID and the subject. Subject 
confidentiality will be maintained when study results are published or discussed in conferences. 
The Sponsor, it’s designee, or governmental regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) for the subjects, and records of receipt, use or disposition of 
the device in this study. The clinical study site will permit access to such records. 
All records will be kept locked and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 Future Use of Stored Specimens 
 
Subjects will be asked for permission to keep any remaining specimens for possible use in future 
research studies. Residual specimens will be stored indefinitely at Fred Hutch. Before conducting 
additional research unrelated to the original research questions, the Fred Hutch IRB will review 
the request and decide whether the request meets minimal risk requirements or whether 
additional specific consent is required. The Fred Hutch IRB serves as central IRB for this issue. 
Subjects may opt out of future research unrelated to the original research question. 
 
Samples may be shared with other investigators at other institutions. The samples will not be 
sold or used directly for production of any commercial product. Tests may include genetic 
research to look at things such as which genes affect infection or how genes work. Each sample 
will be encoded (labeled) only with a barcode and a unique tracking number to protect subject’s 
confidentiality. 
 
There are no benefits to subjects in the collection, storage, and subsequent research use of 
specimens. Reports about future research done with a subject’s samples will NOT be kept in 

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their health records. Subjects can decide if they want their samples to be used for future research 
or have their samples destroyed at the end of the study. A subject’s decision can be changed at 
any time up to the point the specimens are released for research use by notifying the study 
doctors or nurses in writing. However, if a subject consents to future use and some of their blood 
has already been used for research purposes, the information from that research may still be 
used. 
 Disclosure of Individual Research Information 
In this protocol, we intend to provide each DBS arm participant with his/her specific DBS and 
plasma CMV test results sent to and obtained from central laboratory. In addition, we intend to 
provide each participant with an overall summary of the study results at the end of the study. 

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15 
DATA HANDLING AND RECORD KEEPING 
 Data Management Responsibilities 
This study will be inclusive of all adults who meet the inclusion/exclusion criteria, regardless of 
religion, sex, or ethnic background. Children between 15 and 18 years of age are also included. 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The Emmes Company, LLC will serve as the Statistical and Data Coordinating Center for this 
study and will be responsible for data management, quality review, analysis, and reporting of the 
study data. 
 Data Capture Methods 
Clinical data (including AEs, concomitant medications, and CMV disease status) and clinical 
laboratory/virologic data will be entered into a 21 CFR Part 11-compliant Internet Data Entry 
System (IDES) provided by The Emmes Corporation. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 Types of Data 
Data for this study will include virologic and clinical data. 
 Timing/Reports 
Reports on subject’s compliance with the testing algorithm will be generated semiannually in 
order to assess overall study conduct. DSMB reports will be generated as previously described in 
section 9.5.1. 

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 Study Records Retention 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. 
Records and documents pertaining to the conduct of this study, including CRFs, data collection 
forms, other source documents, consent forms, and laboratory test results, must be retained by 
the investigator for at least 2 years after the date that the records are no longer required for 
supporting a premarket approval application; or until 2 years after the investigation discontinued 
and FDA has been notified. No study records will be destroyed without prior authorization from 
DMID. Informed consent forms for future use will be maintained as long as the samples exist. 
 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements. The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly. These practices are consistent with 
ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
For this protocol, since adherence to surveillance testing is a key outcome of the study that will 
be captured as an endpoint, the lack completion of scheduled surveillance tests (including 
confirmatory tests at the physician’s office or blood draw facility) or inadequate sample quality 
will not be recorded as protocol deviations but will be captured on case report forms. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported via The Emmes 
Corporation’s IDES. All deviations from the protocol must be addressed in study subject source 
documents. A completed copy of the DMID Protocol Deviation Form (IDES form) must be 
maintained in the regulatory file, as well as in the subject’s source document. Protocol deviations 
must be sent to the local IRB/IEC per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB/IEC requirements. 
 

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16 
IDE REPORTING REQUIREMENTS AND PROCEDURES 
 Reporting to FDA, investigators and IRBs for Study Conducted Under 
IDE  
DMID will comply with all FDA reporting requirements and timelines as outlined in 21 CFR 
812.3(s), 812.46 and 812.150. In addition to safety reporting as outlined in Section 9.0 of this 
protocol, DMID will report the following: 
• Within 5 working days of receipt of notice or becoming aware of the event, DMID will 
notify FDA and all participating investigators responsible for reporting to local IRBs of 
the following: withdrawal of approval of the study by a reviewing IRB or use of the 
device by an investigator without first obtaining consent. 
• Within 5 working days of receipt of any withdrawal of approval by FDA, DMID will 
notify all participating investigators responsible for reporting to local IRBs. 
• Within 30 days of receipt of a request by any investigator to return, repair, or otherwise 
dispose of any units of the device, DMID will notify FDA and all participating 
investigators responsible for reporting to local IRBs of the request and reasons for that 
request. 
• DMID will report annually to the FDA and all participating investigators on the progress 
of the study and will report a list of current investigators on the study to FDA at 6 month 
intervals. 
 Investigator required reporting  
In addition to safety reporting as outlined in section 9.0 of the protocol, the investigators will 
report to DMID, within 5 working days the following: 
• Any use of the device without first obtaining informed consent 
• Withdrawal of approval by the investigator’s reviewing IRB. 
. 
 
 

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17 
PUBLICATION POLICY 
Following completion of the study, the results may be published in a scientific journal or 
presented at a scientific symposium or congress. All investigators funded by the NIH must 
submit or have submitted for them to the National Library of Medicine’s PubMed Central 
(http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication.  
 
All clinical trials supported by the NIH must be registered on ClinicalTrials.gov no later than 21 
days after enrollment of the first subject. This study will be registered in accordance with this 
policy by DMID, as the Sponsor and responsible party for this trial. Results will be submitted 
within 12 months following the primary completion date of the study, unless a waiver for 
delayed posting is granted. As part of this posting, a copy of the protocol and the Statistical 
Analysis Plan will also be posted.   
 

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18 
LITERATURE REFERENCES 
1.  
Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus Reactivation in Critically 
Ill Immunocompetent Patients. JAMA. 2008;300(4):413. doi:10.1001/jama.300.4.413. 
2.  
Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease and mortality in 
recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and 
T-cell immunity. Blood. 2003;101(2):407-414. doi:10.1182/blood-2002-03-0993. 
3.  
Green ML, Leisenring W, Stachel D, et al. Efficacy of a viral load-based, risk-adapted, 
preemptive treatment strategy for prevention of cytomegalovirus disease after 
hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18(11):1687-
1699. doi:10.1016/j.bbmt.2012.05.015. 
4.  
Mbuagbaw L, Mursleen S, Lytvyn L, Smieja M, Dolovich L, Thabane L. Mobile phone 
text messaging interventions for HIV and other chronic diseases: an overview of 
systematic reviews and framework for evidence transfer. BMC Health Serv Res. 
2015;15(1):33. doi:10.1186/s12913-014-0654-6. 
5.  
Gurol-Urganci I, de Jongh T, Vodopivec-Jamsek V, Atun R, Car J. Mobile phone 
messaging reminders for attendance at healthcare appointments. In: Car J, ed. Cochrane 
Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 
2013:CD007458. doi:10.1002/14651858.CD007458.pub3. 
6.  
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Balthesen M, Messerle M, Reddehase MJ. Lungs are a major organ site of 
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disease on long-term recipient and kidney graft survival. Kidney Int. 2004;66(1):329-337. 
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Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir 
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Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. 
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Zaia JA, Gallez-Hawkins GM, Tegtmeier BR, et al. Late cytomegalovirus disease in 
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Nakamae H, Kirby KA, Sandmaier BM, et al. Effect of conditioning regimen intensity on 
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Erard V, Guthrie KA, Seo S, et al. Reduced Mortality of Cytomegalovirus Pneumonia 
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in Hematopoietic-Cell Transplantation. N Engl J Med. 2013;13369(26):1227-1236. 
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Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for Cytomegalovirus Prophylaxis 
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471-05519-0. Can J Stat. 1982;10(1):64-66. doi:10.2307/3315078. 
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cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, 
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2008;111(11):5403-5410. doi:10.1182/blood-2007-11-121558. 
 

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APPENDIX A: DBS CMV PCR ASSAY COMPARISON 
Description 
Procedure in Publication 
Current Procedure 
Filter paper used 
Whatman FTA Elute cards 
Whatman 903 Protein Saver cards 
Size of each punch 
3 mm in diameter 
6 mm in diameter 
Number of punchs used  
for DNA extraction 
4 
2 
PCR master mix 
QuantiTect Muliplex PCR mix 
with ROX 
QuantiTect Muliplex PCR NoROX 
mix 
PCR Machine 
7900HT sequence detection system QuantStudio 7 flex real-time PCR 
system 
IU conversion 
1 IU=  4 copies (AcroMetrix)* 
1 IU=1.4 copies (WHO) 
Internal control template Spiked into PCR master mix 
Spike into extraction lysis buffer 
Internal control primers 
and probe 
EXO 
EXO BS 
DNA Elution volume 
100 ul 
100 ul 
Amount of DNA used 
for each PCR 
20 ul 
20 ul 
CMV primers and probe 
gB and IE-EX4 
gB and IE-EX4 
CMV PCR standard 
1e1 to 1e5 
1e1 to 1e5 
 
 

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APPENDIX B: DEFINITION OF END-ORGAN CMV DISEASE 
CMV Disease 
Clinical Signs 
and Symptoms 
Proven 
Probable 
Note 
Pneumonia 
Pneumonia (e.g. 
new infiltrates on 
imaging, hypoxia, 
tachypnea and/or 
dyspnea) 
Clinical signs and symptoms with 
CMV in lung tissue by virus 
isolation, rapid culture, 
histopathology, IHC, or DNA 
hybridization 
Clinical signs and symptoms with 
detection of CMV by viral 
isolation, rapid culture of BALF, 
quantitation of CMV DNA in 
bronchoalveolar lavage fluid 
(BALF) 
Quantitative PCR on lung tissue 
could be defined as “possible” 
Gastrointestinal 
(GI) disease 
Upper and/or 
lower GI 
symptoms 
Clinical signs and symptoms with 
macroscopic mucosal lesions plus 
CMV documented in tissue by 
virus isolation, rapid culture, 
histopathology, IHC, or DNA 
hybridization 
Clinical signs and symptoms with 
CMV documented in tissue but 
without the requirement for 
macroscopic mucosal lesions 
CMV documented in blood by 
NAT (PCR) or Ag or PCR from 
tissue is not sufficient for CMV 
GI disease diagnosis. These could 
be defined as “possible”. 
Retinitis 
Retinitis 
Judged by an ophthalmologist 
Not used 
Diagnosis could be supported by 
vitreous fluid by NAT (PCR) 
Encephalitis/ 
Ventriculitis 
Central nervous 
system (CNS) 
symptoms 
Clinical signs and symptoms with 
CMV documented in tissue by 
virus isolation, rapid culture, 
histopathology, IHC, or DNA 
hybridization 
Clinical signs and symptoms with 
CMV documented in in CSF 
without visible contamination 
plus abnormal imaging or EEG 
Not used 
Other Organs 35 
Most organs 
Clinical signs and symptoms with 
CMV documented in tissue by 
virus isolation, rapid culture, 
histopathology, IHC, or DNA 
hybridization 
Not used 
Not used 

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APPENDIX C: SCHEDULE OF EVENTS 
Visit/Contact 
Screening1 
Enrollment2 
Initial Study Visit3 
DBS 
self-
collection 
Plasma 
Collection4 
Quarterly 
Contact 1 
Quarterly 
Contact 2 
Quarterly 
Contact 3 
Final 
Study 
Visit 
Training 15 
Training 26 
Training 37 
Discharge 
Days after HCT 
60-180 
60-365 
60-365 
90 
180 
270 
365 
Window (days) 
N/A 
  
 
±14 
±14 
±14 
(+120) 
Confirm informed consent 
  
X 
 
 
 
  
  
 
  
  
  
  
Eligibility assessment 
X, Z 
  
 
 
 
  
  
 
  
  
  
  
Randomization 
  
X 
 
 
 
  
  
 
  
  
  
  
Review of medical history 
 
X, Z 
 
 
 
 
 
 
 
 
 
 
Review of concomitant medication 
 
X, Z 
 
 
 
X 
 
 
X 
X 
X 
X, Z 
Confirm CMV monitoring interval 
  
  
 
 
 
X, Z 
  
 
X 
X 
X 
  
Adherence counseling8 
  
X   
  
 
  
  
  
  
DBS collection and website training9 
  
  
Y 
Y 
Y 
 
Y10  
 
  
  
  
  
Provision of initial study kits 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
1 It is recommended to have screening done approximately one month prior to planned discharge from the primary transplant clinic 
2 Screening, enrollment, and initial study visit (trainings for DBS arm) may occur on the same day as long as all trainings are completed by subjects with 
proficiency and confirmed by study personnel prior to discharge from primary transplant clinic. 
3 Trainings 1-3 must be completed prior to planned discharge from the subject’s primary transplant clinic. 
4 Confirmatory plasma sample will be collected from DBS arm subjects if they had a CMV positive DBS. 
5 Training with study staff supervision. 
6 Training with study staff supervision. 
7 Training without study staff supervision. 
8 Adherence counseling should be done on all randomized subjects after enrollment but prior to discharge from primary transplant clinic. 
9 DBS collection is required at each DBS training visit. Website and mobile technology training may be optional for training 2 and 3 as necessary. 
10 DBS collection starts the week after discharge and ends approximately one-year post-HSCT 

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Visit/Contact 
Screening1 
Enrollment2 
Initial Study Visit3 
DBS 
self-
collection 
Plasma 
Collection4 
Quarterly 
Contact 1 
Quarterly 
Contact 2 
Quarterly 
Contact 3 
Final 
Study 
Visit 
Training 15 
Training 26 
Training 37 
Discharge 
Days after HCT 
60-180 
60-365 
60-365 
90 
180 
270 
365 
Window (days) 
N/A 
  
 
±14 
±14 
±14 
(+120) 
Kit integrity monitoring11 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
Subject questionnaire12 
  
  
 
 
 
Y 
Y 
 
  
  
  
Y 
Provider questionnaire13 
 
 
 
 
 
 
 
 
 
 
 
Y 
Safety monitoring 
  
  
 
 
 
  
  
 
X 
X 
X 
X 
Obtain interim medical records14 
  
  
 
 
 
  
  
 
X 
X 
X 
X, Z 
 
X = performed for all randomized subjects 
Y = performed for DBS arm subjects only 
Z = performed for observational cohort only 
 
GRAY columns may not be required. Depending on when a subject enrolls in the study, the duration of participation will be between 26 and 44 weeks. Columns marked in GRAY 
apply to those subjects whose participation includes these time points. If the scheduled quarterly visit is within 10 days of subject randomization, the corresponding quarterly visit 
will be waived. 
 
 
 
 
11 Subjects are instructed to report of any failures in DBS kits during the duration of study participation. At each time of subject reporting, study staff is 
responsible for uploading the reported information to Advantage eClinical eCRF. If reported problem meets adverse (AE) criteria, a separate AE form must be 
submitted.  
12 Patient questionnaire will be given after 3rd training session, 1 month after discharge, and at the end of study. 
13 Primary care providers will be given a questionnaire at the time of last quarterly contact for medical records review. 
14 Obtain CMV testing frequency and results, presence of CMV disease, use of antivirals of CMV treatment, and use of steroids for GVHD 

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APPENDIX D: SAFETY REPORTING 
1. Adverse Event 
 
Is the event considered Unexpected? 
 
NO 
 
YES 
Reporter: 
Local clinical site 
 
Local clinical site 
Reports to: 
Data Center 
& 
Local IRB 
 
Data Center 
& 
Local IRB 
When: 
with timely 
completion of CRF 
for quarterly  
follow-up 
 
per local 
guidelines 
 
within 10 calendar 
days of site 
knowledge of event 
 
per local 
guidelines 
Format: 
Adverse Event 
CRF submitted via 
Advantage EDS for 
subject's quarterly 
follow-up 
per local 
guidelines 
 
Adverse Event 
CRF submitted via 
Advantage EDS for 
subject's quarterly 
follow-up 
per local 
guidelines 
 
  
 
 
 
  
 
 
Reporter: 
Coordinating Center 
 
Coordinating Center 
Reports to: 
Central IRB 
 
All clinical sites 
& 
Central IRB 
When: 
at time of annual review 
 
within 2 working 
days 
 
within 10 calendar 
days of knowledge 
of event 
 
 
 
 
 
 
 
Reporter: 
 
 
 
 
Local clinical sites 
 
 
Reports to: 
 
 
 
 
Local IRB 
 
 
When: 
 
 
 
 
per local guidelines 
 
 
 
 

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2. Serious Adverse Event of Special Interest 
Reporter: 
Local clinical site 
Reports to: 
DMID Pharmacovigilence Group 
& 
Local IRB 
When: 
within 1 working day of site awareness 
 
per local guidelines 
Format: 
SAESI form via fax or email 
 
per local guidelines 
 
 
 
 
 
 
 
 
Reporter: 
DMID Pharmacovigilence Group (reports individual events) 
 
 
Reports to: 
DMID Medical Monitor and  
DMID Clinical Project Manager 
& 
Local clinical sites  
& Coordinating Center 
 
 
 
Has a potential trend or 
suspicious pattern been identified? 
 
 
 
 
 
 
 
 
 
 
YES 
NO 
 
 
 
 
Reporter: 
DMID Medical Monitor  
(reports perceived trend) 
(end) 
 
Local clinical sites  
& Coordinating Center 
(individual events) 
 
 
Reports to: 
DSMB for review in ad hoc meeting 
 
 
Local & Central IRBs,  
respectively 
 
 
When: 
 
 
 
 
per local guidelines 
 
 
Reporter: 
DSMB  
(reports evaluation of potential trend) 
 
 
 
 
 
Reports to: 
DMID Medical Monitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporter: 
DMID Medical Monitor 
(reports DSMB evaluation) 
 
 
 
 
 
Reports to: 
FDA 
& 
Local clinical sites and 
Coordinating Center 
 
 
 
 
 
When: 
within 10 working days  
after receipt of DSMB evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reporter: 
 
 
Local clinical sites and 
Coordinating Center 
 
 
 
 
 
Reports to: 
 
 
Local & Central IRBs, 
respectively 
 
 
 
 
 
When: 
 
 
per local guidelines 
 
 
 
 
 
3. Unanticipated Problems 

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Reporter: 
Local clinical site 
Reports to: 
DMID 
& 
Local IRB 
When: 
as soon as possible, but no later than 10 working days after knowledge of event 
 
per local 
guidelines 
Format: 
?? 
 
 
 
 
 
 
 
Reporter: 
DMID (reports 
individual event) 
  
 
 
 
Immediate DMID evaluation:   
Does event represent an unreasonable risk to subjects? 
 
 
Reports to: 
Coordinating Center 
 
 
 
 
 
 
 
 
Reporter: 
Coordinating Center 
(reports individual 
event) 
 
 
 
Reports to: 
Central IRB 
 
 
 
When: 
per local guidelines 
 
 
 
 
 
 
 
 
 
YES 
NO 
 
 
 
 
 
Termination of all investigations 
 or parts of investigations 
presenting risk 
  
 
 
 
 
 
Termination shall occur no later 
than 5 working days after 
determination, and no later than 
15 working days after receipt of 
notification from local clinical site 
 
 
 
 
 
 
 
 
 
 
 
Reporter: 
 
 
DMID (reports results of evaluation, 
 including whether or not to terminate) 
 
 
Reports to: 
 
 
FDA 
& 
Local clinical sites and 
Coordinating Center 
 
 
When: 
 
 
no later than 15 working days  
after DMID first receives notice of event. 
 
 
 
 
 
 
 
 
 
Reporter: 
 
 
 
 
Local clinical sites and 
Coordinating Center 
 
 
Reports to: 
 
 
 
 
Local & Central IRBs, 
respectively 
 
 
When: 
 
 
 
 
per local guidelines