Conditions: Cytomegalovirus Infection
Keywords: CMV cytomegalovirus infections ganciclovir liver transplant preemptive therapy prophylaxis valganciclovir
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 205
Healthy volunteers: no

Brief summary:
This is a trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in R-D+ liver transplant patients. Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir, 900 mg orally once daily or preemptive therapy (weekly monitoring for CMV viremia by plasma PCR) for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia and continued until plasma PCR is negative on two consecutive weekly PCR tests). A minimum of 176 subjects will be enrolled in the study. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients.

Detailed description:
This is a prospective, randomized, multicenter trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in seronegative recipient- seropositive donor (R-D+) liver transplant patients.Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir 900 mg orally once daily or preemptive therapy for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia (monitored weekly) and continued until plasma PCR is negative on two consecutive weekly PCR tests. Study participants will be followed during the intervention period (100 days post randomization) and until 12 months post-transplant for CMV disease, toxicity, and clinical outcomes (opportunistic infections, rejection, graft loss and mortality). Drug safety labs will be assessed and recorded for the entire treatment period in both the prophylaxis and preemptive group. Re-transplantation and all-cause mortality will also be assessed at study closure and no longer than 5 years after enrollment. Additionally, the impact of the two CMV prevention strategies on CMV-specific cellular and humoral immune responses will be evaluated at 100 days after randomization, and 6 and 12 months post-transplant. A minimum of 176 subjects will be enrolled in the study. Allowing for over-enrollment to replace dropouts, up to 205 subjects may be enrolled to achieve the target enrollment of 176. Subjects will be randomized into one of the two groups in 1:1 ratio. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients. The secondary objectives are:1) to assess the two preventive strategies for clinical outcomes (major bacterial, fungal and non-CMV viral infections, rejection, graft loss and mortality) at one year post transplantation; 2) to assess the two preventive strategies for hematologic toxicity (assessment of neutropenia and receipt of hematopoietic growth factor during study days 1-107).

Arms:
arm 1: 900 mg of Valganciclovir given orally twice daily to Preemptive Therapy subjects upon detection of CMV viremia until plasma PCR is negative on two consecutive weekly PCR test. All dosages adjusted for renal dysfunction. n=88 arm 2: 900 mg of Valganciclovir given orally once daily to subjects for 100 days post transplantation. All dosages adjusted for renal dysfunction. n=88

Interventions: intervention 1: Valganciclovir
Intervention descriptions: intervention 1: Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 100 days post transplantation as prophylaxis. Valganciclovir, 900 mg given orally twice daily to Preemptive Therapy group subjects as a PET only after a positive CMV PCR test and stopped after PCR is negative for 2 consecutive weeks.

Protocol document:
Prot_SAP_000.pdf: 
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Prophylaxis versus Preemptive Therapy for the Prevention of 
CMV in High-Risk R-D+ Liver Transplant Recipients 
 [CMV Antiviral Prevention Strategies  
In D+R- Liver Transplants (“CAPSIL”)] 
 
DMID Protocol Number: 11-0073 
 
DMID Funding Mechanism: Contract # HHSN272201100041C 
IND status:  
DMID Clinical Project Manager: Walla Dempsey, Ph.D. 
Co-Principal Investigators: Nina Singh, MD and Ajit P. Limaye, M.D 
Version Number: 4.0 
January 21, 2016 
 


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STATEMENT OF COMPLIANCE 
 
Each investigator must adhere to the protocol as detailed in this document. Each investigator 
will be responsible for enrolling only those study participants who have met protocol eligibility 
criteria. This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP) and the following applicable regulatory 
requirements: 
 
U.S. Code of Federal Regulators applicable to clinical studies (45 CFR 46 and 21 CFR 
including parts 50 and 56 concerning informed consent and IRB regulations; and if under IND, 
21 CFR 312).” 
 
 
Completion of Human Subjects Protection Training 
Refer to: 
 
Http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html 
Http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp 
 


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                                                  Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICHE6 guidelines. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Statement of Compliance ............................................................................................................ ii 
List of Abreviations ..................................................................................................................... ix 
Protocol Summary ..................................................................................................................... xi 
1 
Key Roles .......................................................................................................................... 1 
2 
Background Information and Scientific Rationale................................................................ 4 
2.1 
Background .............................................................................................................. 4 
2.2 
Rationale .................................................................................................................. 4 
2.2.1 
Proposed mechanism for protection against late-onset CMV with 
preemptive therapy compared to prophylaxis (preliminary observations) ..... 6 
2.2.2 
Valganciclovir use ....................................................................................... 7 
2.3 
Potential Risks and Benefits ..................................................................................... 9 
2.3.1 
Potential Risks ............................................................................................ 9 
2.3.2 
Other risks ................................................................................................. 13 
2.3.3  Potential benefits ....................................................................................... 13 
3 
Objectives ........................................................................................................................ 14 
3.1    Study Objectives...................................................................................................... 14 
3.1.1 
 Primary objective ...................................................................................... 14 
3.1.2 
 Secondary objectives ............................................................................... 14 
3.1.3 
 Exploratory objectives .............................................................................. 14 
3.2 
Study Outcome Measures ...................................................................................... 14 
3.2.1 
 Primary outcome measure ....................................................................... 14 
3.2.2 
Secondary outcome measures (compared between 2 groups) .................. 14 
3.2.3 
 Exploratory end-points (compared between 2 groups) ............................. 15 
4. 
Study Design .................................................................................................................... 16 
5. 
Study Population .............................................................................................................. 17 
5.1  
Recruitment Strategies ........................................................................................... 17 
5.2  
Subject Inclusion Criteria ........................................................................................ 17 
5.3  
Subject Exclusion Criteria ...................................................................................... 17 
5.4  
Study Procedures ................................................................................................... 18 
5.4.1 
Screening .................................................................................................. 18 
5.4.2 
Randomization .......................................................................................... 18 
5.4.3 
Discontinuation from Study and Withdrawal .............................................. 19 
6 
Study Intervention/Investigational product ........................................................................ 21 
6.1 
Study Product Acquisition/Description .................................................................... 21 
6.2  
Valganciclovir Dosing and Administration ............................................................... 21 
6.2.1    Dosage ..................................................................................................... 21 
6.2.2   Drug administration .................................................................................. 22 
6.2.3 
 Conditions limiting valganciclovir administration ....................................... 23 
6.2.4 
 Rejection episodes ................................................................................... 23 
6.2.5 
Graft loss (retransplantation) ..................................................................... 23 
6.3 
Dose Modifications for Renal Dysfunction .............................................................. 24 
6.4 
Medication Compliance .......................................................................................... 24 


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6.5 
Concomitant Medications ....................................................................................... 25 
7 
STUDY SCHEDULE ......................................................................................................... 26 
7.1    Screening ............................................................................................................... 26 
7.2  
Consent .................................................................................................................. 26 
7.3 
Baseline research procedures pre-randomization (study day 0) ............................. 27 
7. 4 
Randomization (Study day 1) ................................................................................. 27 
7. 4.1 Randomization procedure ......................................................................... 28 
7. 4.2 Post-randomization baseline laboratory assessments ............................... 28 
7. 5 
 Treatment phase (study days 1-100) ..................................................................... 29 
7. 5.1 Prophylaxis group only .............................................................................. 29 
7. 5.2 Preemptive therapy group only .................................................................. 29 
7. 5.3 Laboratory assessments ........................................................................... 29 
7.6 
Follow up laboratory procedures ............................................................................ 31 
7. 6.1  7 day Post End of Treatment .................................................................... 31 
7.6.2  Immunologic studies (immune assays and lymphocyte count) All 
subjects ..................................................................................................... 32 
7.6.3 
Pregnancy test for all females of childbearing potential ............................. 32 
7.6.4 
Suspected CMV disease sample collection (Study day 1 – 12 month)....... 32 
7.6.5   CMV resistance testing ............................................................................. 33 
7. 7 
Non-laboratory Procedures and Clinical Assessments Schedule (see also 
Schedule of Procedures appendix A) .................................................................... 33 
7.7.1 
Study day 1-100 ........................................................................................ 33 
7.7.2 
Study day 1-107 ........................................................................................ 34 
7.7.3 
Study day 1 through one year ................................................................... 34 
7.7.4 
Adverse Event Monitoring and Reporting (Study day 1 through 7 days 
post end of study treatment phase) ........................................................... 35 
7.7.5 
Study Specific Medication Compliance Visit (Study day 30, 60, and end 
of treatment +14 days) .............................................................................. 35 
7.8 
Early Termination Visit ........................................................................................... 35 
7.8.1  Withdrawal of consent ............................................................................... 35 
7.8.2  Early termination for re-transplantation between study day 30 and 365 ..... 35 
7.9 
Therapy Discontinuation ......................................................................................... 36 
7.10  Final Study Visit ..................................................................................................... 36 
7.11 Study Closure......................................................................................................... 36 
7.12 Total blood volume collected .................................................................................. 36 
7.13 Future Use of Stored Specimens............................................................................ 37 
8 
Study Procedures/Evaluations .......................................................................................... 38 
8.1 
Clinical Evaluations ................................................................................................ 38 
8.1.1    Baseline demographics/medical history .................................................... 38 
8.1.2 
Adverse event assessment ....................................................................... 38 
8.1.3 
Neutropenia assessment ........................................................................... 38 
8.1.4 
Assessment of CMV disease ..................................................................... 39 
8.1.5 
Secondary and Exploratory Outcome Assessments .................................. 41 


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8.1.6    Procedure for clinical data collection ......................................................... 41 
8.2 
Laboratory Evaluations ........................................................................................... 41 
8.2.1  Hematology safety labs ............................................................................. 42 
8.2.2 
Chemistry safety labs ................................................................................ 42 
8.2.3 
CMV PCR surveillance monitoring (To be assessed in preemptive 
therapy subjects only) ............................................................................... 42 
8.2.4 
Special Assays or Procedures ................................................................... 43 
8.2.5 
Specimen Preparation, Handling, and Shipping ........................................ 44 
9 
Assessment of Safety ....................................................................................................... 45 
9.1 Responsibilities .......................................................................................................... 45 
9.2 
Adverse Event (AE) Definitions .............................................................................. 45 
9.2.1 
ICH E6 Definition ....................................................................................... 45 
9.2.2 
FDA Definition ........................................................................................... 46 
9.2.3 
CAPSIL Definition ..................................................................................... 46 
9.3 
Documentation of Reportable AEs ......................................................................... 46 
9.4 
Investigator’s Assessment of Adverse Events ........................................................ 46 
9.4.1 
Serious Adverse Events (Assessment of Seriousness) ............................. 47 
9.4.2 
Assessment of Severity ............................................................................. 49 
9.4.3 
Assessment of Relationship to Study Product or Procedure ...................... 49 
9.5 
Reporting Interval ................................................................................................... 50 
9.6 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND ............ 50 
9.7 
Reporting of Pregnancy .......................................................................................... 50 
9.8 
Safety Monitoring By the DMID Safety Oversight Mechanism ................................ 51 
9.8.1 
Data and Safety Monitoring Board ............................................................. 51 
9.8.2 
Discontinuation of Study Enrollment and Study Product Administration 
for all Subjects in the Study ....................................................................... 51 
9.8.3   Halting rules ............................................................................................... 52 
10 
End-Points Committee (EPC) ........................................................................................... 53 
10.1 Composition ........................................................................................................... 53 
10.2 Responsibilities and Data Flow .............................................................................. 53 
11  
 Site Monitoring Plan ........................................................................................................ 55 
12 
 Statistical Considerations ................................................................................................ 56 
12.1   Sample size calculations ........................................................................................ 56 
12.2 Treatment groups ................................................................................................... 57 
12.3 Populations for analysis ......................................................................................... 58 
12.3.1 Intent-to-treat (ITT) population ................................................................... 58 
12.3.2 Modified intent-to-treat population ............................................................. 58 
12.3.3 Screen failures .......................................................................................... 58 
12.4 Data Analyses ........................................................................................................ 58 
12.4.1 General considerations ............................................................................. 58 
12.4.2 Missing data .............................................................................................. 59 
12.4.3 Disposition of subjects ............................................................................... 59 
12.4.4 Baseline assessments ............................................................................... 59 


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12.4.5 Duration of treatment, compliance, and participation ................................. 59 
12.5 Primary outcome measures .................................................................................... 60 
12.5.1 Definition ................................................................................................... 60 
12.5.2  Missing with respect to the primary endpoint ............................................. 60 
12.5.3 Primary outcome analysis ......................................................................... 60 
12.5.4 Primary end point-CMV disease [ITT group] includes all randomized 
subjects] .................................................................................................... 60 
12.5.5 Primary end point-CMV disease [modified ITT group] ............................... 61 
12.5.6 End point committee and investigator-determined CMV disease ............... 61 
12.6 Secondary outcome measures ............................................................................... 61 
12.6.1  Clinical outcomes ..................................................................................... 61 
12.6.2 Hematologic toxicity .................................................................................. 63 
12.6.3  Adverse events ........................................................................................ 63 
12.7 Exploratory end-points ........................................................................................... 64 
12.7.1 Clinical outcomes ...................................................................................... 64 
12.7.2  Use of hematopoietic growth factors ........................................................ 67 
12.7.3  Immunologic endpoints [CMV-specific immunity] ...................................... 67 
12.7.4 Cost effectiveness analysis ....................................................................... 68 
12.8          Interim and Final Analysis ............................................................................. 69 
12.8.1 Interim analysis ......................................................................................... 69 
12.8.2 Interim analysis showing futility ................................................................. 70 
12.8.3 Final analysis ............................................................................................ 70 
13    Source Documents and Access to Source Documents ..................................................... 71 
14 
Quality Control and Quality Assurance ............................................................................. 72 
15 
Ethics/Protection of Human Subjects ................................................................................ 73 
15.1 Ethical Standard ..................................................................................................... 73 
15.2 Institutional Review Board ...................................................................................... 73 
15.3 Informed Consent Process ..................................................................................... 73 
15.4 Exclusion of Women, Minorities and Children (Special Populations) ...................... 74 
15.5 Subject Confidentiality ............................................................................................ 75 
15.6 Study Discontinuation ............................................................................................. 75 
15.7 Future Use of Stored Specimens............................................................................ 76 
16 
Data Management Plan .................................................................................................... 77 
16.1     Data management responsibilities ......................................................................... 77 
16.2    Data capture methods ........................................................................................... 77 
16.3   Types of data ........................................................................................................ 78 
16.4   Timing of reports ................................................................................................... 78 
16.5 Study record retention ............................................................................................ 78 
16.6 Protocol deviations ................................................................................................. 78 
17 
Publication Policy ............................................................................................................. 80 
Literature References................................................................................................................ 81 
Supplements/Appendices ......................................................................................................... 87 
Appendix A: Schedule of Events ............................................................................................... 88 


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APPENDIX B: Blood Volume Collected ..................................................................................... 90 
APPENDIX C: Expected events for liver transplant patients ...................................................... 92 
 
 
 
 


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LIST OF ABREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ANC 
Absolute Neutrophil Count 
bid 
Twice a day 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CMV 
Cytomegalovirus 
CONSORT 
Consolidated Standards of Reporting Trials 
CFR 
Code of Federal Regulations 
CrCl 
Creatinine Clearance  
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EPC 
End-Point Committee 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
HCT 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HSV 
Herpes Simplex Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IFN 
Interferon 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MedDRA  
Medical Dictionary for Regulatory Activities 


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mg 
Milligram 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NCI 
National Cancer Institute, NIH, DHHS 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
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 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PET 
Preemptive Therapy 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
po 
Per os (Latin for ‘taken by mouth’) 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life Years 
QC 
Quality Control 
Qd 
RRT 
One a day 
Renal replacement therapy 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOC 
Standard of Care 
SOT 
Solid organ transplant 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SPICE 
Simplified Presentation of Incredibly Complex Evaluations 
US 
United States 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY 
 
Title: Prophylaxis versus Preemptive Therapy for Prevention of CMV in High-Risk R-/D+ Liver 
Transplant Recipients [‘CAPSIL’ Study] 
 
Population: CMV seronegative recipients (18 years of age or older) of a liver transplant from a 
CMV seropositive donor (R-/D+) 
 
Phase: IV 
 
Number of Clinical Sites: 6 
 
Study Duration: 7 years 
 
Subject Participation Duration: Until the closure of the study and not to exceed 7 years from 
enrollment. 
 
Description of Agent or Intervention: Oral Valganciclovir hydrochloride: 2-[(2-amino-6-oxo-6, 
9-dihydro-3H-purin-9-yl) methoxy]-3-hydroxypropyl (2S)-2-amino-3-methylbutanoate. Currently 
marketed as Valcyte ®. 
 
Objectives:  
Primary objective 
The primary objective is to compare prophylaxis versus preemptive therapy using valganciclovir 
for the prevention of CMV disease in R-/D+ liver transplant recipients 
 
Secondary objectives :To assess the two preventive strategies for:  
• Clinical outcomes (major bacterial, fungal and non-CMV viral infections, rejection, 
graft  loss and mortality) 
• Hematologic toxicity (assessment of neutropenia and receipt of hematopoietic 
growth factor during study days 1-107) 
 
Exploratory objectives :To assess the two preventive strategies for:  
• The development of CMV-specific immunity following transplantation 
• Cost effectiveness of the regimens  
 
Study Outcome Measures 
 
Primary outcome measure: The primary outcome measure is the incidence of CMV disease by 
12 months post-transplant.  
Secondary outcome measures (compared between 2 groups) 
1. 
 Clinical outcomes within 12 months post-transplant 
• 
Incidence of late-onset CMV disease (CMV disease occurring  after 
100 days post-randomization) 


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• 
Incidence of major bacterial, fungal, and non-CMV viral infections  
• 
Incidence of allograft rejection 
• 
Incidence of graft loss (retransplantation)                
• 
All-cause mortality 
2.         Hematologic toxicity (assessed until 107 days post-enrollment) 
• 
Incidence of neutropenia (ANC <1,000 and <500/µL) 
• 
Receipt of hematopoietic growth factor during study days 1-107 ) 
 
Exploratory end-points (compared between 2 groups) 
1. 
Clinical outcomes  
• 
Time to onset of CMV disease (disease free survival) through 12 
months post-transplant 
• 
Incidence of graft loss (retransplantation) assessed until study           
closure 
• 
All-cause mortality assessed until study closure. 
• 
Incidence of post-transplant malignancies  
• 
Renal insufficiency requiring renal replacement therapy 
• 
Incidence of opportunistic infections through study closure 
 
2. 
Hematopoietic growth factor (granulocyte colony stimulating factor) for 
neutropenia  
• 
Frequency of use 
• 
Number of dosages of growth factor required 
 
Immunologic endpoints: 
• 
CMV-specific immunity at 100 days, 6 and 12 months post-
transplant 
a. 
CMV-specific T-cell responses 
b. 
CMV-specific neutralizing antibody responses  
 
3.      Cost effectiveness of the 2 approaches: 
• 
Total costs for each regimen 
• 
Cost utility analysis (cost per quality adjusted life-years) 
 
Study Design: This is a prospective, randomized, multicenter trial of preemptive therapy vs. 
prophylaxis for prevention of CMV disease in R-D+ liver transplant patients. Patients meeting 
study criteria and who have provided informed consent will be randomized within 10 days of 
transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir 900 
mg orally once daily or preemptive therapy (weekly monitoring for CMV viremia by plasma PCR) 
for 100 days post- randomization with initiation of oral valganciclovir 900mg orally twice daily at 
onset of CMV viremia and continued until plasma PCR is negative on two consecutive weekly 
PCR tests). Valganciclovir dosages will be adjusted for renal dysfunction. Study participants will 
be followed during the intervention period (100 days post randomization) and until 12 months 
post-transplant for CMV disease, toxicity, and clinical outcomes (opportunistic infections, 
rejection, graft loss and mortality). All-cause mortality, rejection episodes, graft loss and 
retransplantation, opportunistic infections , need for dialysis, and post-transplant malignancies 
will be assessed at one year and until study closure (no longer than 7 years from enrollment 


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maximum). Additionally, the impact of the two CMV prevention strategies on CMV-specific 
cellular and humoral immune responses will be evaluated at 100 days after randomization, and 6 
and 12 months post-transplant. A minimum of 176 subjects will be enrolled in the study. Allowing 
for over-enrollment for dropouts, withdrawals and deaths prior to 6 months, up to 205 subjects 
may be enrolled to achieve the target enrollment with one year follow up. 
 
Estimated Time to Complete Enrollment: Approximately 3.5 years 
 
 


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Schematic of Study Design:  
 
 
 
 
 
 
Pre or post liver transplant patient with CMV negative serology 
 
 
 
 
 
 
-Medical record screening for inclusion/exclusion criteria 
Day of enrollment        -Informed consent 
 
 
 
 
 
-Study specific screening procedures: 
 
 
 
 
 
-Safety labs (must be with-in 48 hours of randomization) 
 
 
 
 
 
-Verification of inclusion/exclusion criteria 
 
 
 
 
Randomization (study day 1) must be within 10 days of transplant 
 
 
             
                    
 
 
 
 
Preemptive therapy  
 
                      
Prophylaxis 
 
 
 
 
 
 
- CMV monitoring (weekly)  
 
 
                 
VGCV  
 
- VGCV upon positive PCR 
    
 
        - AE/SAE monitoring 
 
 
 
 
 
        - Clinical evaluations  
 
 
 
 
 
        - Safety Labs 
 
 
 
 
 
        - Immune assay (day 100) 
 
 
 
 
   
 
 
 
   
       
     Discontinuation of antiviral  
  100 days   
            
            
 
 
Prevention strategy 
 
 
 
 
 
 
 
 
 
 
 
Clinical evaluations 
 
 
 
 
 
 
Immune assay (6 month and 12 month) 
                    
 
      
 
      
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
Final Visit (12 months post-enrollment) 
Interim Analysis (After enrollment of ~60 patients with 12 months follow up) 
                                         Final assessment at study closure 


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1 
Key Roles 
Individuals: 
DMID Clinical Project Manager:  Walla Dempsey, Ph.D. 
Program Officer for Clinical Research 
Virology Branch  
Division of Microbiology and  
      Infectious Diseases, NIAID, NIH, HHS 
Phone: 301 496-7453  
Fax  301 480 1594  
Email:  wdempsey@niaid.nih.gov  
DMID Medical Monitor  
Venus Shahamatdar, M.D. 
Office of Clinical Research Affairs 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
 
 
Office: 301-443-7707 
Fax: 301-480-0728 
Email: venus.shahamatdar@nih.gov 
 
Principal Investigators:  Nina Singh, MD & Ajit Limaye, MD 
 
 
PI:  Nina Singh, MD 
Falk Medical Building, Suite 3-A 
3601 Fifth Avenue,  
Pittsburgh, PA. 15213  
Email:  nis5@pitt.edu 
Phone 412-360-1688 
Fax: 412-360-6312 
 
 
Co PI: Ajit Limaye, MD 
University of Washington Medical Center 
1959 NE Pacific Street, Box 357110 
Seattle, WA 98195  
Email: limaye@u.washington.edu  
Phone -206-598-6131 
 
 


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Institutions: 
Site Investigators 
 
University of California, Los Angeles 
Investigator: Drew J. Winston MD, 
UCLA Medical Center 
10833 Le Conte Avenue 
CHS 42-121 
Los Angeles, CA  90095 
Phone: 310-825-6264 
Fax # 310-206-5511 
Email: dwinston@mednet.ucla.edu 
 
Mount Sinai Medical Center 
Investigator Shirish Huprikar, MD,  
Department of Medicine Mount Sinai 
One Gustave L. Levy Place  
Box 1090  
New York, NY 10029 
Phone: 212-241-6885 
Fax: 212-534-3240 
Email: Sherish.Huprikar@mssm.edu 
 
Mayo Clinic 
Investigator: Raymund R. Razonable, MD,   
Mayo Clinic 
Marian Hall 5 
200 First Street SW 
Rochester, MN 55905  
Phone: 507-284-3747 
Fax: 507-255-7767  
Email: Razonable.raymund@mayo.edu 
 
Emory University 
Investigator: G. Marshall Lyon MD,   
Emory University 
101 Woodruff Circle  
Suite 2101 
Atlanta, GA 30322 
Phone: 404-712-2051 
Fax: 404-712-7246 
Email: Marshall_Lyon@emoryhealthcare.org 
 
 


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University of Pittsburgh  
Investigator:   Fernanda P. Silveira MD, MS 
University of Pittsburgh 
Falk Medical Building, Suite 3-A 
3601 Fifth Avenue 
Pittsburgh, PA 15231 
Phone: 412-648-6512 
Fax: 412-648-6399 
Email: Silveirafd@upmc.edu 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background  
Cytomegalovirus (CMV) is a human herpes virus known to infect ~50-90% of the adults 
and is a major opportunistic pathogen in immunosuppressed populations such as transplant 
recipients. The term CMV infection indicates evidence of replicating virus as detected by 
laboratory testing in a blood sample (viremia). CMV disease on the other hand is defined by the 
presence of symptoms and signs attributable to this virus. CMV disease can manifest as viral 
syndrome with a flu-like illness or tissue invasive CMV disease and there are standardized 
criteria for their definitions in the literature (1, 2). Despite current preventive strategies, this virus 
continues to have a negative impact on outcomes in transplant recipients. The importance of 
preexisting immunity to CMV is evidenced by the substantially higher rates of infection and 
disease in subjects undergoing primary CMV infection (CMV naïve or seronegative recipients of 
CMV-seropositive allografts or R-/D+ recipients). In addition to overt disease, CMV-mediated 
immunomodulation can lead to indirect sequelae such as opportunistic infections, rejection, graft 
loss and reduced survival (3-5). Thus, strategies to optimally reduce the incidence and impact of 
CMV have the potential to significantly improve the outcome of transplantation. 
2.2 
Rationale 
There are two major strategies for CMV prevention in clinical setting; prophylaxis and 
preemptive therapy(6). With the strategy of prophylaxis, antiviral drug is administered to all 
patients at any risk for CMV disease, usually for 100 days post-transplant. In preemptive 
therapy, antiviral drug is specifically targeted to patients deemed to be at highest risk for CMV 
disease, as determined by the detection of early viremia. Prompt initiation of antiviral therapy at 
the first detection of early viremia prevents progression to CMV disease (7-9). Each of the 
strategies has been studied individually and been shown to be effective for the prevention of 
CMV disease (compared to either placebo or no prevention strategy), but there is a striking 
paucity of direct comparative studies. The relative benefit of one strategy versus another has 
long been debated and there is strong support within the transplant community for a well-
designed direct comparison of the two strategies for prevention of CMV disease in high-risk R-
/D+ patients. This study will test the null hypothesis that the incidence of CMV disease in the 
prophylaxis intervention group is equal to the incidence in the preemptive therapy group. 
Defining the optimal strategy for the prevention of CMV is expected to have significant clinical 
benefit in the management of transplant recipients and to provide important insight into the 
immunologic mechanisms that are responsible for control of CMV in this setting. 
 
Although the approach of preemptive therapy has been shown to be useful for 
prevention of CMV in transplant patients in previous studies, the totality of evidence supporting 
its use is more limited than for prophylaxis. As a result, prophylaxis with valganciclovir (given its 
high oral bioavailability and convenient once daily dosing) has emerged as the dominant 
strategy for the prevention of CMV in R-/D+ transplant patients (10, 11).  However, late-onset 
CMV disease, defined as CMV disease occurring after 3 months post-transplant is now 


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recognized as a significant complication with the use of prophylaxis, particularly in R-/D+ 
patients (12-15). An evidence-based review showed that the incidence of CMV disease and 
specifically that of late-onset CMV disease in the valganciclovir era in these patients is 
substantially higher with prophylaxis than preemptive therapy (16). Overall, CMV disease has 
been documented in 2.6% of patients receiving preemptive therapy in the current era and in 
contrast to prophylaxis, it occurs largely within 100 days of transplantation (16). The frequency 
of CMV disease with prophylaxis and preemptive therapy based on studies in recent literature is 
summarized below. While, there are significant limitations of these data, including the fact that 
these are non-comparative studies and include heterogeneous transplant populations, there is a 
clear trend towards higher rates of CMV disease in patients who received prophylaxis compared 
to preemptive therapy. 
 
 
 
 
In a recent evidence-based analysis of CMV prevention based on meta-analytic and 
multiple regression methodologies, 100 days of antiviral prophylaxis did not show superior 
efficacy for late-onset CMV disease and carried a significantly higher risk of neutropenia (28). 
An alternative approach that has been embraced by industry is to extend the duration of 
prophylaxis (2). Yet, prolonging the duration of prophylaxis is not entirely protective against late-
onset CMV disease as evident by data showing CMV disease rate of 16% in the IMPACT study 
and 31-37% in other reports despite 6 months of prophylaxis (18, 19, 29). Ironically, it is 
plausible that shorter courses of antiviral agent implicit in preemptive therapy may be more 
effective for the long-term control of CMV since the lowest disease (30) rates reported with 6 
months of prophylaxis are still substantially higher than those with preemptive therapy (2, 15).  
There is compelling evidence to suggest that late-onset CMV disease is a significant 
contributor to poor outcomes after transplantation. CMV disease occurring after antiviral 
prophylaxis in liver transplant recipients was independently associated with higher overall 
mortality at 1 year (HR, 5.1, p=0.002) and even more strongly with bacterial and fungal 
infection-associated mortality (HR 11, p=0.002) (12).  Furthermore, graft and patient survival in 
liver transplant recipients was significantly worse with late-onset compared to early-onset 
CMV(31). In R-/D+ kidney transplant recipients receiving prophylaxis, tissue‐invasive disease 
was independently associated with allograft loss and mortality (32). Although not all studies 
have documented poor outcomes with late-onset disease, aforementioned data indeed suggest 
that late-onset CMV disease is not a benign occurrence. 
CMV disease rates with antiviral prophylaxis for 3months 
 
Study Sample 
size 
Type of 
transplant 
Drug 
R/D 
status 
Follow 
up 
CMV disease 
(%) 
(9) 
177 
Liver 
VGCV 
R-/D+ 
12 mo. 
19 
(17) 
29 
Liver 
VGCV 
R-/D+ 
12 mo. 
30 
(12) 
38 
Liver 
OGCV 
R-/D+ 
12 mo. 
26 
(2) 
163 
Kidney 
VGCV 
R-/D+ 
12 mo. 
36.8 
(18) 
158 
Kidney-panc 
VGCV 
R-/D+ 
12 mo. 
39 
(19) 
25 
Kidney 
VGCV 
R-/D+ 
12 mo. 
40 
(13) 
67 
Liver 
OGCV/VGCV 
R-/D+ 
12 mo. 
28 
(14) 
54 
Liver 
VGCV 
R-/D+ 
19mo. 
26 
(15) 
39 
Kidney 
OGCV 
R-/D+ 
12 mo. 
31 
CMV disease rates with preemptive therapy 
 
Study 
Sample  
size 
Type of  
transplant 
Drug 
R/D  
status 
Follow up 
CMV disease  
(%) 
(20) 
41 
Liver 
OGCV 
R-/D+ 
4 mo. 
0 
(21) 
22 
Liver, Kidney 
VGCV 
R-/D+, R+ 
12 mo. 
0 
(22) 
36 
Liver 
OGCV/ 
VGCV 
R-/D+ 
20.4 pt/yr 
0 
(23) 
42 
Kidney, KP  
VGCV 
R-/D+ 
12 mo. 
0 
(24) 
36 
Liver 
VGCV 
R-/D+ 
62.8 pt/yr 
0 
(25) 
11 
Liver 
VGCV 
R-/D+ 
18 mo. 
0 
(26) 
30 
Liver 
VGCV 
All 
12 mo. 
0 
 
(27) 
36 
Kidney 
VGCV 
R-/D+,R+ 
12mo. 
5.5 
 
 
 
 
 
 
 


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Table 1: Proportion of responders for CMV-specific CD8 lymphocytes producing IFN- γ 
according to the antiviral strategy 
Assay 
Stimulus 
Preemptive 
(R-D+) 
Prophylaxis 
(R-D+) 
Control 
(R+) 
P-value 
CD8 IFN-γ 
pp65 pepmix 
 
SEB 
8/15 (53%) 
 
14/15 (93%) 
3/19 (16%) 
 
14/19 (93%) 
7/20 (35%) 
 
20/20 (100%) 
0.03 
 
0.19 
Substantial evidence supports a role for CMV-specific immunity in the control of CMV in 
transplant patients (33-36) and there are several lines of evidence suggesting that a greater 
development of CMV-specific protective immune responses with preemptive therapy is the 
underlying mechanism for the relative protection against late-onset CMV disease with this 
approach. First, preemptive therapy, by its inherent design allows for controlled CMV replication 
to occur before an antiviral agent is administered. This antigen exposure is proposed to result in 
immune priming and hence enhancement of CMV-specific humoral and cellular immune 
responses that are critical for long-term control of the virus (37). In contrast, viral replication is 
almost completely suppressed with the use of antiviral prophylaxis (9) thereby preventing 
effective immune priming. Additionally, ganciclovir per se has an anti-proliferative effect on T 
cells (38). For example, at achievable serum concentrations, ganciclovir reduced T-cell 
proliferation by 50% and this effect was comparable to that of cyclosporine (38). There is 
however, precedence that delayed recovery of virus-specific host response is not unique with 
the receipt of prophylaxis for CMV, as this phenomenon has been observed with prolonged 
exposure to other nucleoside agents and for herpes viruses other than CMV (39, 40). 
2.2.1 Proposed mechanism for protection against late-onset CMV with 
preemptive therapy compared to prophylaxis (preliminary observations) 
 
To examine the hypothesis that preemptive therapy results in earlier and more robust 
CMV-specific immunity than prophylaxis, a prospective pilot study at the Universities of 
Washington and Pittsburgh was conducted in liver transplant patients. CMV-specific immune 
responses using multifunctional intracellular cytokine staining (ICS) were assessed at 3 months 
post-transplant in the following cohorts: preemptive therapy (R-/D+, n=16), prophylaxis (R-/D+, 
n=29), and an additional control group that received antiviral prophylaxis (R+, n=24). Although a 
precise quantitative immunologic correlate of protection against CMV disease in transplant 
patients has not been defined, virus-specific multifunctional cytokine-producing CD4 and CD8 T-
cells have recently been  shown to be functionally superior to mono-functional T-cells (41) and 
to be associated with clinical protection (42) in HIV-infected individuals. An association of multi-
functionality with protection against CMV infection/disease has also been suggested in other 
studies (43, 44). There were a significantly higher proportion of patients with detectable 
monofunctional CMV-specific CD8 T-cells among the preemptive therapy group compared to 
prophylaxis; the proportion of responders in the preemptive therapy group was similar to the R+ 
positive control group (Table 1).  
 
 
 
 
 
 
 
 
In addition, quantitative multifunctional intracellular cytokine analysis showed higher 
levels of mono- and polyfunctional CMV-specific IFN-γ-producing CD8 to both pp65 and IE-1 
overlapping peptide pools in the preemptive therapy compared to prophylaxis group (Figure 1). 
Importantly, as for monofunctional CMV-specific CD8 T-cells, the levels among the preemptive 
therapy group were similar to those among the R+ positive control group. 


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Figure 2. Mono- and polyfunctional CMV-
specific  CD8 T cells at 3 months in patients 
with and without late CMV disease. 
Figure 1: Mono- and multi-functional CMV-specific 
CD8 T-cells to pp65 and IE-1 according to antiviral 
strategy at 3 months after SOT 
 
These results suggest greater development of 
CMV-specific T-cell responses with preemptive therapy 
compared to prophylaxis. And similar to data from other 
studies summarized above, the incidence of late-onset 
of CMV disease in this cohort was significantly higher in 
the prophylaxis compared to preemptive therapy group 
(10/29 [34%] vs. 0/19 [0%]), respectively, p=0.0035). 
Multifunctional T cells were more common among 
subjects without CMV disease (Figure 2). However, 
since this was not a randomized controlled study, 
potential confounders (induction vs. no induction 
immunosuppression, intensity of maintenance 
immunosuppression etc.) might also explain, at least in 
part, these apparent differences, and thus there is a 
need to assess these parameters more definitively in 
the context of a randomized controlled trial.  
 
We will conduct immunologic testing for CMV-
specific T-cell and neutralizing antibodies (UL128-131 
epithelial/endothelial targets) in the study subjects. 
Previous studies have considered transplant patients with > 0.4 CMV-specific CD4+ and CD8+ 
T-cells/µL as responders (45). Our study will assess differences in T-cell and antibody-mediated 
responses in the 2 groups and determine thresholds that confer protection against CMV 
disease. 
 
Prophylaxis is considered to have a greater salutary effect on CMV-related indirect 
outcomes (46). However, this has not been incontrovertibly shown in liver transplant recipients. 
In a randomized, placebo-controlled trial, no difference in 
rejection, graft loss or mortality at 12 months was 
observed with the use of oral ganciclovir prophylaxis 
versus placebo (8). Studies comparing ganciclovir with 
other agents e.g., acyclovir have yielded similar results 
(47). A report of the Collaborative Transplant Study which 
is a large database from 435 transplant centers in 44 
countries concluded that unlike other organ transplant 
recipients, CMV prophylaxis had no significant impact on 
the rate of acute rejection or graft survival in liver 
transplant recipients (48). There is also evidence that all 
outcomes with the use of preemptive therapy in liver 
transplant recipients are comparable to those in patients 
who never developed CMV infection (22).  
2.2.2 Valganciclovir use  
The manufacturer’s prescribing information states that valganciclovir is not indicated for 
use in liver transplant recipients. This is based on the results of the PV-16000 trial subgroup 
analysis in which liver transplant recipients receiving valganciclovir versus oral ganciclovir had a 


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higher rate of CMV disease. While not considered to be a statistical aberration (28), no 
published, proposed or biologically plausible explanation exists for these observations. Several 
lines of evidence discussed above suggest that greater development of CMV-specific protective 
immune responses is the underlying mechanism for the protection against CMV disease and 
that reconstitution of these responses is greater following preemptive therapy than prophylaxis. 
Additionally, ganciclovir per se has anti-proliferative effect on T-cells. Preemptive therapy 
appears to better facilitate the development of CMV-specific immune responses that ultimately 
allow for control of CMV and resultant protection from CMV disease.  Thus, it is likely that the 
greater risk of CMV disease with valganciclovir in the PV-16000 trial was unrelated to any 
unique attribute of this drug, but rather to the approach or the manner in which it was employed 
i.e., as prolonged prophylaxis. 
 
 Valganciclovir is widely used as standard care for CMV prevention in liver transplant 
recipients. Furthermore, according to a survey of clinical practices in the US, valganciclovir is 
the most commonly used antiviral agent for prophylaxis in liver transplant recipients. 
International Consensus Guidelines of The Transplantation Society recommend either oral 
ganciclovir or valganciclovir for prophylaxis in R-/D+ liver transplant recipients (11). The 
guidelines of the Canadian Society of Transplantation’s Consensus Workshop on CMV and the 
British Transplantation Society also recommend valganciclovir in liver transplant recipients (30, 
49). In Canada and Europe, valganciclovir is approved for use in liver transplant recipients. 
Thus, use of valganciclovir in context of a clinical trial proposed herein is justifiable.  
 
The other drug that was carefully considered but ultimately rejected was oral ganciclovir. 
The key argument against its use is its poor oral bioavailability and the consideration that the 
most active available anti-CMV agent should be used in the preemptive therapy arm since these 
subjects will have viremia. It is proposed that in a CMV-naïve host, an anti-CMV drug must be > 
93.3% effective to fully inhibit viral growth; the estimated efficacy of iv ganciclovir (5 mg/kg bid) 
for inhibition of viral growth is ~91.5% and that of oral ganciclovir is only~46.5% (50). Use of oral 
ganciclovir in the prophylaxis group was also rejected, the rationale being concerns for low 
bioavailability, large pill burden, and data suggesting that it is associated with a higher incidence 
of resistance compared to valganciclovir (51). Additionally, as of May 2009, oral ganciclovir is 
unavailable from the manufacturer (Ranbaxy) due to issues related to acquisition of raw 
materials. 
 
The usual dosage of valganciclovir when used for prophylaxis is 900 mg orally daily. For 
preemptive therapy, a 900 mg bid dose is used (21, 24). The rationale for the dose in this group 
is that CMV infection (viremia) would already have occurred and therefore the purpose of 
antiviral therapy is to prevent the progression of asymptomatic infection to CMV disease. 
Indeed, preemptive therapy is often termed “early treatment” strategy for the aforementioned 
reason. Since the dose of valganciclovir that achieves blood levels equivalent to 5 mg/kg bid of 
iv ganciclovir (or the treatment dose for CMV) is 900 mg po bid (52), the drug dosage utilized for 
preemptive therapy will be 900 mg bid.  
 
If a subject is unable to tolerate oral medications, intravenous ganciclovir may be 
substituted for oral valganciclovir because the study intends to compare the approach to 
prevention of CMV and not a particular formulation of ganciclovir. Since drug levels achievable 
with valganciclovir are similar to that with intravenous ganciclovir, brief substitution with the 


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latter agent is unlikely to confound any of the end-points and will prevent unnecessary 
discontinuation of the drug and exclusion of subjects. 
The participating sites are currently using valganciclovir prophylaxis for 100 days after 
liver transplantation for CMV prevention as standard of care with drug costs charged to the 
patient or third-party payers as part of routine clinical care.  In this study, one group of subjects 
will continue to receive standard of care (valganciclovir prophylaxis) and the other group will 
receive preemptive therapy with valganciclovir only upon evidence of CMV infection.  For the 
group randomized to preemptive therapy, the drug use is estimated to be 43% less. No 
additional costs for valganciclovir use for study purposes will be incurred by the participating 
institution, subject or another party for participants randomized to either preemptive therapy or 
to prophylaxis. 
Use of model for end-stage liver disease (MELD) scoring system as the basis for 
prioritizing organ allocation by the United Network for Organ Sharing in the current era has led 
to a substantially higher number of patients undergoing transplantation who have renal 
dysfunction or are requiring dialysis than time in the previous years (53,54). In order that our 
study is considered representative of liver transplantation practices at present and in order for 
our findings to be generalized to the transplant population undergoing in current clinical settings, 
it is important to include liver transplant subjects that require dialysis. Data in patients on 
dialysis have documented no pertinent issues that could influence the pharmacokinetics and 
bioavailability of valganciclovir in the study subjects (55). Furthermore, all study sites are 
currently using valganciclovir in dialyzed patients as standard of care. Receipt of dialysis has no 
effect on CMV disease rate in transplant recipients. However, given higher post-transplant 
mortality in patients receiving dialysis (56), subjects will be stratified by receipt of dialysis and 
sample size calculations will take into consideration the mortality within the first year. 
We propose to conduct a randomized trial comparing prophylaxis versus preemptive 
therapy for the prevention of CMV disease in R-/D+ liver transplant recipients. The key goals of 
the study are to assess the efficacy of the 2 clinically used approaches for CMV prevention and 
not the efficacy of the drug per se. In this regard, this is a strategy trial based on the clinical 
practice of medicine using a drug that is currently the standard of care in these patients. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
2.3.1.1 
Overview 
The majority of transplant centers in the United States are currently routinely using 
valganciclovir or intravenous ganciclovir for prevention of CMV infection and disease in liver 
transplant recipients, either as primary antiviral prophylaxis or in a preemptive therapy strategy 
(10).  Similarly, acyclovir at HSV suppressive doses is routinely used for the prevention of HSV 
reactivation for the first month post-transplant in patients who are not receiving CMV 
prophylaxis, and is a grade I recommendation in the American Society of Transplantation SOT 
ID Guidelines (53). The current study proposes to use these same antiviral drugs that are 
already in routine use in the majority of liver transplant centers. The present study will 
systematically compare two different strategies using the same antiviral drugs that are already 


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routinely used at US liver transplant centers. As a result, the potential risks of the antiviral 
medications for study subjects in the present study are deemed to not be different than in 
standard clinical practice. Similarly, since both CMV prevention strategies (prophylaxis and 
preemptive therapy) are currently used in clinical practice in US and European liver transplant 
centers, there is no anticipated increased risk to study participants of randomization to one or 
another strategy.  The potential toxicities/side-effects of each of these agents are provided in 
the subsequent sections. 
2.3.1.2 
Ganciclovir  
Valganciclovir when taken by mouth is rapidly converted in the body to its active form, 
ganciclovir. It is estimated that tens of thousands of persons have received either intravenous or 
oral formulation ganciclovir over the last 22 years since its initial approval. Based on its efficacy 
and general tolerability, ganciclovir is currently recommended as a first-line agent for prevention 
and treatment of CMV infection and disease in HIV, solid-organ transplant, and hematopoietic 
cell transplant (HCT) populations (49, 54). See the package insert for more information. 
Ganciclovir is generally well-tolerated. The most common adverse effects, which appear to be 
related to longer durations of exposure and use of concomitant drugs with similar toxicities, are 
various hematological adverse effects, most commonly leukopenia and neutropenia which are 
reversible after drug discontinuation. The potential toxicities of ganciclovir have been 
extensively studied in vitro, in vivo, and in placebo-controlled studies in humans. Based on 
animal and cell culture data, ganciclovir is considered a potential human carcinogen, teratogen, 
and mutagen. It is also considered likely to cause inhibition of spermatogenesis. No human data 
exist that estimate the actual risk of these effects. Thus, it is used judiciously and handled as a 
cytotoxic drug in the clinical setting.  
 
2.3.1.2.1.1. 
Hematologic toxicity  
 
 Neutropenia is the principal toxicity of ganciclovir and valganciclovir. The incidence is 
highest in HCT recipients and HIV-infected individuals, followed by pediatric patients with 
congenital CMV disease and organ transplant recipients. Many studies have demonstrated the 
effect occurs late after drug administration (9,55, 56). In fact several studies in HCT recipients, 
the most susceptible population for this complication, show that the median time of onset is 5 
weeks after start of drug administration. Neutropenia was documented in 8.2% of the patients 
who received 100 days of valganciclovir in the PV-16000 study however discontinuation of the 
drug was required in only 2% (9). Another recent randomized trial of valganciclovir vs. 
ganciclovir at treatment doses (900 mg twice daily and 5 mg/kg twice daily, respectively) for 
CMV disease in SOT recipients showed a neutropenia rate of 1.2% and 0%, respectively, at 21 
days of treatment (57). Ganciclovir-related neutropenia is reversible (9, 55, 57). The time to 
recovery can be hastened by administration of G-CSF (54).   
 
Most placebo-controlled randomized studies, including those in stem cell transplant 
patients, do not show a difference in the incidence of thrombocytopenia and platelet transfusion 
requirements (8, 9, 57-60).  However, there are rare anecdotal reports of ganciclovir-related 
pancytopenia. One study of ganciclovir prophylaxis in HCT recipients reported delayed platelet 
engraftment (61). Overall, the potential to cause thrombocytopenia is considered low. 
 


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A trend towards anemia has been shown to occur in HIV-infected patients treated with 
valganciclovir. However, no strong evidence exists in transplant recipients and other patient 
populations, suggesting that the effect may be related to concomitant medications specific to the 
HIV setting. One recently completed phase III randomized trial of prolonged valganciclovir 
prophylaxis in HCT recipients, a population that would be considered at particularly high risk for 
this complication, did not show an increased rate of anemia or red blood cell transfusion 
requirements (62).  Other recent randomized trials also did not show an increased risk of 
anemia (9, 63).  
 
Key studies summarizing the incidence of neutropenia with valganciclovir use in organ 
transplant recipients are shown below. 
 
 
 
 
2.3.1.2.2 
Renal toxicity 
Results from randomized trials do not support a role for ganciclovir or valganciclovir as 
causes of renal toxicity. None of the recently conducted randomized trials shows an increased 
risk or renal toxicity (62, 63),  however, two earlier trials, one in heart transplant recipients with 
IV ganciclovir (67, 68) showed increased rates of renal insufficiency. While the potential to 
cause direct toxicity appears to be low, we will monitor renal function closely and adjust doses 
based on creatinine clearance according to the package insert.  
 
2.3.1.2.3 
Neurotoxicity 
 
This is rarely observed and is not statistically significant between study arms of most 
randomized trial except one study in HCT recipients (63). This effect probably occurs only in a 
setting of concomitant drugs with neurotoxic potential and high blood levels of ganciclovir in the 
setting of renal insufficiency.  
 
2.3.1.2.4 
Carcinogenicity 
Ganciclovir and valganciclovir are considered potential human carcinogens (see 
package insert). No studies have been performed to systematically assess this potential in 
humans. Although tens of thousands of transplant and HIV infected patients have been treated 
Reference 
Incidence of neutropenia (n/n) 
Discontinuation of valganciclovir 
(64) 
4% (2/47) 
2 ( resolved in both) 
(9) 
8.2% 
2% 
(57) 
1.2% (2/164) 
Not known 
(65) 
4% (2/49) 
0% 
(66) 
5.7% (4/70) 
0% 
(2) 
15% (25/164) 
<1% 


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with ganciclovir over the past ~20 years, no reports of an increased risk of cancer have been 
published. However, this does not rule out possible carcinogenic effect.  
 
 
2.3.1.2.5 
 
Teratogenicity 
There are potential reports of ganciclovir-associated teratogenicity in laboratory animals 
but not in humans. Nevertheless, this drug is contraindicated in patients who are or are planning 
to become pregnant. For the purposes of this study, all subjects will be screened and excluded 
for pregnancy/possible pregnancy.   For the three months following receipt of ganciclovir, 
abstinence or an effective method of birth control for both partners is recommended. 
 
2.3.1.2.6 
Summary of human toxicity data 
Ganciclovir-related neutropenia occurs very uncommonly in persons without underlying 
bone marrow dysfunction and generally occurs at a median of 5 weeks after drug exposure. In 
patients without underlying bone marrow dysfunction, two recent trials showed very low rates of 
neutropenia after 3-4 weeks of ganciclovir at doses similar to those proposed in this protocol 
(2% within first 4 weeks with prophylaxis of 900 mg VGCV/day (9); 1.2% at day 21 with 900 mg 
valganciclovir twice daily; 0% at day 21 with 5 mg/kg ganciclovir twice daily (57). There is no 
convincing evidence that ganciclovir or valganciclovir cause thrombocytopenia. 
 
Anemia has been observed in HIV-infected subjects, but there is no evidence that it is a 
problem in transplant patients or in the treatment of congenital disease. 
There may be some risk of renal toxicity, however, this was not consistently observed across 
randomized trials. Other potential safety issues include teratogenicity and carcinogenicity.  
 
Summary of ganciclovir and valganciclovir toxicities  
Adverse effect 
Human data 
Documented in randomized trials 
Neutropenia 
 
Yes 
Yes 
Thrombocytopenia 
 
Yes 
No 
Anemia 
 
Yes 
Some (HIV only) 
Renal dysfunction 
 
Yes 
   No (none in recent trials) 
Gastrointestinal 
effects 
Yes 
Yes 
Tumors 
No 
 
No 
Birth Defects 
No 
 
No 
Data in Table summarized from references 9, 55-63 


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2.3.2 Other risks   
 
 
2.3.2.1 Blood draws 
Bruising, soreness, anemia, or very rarely, infection, may occur as a result of 
venipuncture used to obtain blood from the participant’s vein. The participant may feel 
lightheaded when the blood is drawn. Every attempt will be made to coordinate research blood 
draws with clinical blood draws to avoid extra needle sticks. The schedule of blood draws 
needed for the study are very similar to the schedule of blood draws that are considered  
standard of care post liver transplant.  Only at time points at which blood is not being drawn for 
clinical purposes but needed for study purposes will a separate venipuncture be performed. 
Approximately 312 ml (~20 tablespoons) of blood will be collected specifically for study 
purposes over the 12 months of study participation in the preemptive therapy group and 172 ml 
(~11 tablespoons) in prophylaxis group. This total blood volume over the study period is well 
within accepted limits of blood draw.  
 
 
2.3.2.2 Invasion of privacy  
Personal Health information is to be collected about study participants during this study. 
There is a theoretical risk (as for any research study) that the participant’s privacy may be 
breached. Study staff will take numerous precautions to protect participant privacy. Only 
authorized study personnel will access medical records and only specific clinical and laboratory 
information will be extracted from the medical record. Study codes (rather than subject 
identifiable information) will be used for all data collection documents. All study specimens will 
be de-identified and marked with only study codes before being sent to the central study 
laboratory. All study personnel have been appropriately trained regarding subject privacy and 
HIPAA regulations. Confidentiality of subject information will be strictly observed, and final 
publication of results will not include any subject identifiable information. 
2.3.3  
Potential benefits 
 
There are no known direct benefits to study participants. All study participants will be 
followed more closely than is typically done during the course of routine clinical care. As a 
result, it is possible that some medical problems (specifically CMV disease) might be detected 
earlier for study participants than would have been the case if they had not been in the study.  
 


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3 
OBJECTIVES 
3.1    Study Objectives 
3.1.1  
Primary objective 
 
The primary objective is to compare prophylaxis versus preemptive therapy using 
valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients 
3.1.2  
Secondary objectives  
To assess the two preventive strategies for:  
• 
Clinical outcomes (major bacterial, fungal and non-CMV viral infections, rejection, 
graft loss and mortality) at one year post transplantation. 
• 
 Hematologic toxicity  (assessment of neutropenia and receipt of hematopoietic 
growth factor during study days 1-107) 
3.1.3  
Exploratory objectives  
To assess the two preventive strategies for:  
• 
The development of CMV-specific immunity following transplantation 
• 
Cost effectiveness of the regimens 
• 
Differences in clinical outcomes (mortality, OI, malignancies, and the need for 
renal replacement therapy) at 1 to 7 years post transplantation. 
3.2 
Study Outcome Measures 
3.2.1  Primary outcome measure 
 
The primary outcome measure is the incidence of CMV disease by 12 months post-
transplant.  
3.2.2 Secondary outcome measures (compared between 2 groups) 
1. 
 Clinical outcomes within 12 months post-transplant 
• 
Incidence of late-onset CMV disease (CMV disease occurring  
after 100 days post-randomization) 
• 
Incidence of major bacterial, fungal, and non-CMV viral infections  
• 
Incidence of allograft rejection 
• 
Incidence of graft loss (retransplantation)                


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• 
All-cause mortality 
2.          Hematologic toxicity (assessed until 107 days post-enrollment) 
• 
Incidence of neutropenia (ANC <1,000 and <500/µL) 
• 
Hematopoietic growth factor (granulocyte colony stimulating 
factor) for neutropenia -  (receipt of hematopoietic growth factor during 
study days 1-107) 
 
3.2.3  
Exploratory end-points (compared between 2 groups) 
 
1. 
Clinical outcomes  
• 
Time to onset of CMV disease (disease free survival) through 12 
months post-transplant 
• 
All-cause mortality, rejection episodes, graft loss and 
retransplantation, opportunistic infections, need for dialysis, and post-
transplant malignancies will be assessed until study closure (7 years 
from enrollment maximum). 
 
 
2. Immunologic endpoints: 
• 
CMV-specific immunity at 100 days, 6 and 12 months post-
transplant 
a. 
CMV-specific T-cell responses 
b. 
CMV-specific neutralizing antibody responses  
 
3.   Cost effectiveness of the 2 approaches: 
• 
Total costs for each regimen 
• 
Cost utility analysis (cost per quality adjusted life-years) 


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4. 
STUDY DESIGN 
This is a /prospective, randomized, multicenter trial of prophylaxis versus preemptive 
therapy for the prevention of CMV disease in R-/D+ liver transplant subjects. Subjects meeting 
study criteria and who have provided informed consent will be randomized within 10 days post-
transplant to receive, in an open label design, either prophylaxis with valganciclovir 900 mg 
once daily for 100 days or preemptive therapy (weekly monitoring for CMV viremia by plasma 
PCR weekly for 100 days post-randomization with initiation of valganciclovir 900 mg twice daily 
at onset of CMV viremia and continued until plasma PCR is negative on two consecutive weekly 
PCR tests). All dosages will be adjusted for renal dysfunction. Subjects will be followed during 
the intervention period (100 days post randomization) and until 12 months post-transplant for 
CMV disease, toxicity, and clinical outcomes (opportunistic infections, rejection, graft loss, 
retransplantation and mortality).  
All-cause mortality, rejection episodes, graft loss and retransplantation, 
opportunistic infections (bacterial, fungal), need for dialysis, and post-transplant malignancies 
will be assessed until study closure (7 years from enrollment maximum). 
Additionally, the impact of the two CMV prevention strategies on CMV-specific cellular 
and humoral immune responses will be evaluated at 100 days after randomization, and 6 and 
12 months post-transplant.   
It is anticipated that ~20-22% of all liver transplant recipients will belong to the R-/D+ 
group and will qualify for the study. Approximate time to enrollment will be 3.5 years. A minimum 
of 176 subjects will be enrolled in the study. Allowing for over-enrollment to replace dropouts, up 
to 205 subjects may be enrolled to achieve the target enrollment of 176 (see section 5.4.3.3). 
There will be a single interim analysis for the primary endpoint of CMV disease as adjudicated 
by an independent End Points Committee. This analysis will be conducted after~ 60 subjects 
have been enrolled and followed for 1 year.  Study closure will occur 2 years after the enrollment 
of the last subject. 


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5. 
STUDY POPULATION 
                 
 
Male and female liver transplant patients of any ethnicity are eligible for screening and 
enrollment.  
5.1  Recruitment Strategies 
Site investigators are all clinicians and also care providers for the liver transplant 
recipients at their respective institutions and therefore have direct access to the study 
population. The study population will be drawn from in hospital setting. Potential subjects will be 
identified by the site investigators and the study coordinators. Although the subjects may return 
to their hometown, which may be remote from the transplant center, close and longitudinal 
follow up of patients is a standard of care at all transplant centers. 
5.2  Subject Inclusion Criteria 
Subject must:  
1. Be > 18 years of age 
2. Have negative CMV serology (confirmed within 6 months of transplant) and 
receive a liver from a donor with positive CMV serology (R-/D+) 
3. Have received their first orthotopic liver transplant (the transplanted liver may 
be deceased donor or live donor graft) within 10 days prior. 
4. Have absolute neutrophil count > 1000/ µL at randomization 
5. If female, and not postmenopausal or surgically sterile, must have negative 
pregnancy test (serum or urine) within 48 hours prior to randomization and 
must also agree to use medically approved method of contraception. 
Acceptable methods include: barrier method, intrauterine device (hormonal or 
non-hormonal), oral hormonal contraceptives, abstinence for 100 days after 
randomization and 3 months after valganciclovir cessation. If male, and has not 
had a vasectomy, he must agree to practice barrier method of contraception for 
100 days after randomization and 3 months after valganciclovir cessation 
6. Subject or legally authorized representative has provided written informed 
consent. 
5.3  Subject Exclusion Criteria 
Subject must not: 
1. Be currently enrolled in any interventional trial of an investigational 
therapeutic agent unless co-enrollment has been approved by study PIs 
and the DMID prior to enrollment  


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2. Have hypersensitivity to acyclovir, ganciclovir or valganciclovir 
3.  Be breast-feeding mother 
4.  Have known HIV infection (based on testing performed during the transplant 
evaluation process). 
5.  Be undergoing multi organ transplant or have undergone prior organ  
transplant 
6. Have expected life expectancy of less than 72 hours. 
 
5.4  Study Procedures 
5.4.1 Screening  
 
Potential subjects will be identified via assessment of medical record information using 
IRB-approved procedures. Since the investigating physician at all sites is both the caregiver and 
investigator, IRB-approved waiver [addressing Federal Policy criteria (45CFR 46.116(d)] for the 
screening portion of the consent will be obtained to access the medical record to identify 
potential research subjects. Medical records during screening will be reviewed for the limited 
purpose of determining potential eligibility of the subjects for the study. Eligible subjects will then 
be approached for informed consent. All subjects will provide an informed consent prior to 
enrollment in the study.  
 
 
 After appropriate informed consent has been obtained and before randomization of the 
subject, the following clinical laboratory tests as defined in the inclusion and exclusion criteria 
will be performed: 
• 
In women of child bearing potential only: pregnancy test (serum or urine) - the 
results of this must be negative before proceeding. Pregnancy testing completed 
as SOC with-in 48 hours of randomization is acceptable.  
• 
CMV serology (if not performed within 6 months of the transplant), absolute 
neutrophil count and serum creatinine level. These tests are performed as 
standard of care and are not study specific evaluations. 
5.4.2 Randomization  
 
Subjects will be randomized in 1:1 allocation to one of 2 study groups. All subjects that 
have met all criteria for study enrollment and have given written informed consent will be 
randomized via a web-based randomization system at the study web-portal. 
The study team member randomizing the subject will get an immediate message providing 
group assignment.  Randomization at each site will be stratified by: 1) the receipt of lymphocyte 
depleting induction and 2) dialysis at time of randomization. Randomization will occur as soon 
as it is feasible, but no later than 10 days after transplantation. Inadvertently randomized 


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subjects who do not meet the inclusion/exclusion criteria or those who are withdrawn prior to 
receiving the study drug will be replaced.  
 
Subjects receiving lymphocyte depleting induction at the time of transplantation (even for 
those randomized to the preemptive therapy group) may receive up to 10 days of antiviral 
therapy with valganciclovir or IV ganciclovir after transplantation. Additionally, if the treating 
physician prescribes valganciclovir or IV ganciclovir for any length of time prior to 
randomization, it will not preclude subject enrollment. For subjects assigned to the prophylaxis 
group, the first dose of study drug should be given on the day of randomization regardless of 
lymphocyte induction. For subjects in the preemptive group that have received lymphocyte 
depleting induction, antiviral therapy with valganciclovir or IV ganciclovir will be given for ten 
days then stopped. Subjects that have not received lymphocyte depleting induction, but have 
received doses of valganciclovir or IV ganciclovir after transplantation prior to randomization, will 
have the pre-randomization treatment stopped and begin study treatment on randomization day 
based on their assigned group. 
 
 
5.4.3 Discontinuation from Study and Withdrawal 
 
5.4.3.1             Discontinuation from study 
 
Under certain circumstances, an individual subject may be terminated from participation 
in this study. The site investigator must discuss potential subject discontinuation with the study 
PIs as soon as possible. Specific events that will result in discontinuation include: 
 
• 
Site investigator decides to terminate participation for reasons of subject safety or to 
prevent compromising the scientific integrity of the study 
• 
New scientific developments indicate that the treatment is not in the subject’s best 
interest  
• 
Subject was inappropriately enrolled based on inclusion/exclusion criteria 
• 
Subject undergoes retransplantation after 30 days  after randomization (please see  
section 6.2.5 for  rationale) 
• 
Study is terminated  
For subjects who have received study product and discontinue from the study for any of the 
aforementioned reasons, every effort will be made to complete the safety specific evaluations. 
 
5.4.3.2  
Withdrawal  
A subject may be withdrawn from study for the following reasons: 
• 
Subject refuses further participation (consent withdrawn) 
• 
Inappropriate enrollment (subject did not meet the inclusion criteria or met the 
exclusion criteria) 


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The date of last contact with the subject and the reason for withdrawal will be recorded 
in the CRF.   
 
 
5.4.3.3  
Handling of discontinuations and withdrawals 
 
 
Should a subject discontinue prematurely, follow up assessments will be conducted per 
protocol. If the reason for removal of a subject from the study is an AE, specific event or test will 
be recorded on the CRF and follow up assessments will be continued. The exception to this 
would be if consent is fully withdrawn to any further collection of data. In the event that a subject 
discontinues participation after randomization but prior to receiving study drug or the subject 
was inappropriately enrolled, the subject will be replaced. No additional procedures or follow-up 
will be performed on subjects who discontinue prior to receiving study drug.  
For subjects who withdraw consent from the study prior to receiving study product, there 
will be no further collection of data or study specific procedures. For a subject that has received 
study product then withdraws consent, the subject will not be required, but will be encouraged to 
complete safety specific evaluations. 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1 
Study Product Acquisition/Description 
Valganciclovir is the standard of care for CMV prevention at all participating centers. 
Valganciclovir will be used on an open-label clinical basis and billed to the subject and/or 
insurer.  The subjects may fill prescription at any pharmacy per standard clinical care at that 
institution. No medication will be provided specifically for study purposes. 
 
Valcyte ® (valganciclovir HCl tablets) is available as 450 mg pink convex oval tablets 
with "VGC" on one side and "450" on the other side. Each tablet contains valganciclovir HCl 
equivalent to 450 mg valganciclovir.  The dispensing of valganciclovir will be according to 
manufacturer recommendations and routine institutional practices at the transplant center. 
 
It is possible that a generic formulation of valganciclovir might be approved and become 
available during the study period. Investigators may use either formulation of valganciclovir  
(brand vs. generic equivalent) for study subjects at the protocol-described doses according to 
institutional standards. Because of the uncertainty of if/when generic valganciclovir might 
become available; it will not be possible to specifically control for this variable in the pre-defined 
analytic plan. However, we will include post-hoc analyses to assess the potential impact of 
generic formulations of valganciclovir on the study safety and efficacy endpoints. 
 
 
For this protocol, all references to “study drug” are referring to valganciclovir when 
prescribed per Section 6.2, and beginning with Study Day 1. “Study drug” includes dose 
adjustment when indicated and the use of ganciclovir when indicated per clinical care. 
 
6.2  Valganciclovir Dosing and Administration 
 
 
6.2.1    
Dosage  
 
Subjects assigned to the prophylaxis arm will receive valganciclovir at a dose of 900 mg 
po qd. Subjects assigned to the preemptive arm will receive valganciclovir 900 mg po bid upon 
detection of CMV viremia (at any level). Dose adjustments will be made for those subjects with 
renal dysfunction. 


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6.2.2   
Drug administration 
 
Drug administration will take place initially at the transplant hospital while the subject is 
an in-patient and will be administered by the clinical care team responsible for administering all 
other inpatient medications. If transferred or readmitted to a skilled nursing facility, rehabilitation 
facility, or outside hospital, the drug will be administered by the clinical care team responsible 
for administering all other medications at these facilities. If discharged home, the subject will 
self-administer the medication and compliance will be assessed as described in section 6.4. 
6.2.2.1 
 
Prophylaxis group  
Subjects assigned to the prophylaxis arm will receive valganciclovir at a dose of 900 mg 
po qd (adjusted for renal dysfunction). Study drug will be given on the day of randomization 
(considered Day 1 of the study) and will be administered for 100 days.  
For subjects randomized to the prophylaxis group that have been receiving prophylaxis 
therapy for CMV as part of their standard care prior to randomization, the prophylaxis dose will 
not be repeated on study day 1 if a dose has already been administered. However, if a dose 
was given as standard care, the dose will be counted as the 1st day of the 100 days of study 
treatment doses.  
6.2.2.2. 
Preemptive therapy group 
Day of randomization will be considered study Day 1 and all subsequent study days will 
start accordingly. Day 1 will begin immediately after randomization. In the event that a 
preemptive subject has already received a dose of valganciclovir as standard care prior to 
randomization on study Day 1: study Day 1 will still remain the day of randomization and the 
dose given prior to randomization will not be considered a protocol deviation. Subjects in the 
preemptive therapy group will undergo weekly testing of plasma using real-time CMV PCR for 
100 days post randomization at the central site laboratory (see study manual for details of 
shipping and test result reporting). Valganciclovir 900 mg po bid (dose adjusted for renal 
function) will be employed upon detection of CMV viremia (at any level) and started within one 
week of initial positive PCR and continued until two consecutive tests performed one week apart 
are negative. Therapy will then be discontinued and weekly blood CMV PCR monitoring will 
continue until day 100 post randomization. Subjects with recurrent viremia (at any level) within 
100 days post randomization will be treated with a repeat course of valganciclovir 900 mg po bid 
(dose adjusted for renal function) using similar criteria for discontinuation as for the initial 
episode of viremia. In the rare case in which viremia remains detectable at low levels or two 
negative PCRs cannot be achieved beyond 100 days post randomization, treatment with 
valganciclovir may be discontinued if the clinical team or the investigator deems that 
valganciclovir is no longer warranted. 
All subjects assigned to the preemptive therapy group will receive acyclovir 400 mg po 
bid (adjusted for renal dysfunction) for at least 28 days after transplant for HSV prophylaxis as 
standard of care. Acyclovir will be discontinued during valganciclovir/iv ganciclovir preemptive 


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therapy within this period. This dose of acyclovir has no effect on CMV and is considered 
standard practice in the absence of routine use of valganciclovir post-transplant (53).  
6.2.3  
Conditions limiting valganciclovir administration 
 
Subjects in either group who are unable to take valganciclovir orally at any time 
during the study period may receive IV ganciclovir until oral valganciclovir can be resumed. 
Subjects in either group may also be switched to IV ganciclovir if conditions that preclude use of 
oral valganciclovir develop such as inability to take oral medications or reduction in CrCl to < 10 
ml/min or requirement for dialysis. These subjects may remain on IV ganciclovir until 
valganciclovir can be resumed. For handling of interruptions of valganciclovir due to neutropenia 
please see section 7.6.2. 
6.2.4  
Rejection episodes  
 
Rejection episodes requiring lymphocyte depleting induction therapy are highly 
unusual in the current era. Nevertheless, subjects in either study group who receive lymphocyte 
depleting agent for the treatment of rejection at any time during the study period will receive 
valganciclovir 900 mg po qd or iv ganciclovir 5 mg/kg/d (if unable to take orally or use of oral 
valganciclovir is not possible) for up to one month. Valganciclovir and IV ganciclovir dosages will 
be adjusted for renal dysfunction. Subjects receiving other forms of augmented 
immunosuppression, including corticosteroids boluses or recycles will not receive concurrent 
antiviral agents. 
6.2.5 Graft loss (retransplantation) 
 
 
Subjects in either group undergoing retransplantation shall remain in the 
assigned study group. For subjects retransplanted within 30 days of randomization, the study 
drug (prophylaxis group) or surveillance monitoring for CMV PCR (preemptive therapy group) 
will be continued for 100 days from initial randomization.  Subjects retransplanted after 30 days 
of randomization will be withdrawn from the study and receive standard care at that point since 
prolonged drug continuation can potentially impact the study outcomes, particularly the 
immunological end-points. The number of retransplantations after 30 days is expected to be low 
(less than 2 percent). 
 
 
 
 
 
 
 


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6.3 
Dose Modifications for Renal Dysfunction 
Dose modifications are recommended for subjects with renal impairment as outlined below.   
 
*Note: Manufacturer’s instructions recommend IV ganciclovir 0.625mg/kg/ dose three times / week 
following hemodialysis in this setting. Some centers use valganciclovir 450 mg orally thrice weekly (after 
hemodialysis) instead of IV ganciclovir for patients on hemodialysis. Sites may follow standard medical 
practices at the transplant center for valganciclovir administration in hemodialyzed patients. 
 
 
Recommended renal dosage adjustments for valganciclovir, ganciclovir, and acyclovir 
are standard medical practice and are recommended but not required for study. Renal dosage 
adjustments may be made by the study investigators and /or the clinical treating team when 
indicated. Switches between valganciclovir and ganciclovir are also standard medical practice 
and may be made by the study investigator and/or the clinical team when indicated. Please see 
Manual of Procedures for additional suggested renal dosage adjustments. 
6.4 
Medication Compliance 
 
Compliance with valganciclovir will be assessed by the study coordinator using subject 
self-reporting 30, 60 days post randomization, and end of treatment.  These assessments may 
occur up to 14 days after the specified visit day. Subjects will be asked about their recall of 
missed doses by questions asked in a nonjudgmental manner. Self-report correlates well with 
actual medication intake when a trusting subject-provider relationship exists as in transplant 
setting. Accuracy of the self-report can be maximized by (i) approaching the subject in a matter 
of fact and non-judgmental way, (ii) asking about the most recent days and missed doses, and 
(iii) using prompts to help recall. Pharmacy refill tracking was not deemed feasible for this study 
as the subjects may fill their antiviral medication from pharmacy other than the hospital 
pharmacy. Compliance to treatment regimen should be encouraged. However, it is expected 
that some patients will not be able to comply with all doses due to the chronicity of the condition 
Prophylaxis group valganciclovir dose modification  
CrCl (mL/min) 
Valganciclovir dose  
> 60 
900mg once daily 
40-59 
450mg once daily 
25-39 
450mg every 2 days 
10-24 
450mg twice weekly 
<10 (on hemodialysis) 
Please see foot note below* 
Preemptive therapy group valganciclovir dose modification 
CrCl (mL/min) 
Valganciclovir  dose  
> 60 
900mg twice daily 
40-59 
450mg twice daily 
25-39 
450mg once daily 
10-24 
450mg every 2 days 
<10 (on hemodialysis) 
Please see foot note below* 


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and underlying/concomitant illness.  Therefore, compliance will not be reported as protocol 
deviations since overall compliance measures will be recorded for analysis. 
6.5 
Concomitant Medications 
• 
Use of oral ganciclovir is prohibited during the study period. 
• 
Intravenous ganciclovir may be used in subjects who are: unable to take oral 
medications; develop creatinine clearance less than 10ml/min or require 
hemodialysis; and during concomitant administration of lymphocyte depleting 
therapy (ATG, OKT3, alemtuzumab) as specified in protocol 5.4.2. For guidance 
for ganciclovir IV dose adjustment for subjects with renal impairment, please 
refer to Manual of Procedures (MOP). 
• 
CMV prophylaxis with ganciclovir derivatives is adequate for herpes simplex virus 
(HSV) prevention. Guidelines recommend HSV prophylaxis with low-dose 
acyclovir within first month post-transplant in subjects who are not receiving other 
HSV-active antiviral therapy (53). Thus, subjects assigned to the preemptive 
therapy group will be allowed to receive low-dose acyclovir (400 mg po bid) for at 
least 28 days post-transplant as routine care. This dose of acyclovir has no effect 
on CMV. Acyclovir should be discontinued if preemptive therapy group subjects 
initiate valganciclovir. Acyclovir is not necessary in the prophylaxis group since 
valganciclovir has activity against HSV. For guidance for acyclovir dose 
adjustment for subjects with renal impairment, please refer to MOP. 
• 
Use of CMV hyper immune globulin is prohibited except for the treatment of CMV 
disease as deemed necessary by the treating physician.  
• 
Use of cidofovir and foscarnet is prohibited except for confirmed or suspected 
ganciclovir-resistant CMV disease. 
• 
Immunosuppressant medications taken during study days 1-100 and any 
immunosuppression medications taken for rejection episodes during the 12 
month period will be recorded. Immunosuppressive agent blood levels measured 
as standard of care during study days 1-100 will be recorded. 
• 
Concomitant drugs with known hematologic toxicity or potential of drug 
interactions with valganciclovir  that are taken during study days 1-100 will be 
recorded. These include: trimethoprim-sulfamethoxazole, dapsone, pentamidine, 
amphotericin B, abelcet, ambisome, probenecid, and imipenem. 
• 
Use of acyclovir, valacyclovir or famciclovir is permitted without dose limit for the 
duration determined to be appropriate by the investigator for the  prevention and 
or treatment of herpes simplex or herpes zoster  
 


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7 
STUDY SCHEDULE 
7.1    Screening  
 
 
 
Site investigators are also clinicians and care providers for the liver transplant 
service at their respective institutions and therefore have direct access to the study population 
and medical records. Potential subjects will be identified via assessment of medical record 
information using IRB-approved procedures. Since the investigating physician at all sites is both 
the caregiver and investigator, IRB-approved waiver [addressing Federal Policy criteria (45CFR 
46.116(d)] for the screening portion of the consent will be obtained to access the medical record 
to identify potential research  subjects. Medical records during screening will be reviewed for the 
limited purpose of determining potential eligibility of the subjects for the study.  
 
Initial screening will include subjects with known negative CMV serology that have not 
been approached for consent. If these patients are found to be ineligible prior to consent, they 
will be recorded on the electronic screening and randomization form noting reasons for 
exclusion. Data to be collected on screen failures that have not signed consent include only the 
reasons for ineligibility based on study inclusion and exclusion criteria. No research procedures 
will be performed on patients that have not given written informed consent. No identifiable 
information will be collected on patients that have not given written informed consent. 
 
Screening may take place prior to transplant or post-transplant dependent on the 
enrolling site’s preference. Either option is permissible for protocol adherence providing sites 
are using IRB-approved procedures. 
7.2  Consent  
 
 
Potentially eligible subjects or their surrogate, in accordance with the IRB approved 
procedures, may be approached after transplant or prior to transplant for consent if no exclusion 
criteria is met pending final determination of inclusion criteria eligibility. Consent may take place 
prior to transplant or post-transplant dependent on the enrolling site’s preference. Either option 
is permissible for protocol adherence providing sites are using IRB-approved procedures. CMV 
seronegative subjects awaiting liver transplant may be consented prior to transplant. These 
subjects will become eligible for the study if they receive a CMV seropositive liver allograft and 
meet all other eligibility criteria.  
 
 
Once consent has been obtained, the subject is considered enrolled in the study.  In 
case of provisional enrollment due to pending CMV serology (if not performed in the last 6 
month) pending pregnancy test (must be performed with-in 48 hours or randomization), or 
enrollment of CMV seronegative subjects prior to transplant ( must receive donor positive liver), 
the subject will  be randomized only after all eligibility criteria are met . 
 
 
If eligibility cannot be met for any enrolled (consented) subject, the subject will not be 
randomized and instead will become a screen failure and will be replaced. Enrolled subjects that 


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are found to be ineligible will be recorded on the electronic screening and randomization form 
noting reasons for exclusion. Electronic data to be collected on enrolled subjects that become 
screen failures include; date of consent, and reasons for ineligibility based on study inclusion 
and exclusion criteria. Investigative sites will keep a list of all enrolled subjects separate from 
the research regulatory files that contain the subject’s name, date of consent, and study ID. 
Study ID will be assigned by the electronic screening system when final determination of 
eligibility or ineligibility is verified. 
7.3 
Baseline research procedures pre-randomization (study day 0) 
 
 
After consent is obtained but prior to randomization the following study laboratory 
procedures will be performed to verify eligibility. Results obtained as standard care within 48 
hours prior to randomization are acceptable. 
 
o   WBC with differential for absolute neutrophil calculation 
(Subject will be withdrawn if ANC < 1000/µL at baseline) (May use 
results that have been obtained with-in 48 hours prior to 
randomization) 
o Creatinine  with Creatinine Clearance (CrCl) calculated  (May use 
results that have been obtained with-in 48 hours prior to 
randomization) 
o Serum or urine pregnancy test result for females of childbearing 
potential (May use results that have been obtained with-in 48 hours 
prior to randomization). Subject will be withdrawn if positive 
pregnancy test is detected 
 
 
 
In addition, every effort should be made to reconfirm the subject’s CMV serology on a 
preoperative blood prior to randomization. In cases which this is not possible (pre-operative 
blood is no longer available at the local lab at time of consent), the most recent CMV serology 
results obtained within 6 months of transplant will be acceptable for meeting inclusion criteria. 
Subject will be withdrawn if their CMV IgG is found to be positive. 
 
 
7. 4 Randomization (Study day 1) 
 
Subjects that have met all criteria for study enrollment and have given written informed 
consent will be randomized. Subjects must meet all inclusion and no exclusion criteria at the 
time of randomization. The mandatory eligibility check list, provided on the CAPSIL web Portal, 
will be completed by the study team at the time of randomization and kept in the subject study 
file.The day of subject randomization is considered study day 1. 
 


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7. 4.1 Randomization procedure 
 
Subjects that have met all criteria for study enrollment and have given written informed 
consent will be randomized via a web-based randomization system. Full instructions for use of 
the web-portal randomization procedures can be found in the Manual of Procedures. Subjects 
will be randomized to either prophylaxis therapy for CMV disease prevention or preemptive 
therapy for CMV disease prevention. The study team member randomizing the subject will get 
an immediate message providing group assignment.  
 
7. 4.2 Post-randomization baseline laboratory assessments  
 
All subjects will have the following laboratory assessments completed at the transplant 
center on Study day 1 prior to administration of valganciclovir. 
 
The following laboratory assessments are anticipated to have been obtained as standard 
of care (SOC) and will only be drawn specifically for the study if not completed as standard care 
within the allowable specified window. (Standard of care values obtained within 48 hours prior to 
randomization may be used for baseline hematology and chemistry assessments.) 
 
 
Lab values that will be collected at study day 1: 
 
• 
Hematology (SOC results within 48 hours prior to randomization 
acceptable) 
o Hemoglobin  
o Hematocrit  
o Platelets  
o WBC with differential for absolute neutrophil calculation 
(Subject will be withdrawn if ANC < 1000/µL at baseline) 
 
• 
Chemistry (SOC results within 48 hours prior to randomization 
acceptable) 
o Blood urea nitrogen 
o Creatinine  with Creatinine Clearance (CrCl) calculated Total bilirubin  
o AST  
o ALT  
 
 
• 
Baseline blood sample for genetic testing (study specific evaluation)  
 
All subjects that have agreed to genetic testing will have a onetime 10 ml sample of 
blood obtained at baseline. Specific consent for genetic testing will be requested at enrollment. 
Consent for genetic testing will be incorporated into the main consent form and will not 


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constitute a separate informed consent document. Subjects will have the choice to opt out of 
genetic testing although take part in all other aspects of the CAPSIL study. This blood sample 
will be obtained at the transplant center. Samples will be coded with subject study numbers. 
Sites will freeze samples per tube manufacturer’s specifications and retain on site until shipped 
to the Boeckh Lab at Fred Hutchinson Cancer Research Facility.  
 
Genetic samples are not time sensitive or dose dependent and therefore may be drawn 
at any time point after consent for this sampling is obtained. This genetic sample may therefore 
be drawn with eligibility labs (pre-randomization) or the next scheduled standard of care blood 
draw (pre or post-study drug administration) to avoid unnecessary blood draw. If a sample is 
drawn pre-randomization and the subject is not eligible for randomization (screen failure), the 
genetic sample should be destroyed as per the institutions policy.  
 
7. 5  Treatment phase (study days 1-100) 
7. 5.1 Prophylaxis group only  
   Subjects assigned to the prophylaxis group will initiate valganciclovir at a dose of 900 
mg po qd (adjusted for renal dysfunction) on study day 1. For subjects randomized to the 
prophylaxis group that have been receiving prophylaxis therapy for CMV as part of their 
standard care prior to randomization, the prophylaxis dose will not be repeated on study day 1 if 
a dose has already been administered. However, if a dose was given as standard care, the 
dose will be counted as the 1st day of the 100 days of study treatment doses.  
7. 5.2 Preemptive therapy group only 
 
 
Subjects assigned to the preemptive therapy group will undergo weekly CMV PCR 
assessments beginning on study Day 7. Preemptive treatment group will begin preemptive 
antiviral drug therapy during study days 1-100 only when viremia is detected by weekly 
surveillance and will continue preemptive therapy until two consecutive weekly CMV PCRs are 
negative. Valganciclovir 900 mg po bid (dose adjusted for renal function) will be employed upon 
detection of CMV viremia (at any level) and started within one week of initial positive PCR and 
continued until two consecutive tests performed one week apart are negative. Therapy may be 
repeated if further detection of viremia is detected during the 100 day period.  
 
In the event that a preemptive subject has already received a dose of valganciclovir as standard 
care prior to randomization on study Day 1: study Day 1 will still remain the day of 
randomization and the dose given prior to randomization will not be considered a protocol 
deviation. 
 
7. 5.3 Laboratory assessments  
 


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7. 5.3.1           Drug safety labs (To be assessed during treatment period) all 
subjects- Study Days 7, 14, 21, 28, 42, 56, 70, 84, 98)  
(For study days 7, 14, 21, and 28 sample windows are +/-3 days. For study 
visits on study days: 42, 56, 70, 84, 98, samples windows are +/-7 days.) 
 
All subjects will have the following laboratory assessments completed at the transplant 
center while hospitalized. If discharged, laboratory assessments may be collected at routine 
care follow-up clinic appointments, at skilled nursing facilities, rehabilitation facilities, or 
outpatient laboratories. 
 
The following laboratory assessments are anticipated to have been obtained as standard 
of care and will only be drawn specifically for the study if not completed as standard care within 
the allowable specified window.   
Drug safety labs will be assessed and recorded for the entire treatment period in both 
the prophylaxis and preemptive group regardless whether the subject received valganciclovir/iv 
ganciclovir. 
 
 
These labs will be continued at a bi-weekly interval (+/-7 days) in the preemptive 
subjects if receiving valganciclovir therapy after day 98 and continue until end of treatment. 
 
• 
Hematology  
o Hemoglobin  
o Hematocrit % 
o Platelets  
o WBC with differential for absolute neutrophil calculation(ANC) 
 
• 
Chemistry  
o Blood urea nitrogen 
o Serum creatinine with CrCl estimated 
o Total bilirubin  
o AST  
o ALT  
 
 
ANC will be calculated at each safety lab visit. ANC < 1000/ µL will be reported as an 
adverse event (please see protocol section 9.3). 
 
CrCl (based on serum creatinine and most recent weight recorded as standard of care) 
will be estimated and monitored at each safety lab visit to assist in decisions related to 
recommended renal adjustments. (Please refer to MOP for calculation instruction for ANC and 
CrCl) 
 
      7.5.3.2 
CMV PCR surveillance monitoring – preemptive group only - Study 
days  
7,14,21,28,35,42,49,56,63,70,77,84,91,98 (+/-3 days) 
CMV PCR surveillance monitoring to be assessed in preemptive therapy subjects 
only 
 
Subjects in the preemptive group of the CAPSIL study will have CMV PCR serum 
sample obtained specifically for the study at study days: 


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7,14,21,28,35,42,49,56,63,70,77,84,91,98. All sample windows are +/-3 days. CMV PCR 
samples will be obtained at the transplant center if hospitalized, or will be collected during 
routine care follow-up clinic appointments and outpatient laboratories, skilled nursing facilities, 
or rehabilitation facilities. CMV PCR analysis will be completed at the University of Washington 
Medical Center Virology lab. 
 
CMV PCR results will be faxed to the study site within 24 hours of receipt of blood if 
received Monday through Saturday. Samples received on Sundays or holidays will be resulted 
within 48 hours or the next business day. CMV PCR surveillance must continue at weekly 
intervals in preemptive subjects if continuing valganciclovir therapy after day 98 until two 
consecutive negative results weekly.  
 
7.6 
Follow up laboratory procedures 
 
7. 6.1  
7 day Post End of Treatment 
 
 Drug Safety Assessment - all subjects (+/-7 days) 
 
To be completed on all subjects one week after the last study dose of valganciclovir. 
• 
Anticipated to be study day 107 in prophylaxis group 
• 
To be scheduled one week post last study dose of valganciclovir in 
preemptive group (which may be beyond day 107) 
 
All subjects will have the following laboratory assessments completed at the transplant 
center while hospitalized. If discharged, laboratory assessments may be collected at routine 
care follow-up clinic appointments, at skilled nursing facilities, rehabilitation facilities, or 
outpatient laboratories. 
 
The following laboratory assessments are anticipated to have been obtained as standard 
of care and will only be drawn specifically for the study if not completed as standard care within 
the allowable specified window of +/-7 days.   
 
• 
 
Hematology  
o Hemoglobin  
o Hematocrit % 
o Platelets  
o WBC with differential for absolute neutrophil calculation 
• 
Chemistry  
o Blood urea nitrogen 
o Creatinine  
o Total bilirubin 
o AST  
o ALT  


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7.6.2  Immunologic studies (immune assays and lymphocyte count) All 
subjects   
 
98 days, 6 month and 12month (+/- 14 days) 
 
Subjects will have study specific serum samples obtained for Immune Assay testing and 
a lymphocyte count  [proportion of white blood cells (hematology) that are lymphocytes] at study 
day 98, and at 6 months and 12 month (post-transplant) time point. Each sample may be 
obtained within +/- 14 day window. This blood sample may be obtained at the transplant center 
if hospitalized. If discharged, blood may be collected during routine follow-up clinic 
appointments, at outpatient laboratories, skilled nursing facilities, or rehabilitation facilities. 
Lymphocyte counts may be done as standard care at the local lab and recorded for the study 
purpose. If not completed as standard care, the site investigator will order the lymphocyte count 
to be drawn and processed locally and the results will be recorded. 
 
Immune assays will be done by the Boeckh Lab at Fred Hutchinson Cancer Research 
Facility in Seattle Washington. Results of immune assays will be provided only to the 
coordinating center since these results do not impact subject care. All materials, shipping 
supplies, and instructions for immune assays will be provided to the remote location. Please see 
laboratory manual for all process and storage directions. 
 
7.6.3 Pregnancy test for all females of childbearing potential 
 
End of Treatment (+3 month)  
 
All female subjects of childbearing potential will have a onetime post treatment 
pregnancy test. The pregnancy test may be performed on urine or blood and will be performed 
after the end of treatment up to 3 month post end of treatment. 
 
All female subjects of childbearing potential will have a pregnancy test completed at the 
transplant center while hospitalized. If discharged, pregnancy test may be collected at routine 
care follow-up clinic appointments, at skilled nursing facilities, rehabilitation facilities, or 
outpatient laboratories. 
 
7.6.4 Suspected CMV disease sample collection (Study day 1 – 12 month) 
 
 
Subjects in either group suspected to have CMV disease based on the assessment of 
the clinician or the investigator will have a blood sample sent to the central lab for CMV DNA 
PCR testing. This sample collection may occur at any time point throughout the 12 month 


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duration of the study. In preemptive therapy group, this sample will be in addition to the weekly 
CMV testing sample.  This blood sample will be obtained at the transplant center if hospitalized. 
If discharged, blood may be collected during routine follow-up clinic appointments, at outpatient 
laboratories, skilled nursing facilities, or rehabilitation facilities. Resistance testing will be 
completed at the University of Washington virology laboratory. All materials, shipping supplies, 
and instructions will be provided to the remote location. Please see laboratory manual for all 
process and storage directions. These results will be reported to the site via fax. 
 
 
7.6.5   CMV resistance testing 
            Study day 1 – 12 month 
             (This one time study visit may occur at any time point throughout the 12                        
month duration of the study) 
 
For those subjects who demonstrate no reduction in viral load after three weeks of 
ganciclovir/valganciclovir employed for CMV viremia in the preemptive therapy group or for the 
treatment of CMV disease in subjects in either study group, assessment of genotypic resistance 
for UL97 and UL54 mutations may be undertaken. This blood sample will be obtained at the 
transplant center if hospitalized. If discharged, blood may be collected during routine follow-up 
clinic appointments, at outpatient laboratories, skilled nursing facilities, or rehabilitation facilities. 
Resistance testing will be completed at the University of Washington virology laboratory. All 
materials, shipping supplies, and instructions will be provided to the remote location. Please see 
laboratory manual for all process and storage directions. 
 
 
7. 7 Non-laboratory Procedures and Clinical Assessments Schedule 
(see also Schedule of Procedures appendix A) 
 
7.7.1 Study day 1-100 
Drug administration phase 
 
Prophylaxis therapy group will begin to receive antiviral prophylaxis treatment on day 1 
and will continue receiving a daily dose through day 100. Please see protocol section 6.2 for a 
complete description and instructions regarding of prophylaxis dosing. 
 
Preemptive treatment group will begin preemptive antiviral drug therapy during study 
days 1-100 only when viremia is detected by weekly surveillance and will continue preemptive 
therapy until two consecutive weekly CMV PCRs are negative. Therapy may be repeated if 
further detection of viremia is detected during the 100 day period.  
 


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7.7.2 Study day 1-107 
(Drug treatment safety labs phase) 
Monitoring and managing neutropenia 
 
Neutropenia is the most commonly encountered toxicity of ganciclovir formulations (IV 
ganciclovir and valganciclovir). Guidance for the evaluation and management of neutropenia are 
provided in the study manual of operations. If necessary, administration of valganciclovir may be 
interrupted temporarily and subsequently re-started in response to neutropenia. If the drug has 
to be interrupted for more than 14 consecutive days for a given interruption episode, the site 
investigator may contact the study PIs to determine if there are circumstances in which it may 
be appropriate to re-start the drug.  Otherwise, valganciclovir should be discontinued 
permanently and subjects should be followed as discussed in the section on handling of 
discontinuations. 
 
 
7.7.3 Study day 1 through one year 
Outcome data recording 
 
After randomization and throughout the entire study period, all subjects will be followed 
and data collected related to study outcomes. All evaluations monitored will be completed as 
standard of care and not specifically for the study. Data collection and follow-up will be primarily 
achieved by medical record review at each study visit time point. Record reviews will include 
transplant hospital, out-patient clinics, outside hospitals, skilled nursing centers, and 
rehabilitation hospital records. Non-study hospital physicians and/or subjects may be contacted 
to verify whether or not they have had any additional hospitalizations or clinic visits outside of 
the transplant hospital in order to confirm complete collection of all outcome data. 
 
 
Specific outcome data to be followed and recorded include: 
 
• 
Evaluations for suspected and confirmed CMV disease 
• 
All treatments for suspected and confirmed CMV disease 
• 
Evaluations for organ rejection 
• 
All treatments for organ rejection 
• 
Graft loss and need for liver retransplantation 
• 
Fungal, major bacterial, and non-CMV viral infections 
• 
All-cause mortality during the 12 month 
• 
All immunosuppressant taken during 100 days 
• 
Immunosuppressant given for the treatment of rejection episodes for the 12 
month period 
• 
Immunosuppressant medication levels taken as standard of care 
• 
Hospitalization status 
 
 


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7.7.4 Adverse Event Monitoring and Reporting (Study day 1 through 7 
days post end of study treatment phase) 
 
All subjects will be assessed for adverse events throughout the administration of drug 
period plus 7 days. This is anticipated to be study day 1 through 107 for prophylaxis group 
subjects. Preemptive therapy arm monitoring of AEs timelines will be individually determined 
based on the length of treatment for viremia detected during study days 1-100.Please see 
adverse event section for complete description of adverse event monitoring and reporting.  
 
7.7.5 Study Specific Medication Compliance Visit (Study day 30, 60, and 
end of treatment +14 days) 
 
The Clinical Research Coordinator will track valganciclovir administration while the 
subject is in the hospital using hospital medication administration records. If the subject is 
discharged to a skilled nursing facility or rehabilitation facility, medication administration records 
will also be used to track valganciclovir administration. Upon discharge, if at home, the subject 
will be contacted and interviewed at day 30, 60 and end of treatment to assess drug 
compliance.  These interviews may occur up to 14 days after the specified visit day. 
 
A source document designed and provided by the coordinating center will be required to 
verify data acquired by interview with subjects regarding compliance with valganciclovir drug 
regimen. This interview may be conducted in person or by telephone. Using a non-judgmental 
approach, medication compliance will be assessed by interviewing subjects. Subjects will be 
requested to recall the number of missed doses in the previous reporting period. The 
coordinator will calculate percentage of compliance based on the subject’s self- report. The 
compliance interview source document can be found on the CAPSIL website. 
 
7.8 Early Termination Visit 
7.8.1  Withdrawal of consent 
Study subjects may withdraw voluntarily from participation in the study at any time.  
Study subjects may also withdraw voluntarily from receiving the study intervention for any 
reason.  If a study subject withdraws or is discontinued from the study at any time prior to 
completion of the study, the study subject will be encouraged to complete safety follow-up visits 
and allow adverse event monitoring and reporting. All data collected up until date of withdrawal 
will be retained for study analysis.  
 
7.8.2  Early termination for re-transplantation between study day 30 and 365 
 


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Subjects retransplanted after 30 days of randomization will be withdrawn from the study 
and receive standard care at that point since prolonged drug continuation can potentially impact 
the study outcomes. Subjects that require re-transplantation of their liver between study day 30 
and 365 will be terminated from the study. Safety labs will be collected at 7 days post last dose 
of study therapy medication. Adverse events data will be collected for 7 days post last dose of 
study therapy medication. Mortality will be assessed at 1 year and study closure. No other 
endpoints or labs will be collected post-retransplant. 
7.9 Therapy Discontinuation 
 
 
Should a study subject’s therapy be discontinued prematurely for any reason and 
consent has not been withdrawn, all clinical and laboratory evaluations will continue. Safety labs 
will be collected 1 week post last dose of therapy discontinuation. All key endpoints will be 
evaluated and all randomized study subjects will continue to be followed as long as possible 
and included in the final analysis. 
 
7.10  Final Study Visit  
 
 
The planned final study exit visit (with the exception of late outcome assessment at 
study closure, see 7.11) will take place 12 months post-transplant +/- 2 weeks. 
 
7.11 Study Closure 
 
All-cause mortality, rejection episodes, graft loss and retransplantation, opportunistic 
infections (bacterial, fungal), need for dialysis, and post-transplant malignancies will be 
assessed until study closure (7 years from enrollment maximum). 
Study coordinators will review medical records at study closure to obtain study closure 
assessments. 
 
7.12 Total blood volume collected  
 
 Approximately 295.5 ml (~20 tablespoons) of blood will be collected specifically for 
study purposes in the preemptive therapy group and 176.5 ml (~12 tablespoons) in the 
prophylaxis group over the 12 months of study participation. This is depicted in Appendix B. 
Including the  samples for clinical care and study specific samples, the blood volume collected 
over the study period is within accepted limits of blood collection. 
 


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7.13 Future Use of Stored Specimens 
 
Some of the specimens obtained from study participants during this study will be stored 
indefinitely at the University of Washington and  Boeckh Lab Fred Hutchinson Cancer Research 
Center and may be used in future research.  These specimens will be labeled with a code 
number and not with the study participant’s name.  At the time of consent for study participation, 
the study participant or legal guardian will have the opportunity to either agree to have their 
specimens used in future research or decline to have their specimens used in future research.  
The study participant or legal guardian will indicate his/her preference by initialing the 
appropriate line or checking the appropriate box of the Consent Form in the section entitled, 
“Future Use of Specimens”.  Non-protocol designated, future testing of samples will be 
performed only on samples from study participants who have consented for future testing of 
samples.   
 
A repository for residual samples will be established according to OHRP guidelines 
ensuring that code or other personally identifying links will not be distributed to future 
researchers. The specimens will be stored indefinitely at the University of Washington and 
Boeckh Lab Fred Hutchinson Cancer Research Center. Samples from study participants will be 
labeled and coded without study participant’s identifiers.  If the study participant or legal 
guardian has indicated in the signed consent form that he/she does not agree to allow the future 
use of specimens for research, then his/her  specimens will be destroyed at the completion of 
the study. 
 


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8 
STUDY PROCEDURES/EVALUATIONS 
The study procedures and evaluations are summarized in Appendix A 
8.1 
Clinical Evaluations 
8.1.1    Baseline demographics/medical history 
Information will be recorded at the baseline study visit day 1 following randomization.  
Data collected will include basic demographics (information in compliance with the NIH Policy 
on Reporting Race and Ethnicity Data: Subjects in Clinical Research, Aug. 8, 2001 available at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html) gender; age, race; ethnicity. 
Subject weight will be recorded (weight recorded is the most recent weight obtained as standard 
care or obtained by the investigator). Also collected will be specific medical information including 
date of liver transplant, donor age and type (living or deceased), most recent standard of care 
MELD score prior to transplant, underlying liver diseases leading to transplant and co-morbid 
conditions (diabetes, cancer, cardiovascular disease, respiratory disease, renal disease). 
Specific baseline medications will be recorded including immunosuppressive agents, drugs with 
known hematologic toxicity, and any doses of antiviral agents. Standard of care clinical 
laboratory results, donor CMV serology, and study specific laboratory results will be recorded.  
All data will be abstracted from the medical records. Only current medical records from the 
transplant admission will be reviewed for baseline data collection. No past medical records will 
require review with the exception of confirmation of CMV serostatus with-in the allowable study 
window.  No study specific physical examination will take place. 
 
 8.1.2 Adverse event assessment 
 
All subjects will be assessed for adverse events throughout the administration of drug 
period plus 7 days. This is anticipated to be study day 1 through 107 for prophylaxis group 
subjects.  Preemptive monitoring of AEs timelines will be individually determined by treatment 
for viremia detected during study days 1-100.Please see adverse event section for complete 
description of adverse event monitoring and reporting.  
 
 
 
  
8.1.3 Neutropenia assessment 
During active drug treatment, subjects will be monitored for neutropenia. Neutropenia 
with ANC < 1000/µL will be documented and reported as adverse events. Guidance for the 
evaluation and management of neutropenia are provided in the study manual of operations. 


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8.1.4 Assessment of CMV disease 
 
CMV disease includes CMV syndrome or tissue invasive CMV disease. The following 
definition will be used for the study’s primary efficacy analysis: 
 
 
8.1.4.1  
CMV syndrome  
The subject has CMV infection (viremia) identified by a nucleic acid based assay 
[CMV DNA PCR, pp67mRNA or digene hybridization (non-amplification assay)] 
or antigenemia assay or viral culture  
AND at least one of the following clinical/laboratory findings: 
 
 
 
• Fever of ≥ 38°C (100.4°F) 
• Severe malaise 
• Leukopenia defined as: 
White blood cell (WBC) count of <3,500/µL if the 
WBC count prior to the development of clinical 
symptoms is ≥ 4,000/µL or 
WBC decrease of > 20% if the WBC count prior to 
the development of clinical symptoms is < 4,000/µL 
• Atypical lymphocytosis of ≥ 5% 
• Thrombocytopenia defined as: 
Platelet count of < 100,000/µL if the platelet count 
prior to the development of clinical symptoms is ≥ 
115,000/µL or 
Decrease of > 20% if the platelet count prior to the 
development of clinical symptoms is < 115,000/µL 
 
8.1.4.2  
Tissue invasive CMV disease   
 
A diagnosis of organ-specific tissue invasive CMV disease detected by viral 
culture, histopathology/cytology (CMV inclusion cells), immunohistochemical analysis or in situ 
hybridization for CMV in a biopsy or other appropriate sample such as bronchoalveolar lavage 
(BAL), cerebrospinal fluid AND symptoms or signs of organ dysfunction. Detection of CMV by 
PCR in the tissue will be insufficient for the diagnosis of tissue invasive CMV disease. 
Criteria to be met for diagnoses of specific organ CMV tissue invasive disease 
are as follows: 
 
CMV hepatitis: 
• 
Liver biopsy with CMV detected by viral culture, CMV inclusions 
by histopathology/cytology, immunohistochemical analysis or in 
situ hybridization 
 (Other pathogens or etiologies of hepatic dysfunction such as 
rejection may be present and do not exclude the diagnosis of 
CMV hepatitis) 
 
CMV gastrointestinal tract disease (includes esophagitis, gastritis, 
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• 
Detection of CMV in tissue biopsy by viral culture, 
histopathology/cytology with CMV inclusions, 
immunohistochemical analysis or in situ hybridization 
• 
In addition the subject has upper or lower gastrointestinal tract 
symptoms and/or signs such as nausea, vomiting, anorexia, 
dysphagia, odynophagia, cramping, diarrhea or abdominal pain. 
(Other pathogens for example, C. difficile may be present without 
excluding the diagnosis of CMV gastrointestinal disease) 
 
 
 
CMV pneumonia: 
• 
Presence of symptoms and/or signs of pulmonary disease  
• 
AND the detection of CMV in the bronchoalveolar lavage (BAL) or 
lung biopsy. Detection of CMV in the BAL or biopsy may be 
performed by viral culture, histopathology/cytology with CMV 
inclusions, immunohistochemical analysis or in situ hybridization 
for CMV. Detection of CMV by PCR alone is insufficient for the 
diagnosis of CMV pneumonia. Other pathogens may coexist 
without excluding the diagnosis of CMV pneumonia 
 
 
 
CMV retinitis: 
• 
Dilated fundus examination and diagnosis of CMV retinitis by an 
ophthalmologist. 
 
Central nervous system disease: 
• 
Detection of CMV in the CSF by viral culture, CMV DNA/RNA 
PCR assay or in a biopsy sample by culture, 
histopathology/cytology (CMV inclusions) immunohistochemical 
analysis or in situ hybridization 
• 
And Presence of central nervous system (CNS) symptoms 
 
Other tissue invasive CMV disease: 
• 
 Detection of CMV by viral culture, histopathology/cytology with 
CMV inclusions, immunohistochemical analysis or in situ 
hybridization in a biologic specimen (e.g., tissue biopsy) 
• 
AND the subject exhibits signs or symptoms of relevant organ 
dysfunction  
 
 
 8.1.4.3 
Assessment and treatment of subjects with suspected CMV disease 
 
Subjects who develop signs or symptoms of possible CMV disease within 12 
months post-transplant will have a blood sample collected and sent to the central laboratory for 
CMV DNA PCR. CMV testing may also be performed at the local site on blood samples or any 
other relevant biologic samples using locally available assays for CMV detection. All aspects of 
diagnostic workup and CMV treatment will follow routine practices at the transplant center which 


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will include appropriate clinical evaluations and blood cultures to rule out bacterial, fungal or 
other opportunistic infections as a cause of the subject’s symptoms which is a standard of care. 
Other diagnostic laboratory procedures and imaging studies will be performed as warranted by 
the subject’s clinical status and standard medical practices at the site. The treatment for CMV 
disease will be initiated at the site investigator’s or clinical team’s discretion. The choice of anti-
CMV agent, the duration of therapy and subject follow up will be in accordance with standard 
practice at the site 
8.1.5 Secondary and Exploratory Outcome Assessments 
 
All subjects will have data collection throughout the entire study period to capture 
assessments for the study’s primary efficacy analysis, CMV disease. All aspects of diagnostic 
workup and CMV treatment will follow routine practices at the transplant center. All subjects will 
also have data collection throughout the study period to capture study outcomes including: 
rejection episodes and treatment, graft loss, retransplant opportunistic infections (bacterial, 
fungal, non-CMV viral), treatment with anti-viral medications, and hospitalization status. 
 
 
8.1.6    Procedure for clinical data collection 
 
 
Study staff will collect data by reviewing medical records at each study visit. These 
reviews will cover all intervals post-transplant with no omissions. Medical records will be 
reviewed for data pertaining to all study outcome measures, medical history, demographics (as 
described in protocol section 7.2.1), medications, procedures, lab results, and adverse events. 
Data will be entered into the CRF during each medical record review. 
 
8.2 
Laboratory Evaluations  
 
 
Blood for study-specified laboratory evaluations may be obtained by methods such as 
the following:  venipuncture, indwelling heparin-locked intravenous catheter, indwelling saline-
locked intravenous catheter, etc.  As detailed below, blood sample will be obtained for 
assessment of hematology safety labs, chemistry safety labs, whole blood CMV viral 
load/resistance testing, immune assays, and genetic analysis. With the exception of the 
pregnancy test, preemptive group PCR testing, and safety labs, those lab tests which are 
unable to be obtained due to lack of sufficient blood, or are obtained out of window study visits 
will not be reported as protocol deviations.  
 
Initial labs will be obtained at the enrolling transplant center sites.  Later labs (after the 
subjects have been discharged from the transplant center) may be obtained at the subject’s 
local laboratory. It is typical for transplant patients to be released to the care of primary 
physician for routine standard care laboratory assessments when travel distance restricts return 
to the transplant center. These subjects will be having laboratory assessments at various 
remote out-patient clinics, hospitals, nursing facilities, or rehab centers, depending on their 


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home location. The subjects may have their blood drawn at any facility licensed to draw blood. It 
is not required for subjects to be seen by a doctor on the day of their blood draw  
 
Lab analysis for immune assays, CMV PCR, genetic analysis and resistance will be 
done at study specific central labs as specified in the MOP for this study. All materials, shipping 
supplies, and instructions will be provided to the enrolling site by the coordinating center. The 
enrolling site will coordinate with any remote sites and provide shipping supplies and 
instructions. Please see laboratory manual for all process and storage directions. 
 
8.2.1  Hematology safety labs 
Hematology assessments will provide information on the safety of administering the 
valganciclovir. The following will be tested:  white blood cell count, differential (ANC calculation), 
hemoglobin, and platelet count. Hematology results will be collected as standard care and data 
will be recorded from various CLIA certified labs in remote clinics for study purposes. If 
hematology labs are not ordered and drawn as standard care with-in the specified visit window, 
subjects will be required to have a study investigator prescribed hematology assessment at their 
local facility. Please see protocol; section 7.4.3.1 for allowable windows for the collection of lab 
values. 
8.2.2 Chemistry safety labs 
Chemistry assessments will provide information on the safety of administering the 
valganciclovir.  The following will be tested:  AST, ALT, total bilirubin, BUN and creatinine. 
Chemistry results will be collected as standard care and data will be recorded from various CLIA 
certified labs in remote clinics for study purposes. If chemistry labs are not ordered and drawn 
as standard care with-in the specified visit window, subjects will be required to have a study 
investigator prescribed chemistry assessment at their local facility. Please see protocol; section 
7.4.3.1 for allowable windows for the collection of lab values. 
 
8.2.3 CMV PCR surveillance monitoring (To be assessed in preemptive 
therapy subjects only)  
 
Subjects in the preemptive group of the CAPSIL study will have CMV PCR serum 
sample (approximately 10ml) obtained specifically for the study at study days 
7,14,21,28,35,42,49,56,63,70,77,84,91,98. All CMV PCR sample windows are +/- 3 days. CMV 
PCR samples will be obtained at the transplant center if hospitalized, or will be collected during 
routine care follow-up clinic appointments and outpatient laboratories, skilled nursing facilities, 
or rehabilitation facilities. CMV PCR analysis will be completed at the University of Washington 
Medical Center Virology lab. Results will be faxed to the enrolling site from University of 
Washington Medical Center Virology lab. 
 


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8.2.4 Special Assays or Procedures 
8.2.4.1           CMV resistance to ganciclovir  
(as needed during study day 1-365) 
 
 
For those subjects who demonstrate no reduction in viral load after three weeks of 
ganciclovir/valganciclovir employed for CMV viremia in subjects in the preemptive therapy group 
or for the treatment of CMV disease in subjects in either study group, assessment of genotypic 
resistance for UL97 and UL54 mutations may be undertaken. Testing may also be undertaken 
within the 3 weeks at the request of the site investigators after discussion with the study PIs if 
the viral load fails to decline or if there is lack of response to the treatment of CMV disease. 
Please see section 7.5.5 for sample collection for resistance assays.  Testing will be performed 
at the Central Virology lab (U. of Washington Virology Lab). Testing for UL97 and UL54 
mutations conferring resistance to ganciclovir will be performed in a step-wise manner.  If 
genotypic resistance to UL97 is not found, then no further testing will be undertaken. If UL97 
mutation conferring resistance is found then reflexive UL 54 genotyping will be performed.  
Results of genotypic testing will be reported back to the investigators, approximately within one 
month of assessment. The decision to treat resistant CMV, the choice of anti-CMV agent for 
treatment, the duration of therapy and subject follow up will be in accordance with standard 
practice at the site    
 
8.2.4.2       Immune assays and lymphocyte count 
 
Subjects will have study specific serum samples obtained for Immune Assay testing and 
a lymphocyte count  [proportion of white blood cells (hematology) that are lymphocytes] at study 
day 98, and at 6 months and 12 month (post-transplant) time point. . Immune assays will be 
done by the Boeckh Lab at Fred Hutchinson Cancer Research Facility in Seattle Washington. . 
Results of immune assays will be provided only to the coordinating center since these results do 
not impact subject care. Lymphocyte counts may be processed at the transplant center local 
laboratory or at the subject’s local laboratory. Results of the Lymphocyte count will be recorded 
in the CRF. 
 
8.2.4.3  
Genetic testing 
 
 
This clinically well characterized cohort with an anticipated high-incidence of outcomes 
of interest (CMV, other infectious and non-infectious complications) has the potential for 
significantly advancing our understanding of the pathogenesis of post-transplant complications. 
We propose to collect a blood sample for future testing to assess host immune response 
polymorphism to identify potential immunologic correlates of susceptibility (or protection) against 
CMV infection and/or disease. We will characterize immune and adaptive immune responses to 
CMV (for example CMV-specific T-cell responses, antibodies to CMV) as a potential explanation 
for protection against late-onset CMV disease in subjects who receive preemptive therapy 
compared to antiviral prophylaxis. Additionally, we propose to explore if there were any 
associations between polymorphisms in a range of genes and risk of other infectious and non-
infectious complications after liver transplant.  
 


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We will obtain informed consent for ‘future use of samples for genetic testing’ at the time 
of enrollment into this study according to applicable local and other regulatory requirements. All 
proposed future genetic studies will be submitted for local IRB review and all applicable 
regulatory requirements will be met. However, no further subject consent will be sought for 
genetic studies related to infectious and non-infectious complications after liver transplant. 
Subjects will have the choice to opt out of future genetic testing at the time of initial consent 
although participates in all other aspects of the study. If consent is given for genetic testing a 
onetime sample of blood (10ml) will be obtained at the transplant center and shipped to Boeckh 
Lab at Fred Hutchinson Cancer Research Facility for future genetic analysis. The current award 
does not include funding to perform such studies so we propose to store samples indefinitely 
until such funding becomes available. Several safeguards will be implemented (Please see the 
MOP) to ensure that samples for genetic testing are stored only from subjects who have 
provided specific consent for such testing. 
 
8.2.4.4  
Pregnancy testing 
 
All female subjects of child bearing potential will have a pregnancy test as follows: First, 
at baseline (within 48 hours prior to randomization) and at the end of treatment (window of up to 
3 month post study treatment). This may be done on urine or blood sample. Positive results at 
baseline will result in exclusion from study.  
 
8.2.4.5 Suspected CMV disease sample collection 
 
 
Subjects in either group suspected to have CMV disease based on the assessment of 
the clinician or the investigator will have a blood sample sent to the central lab for CMV DNA 
PCR testing. This sample collection may occur at any time point throughout the 12 month 
duration of the study. In preemptive therapy group, this sample will be in addition to the weekly 
CMV testing sample.  CMV PCR analysis will be completed at the University of Washington 
Medical Center Virology lab. Results will be faxed to the enrolling site from the University of 
Washington Medical Center Virology lab. 
8.2.5 Specimen Preparation, Handling, and Shipping 
Specific instructions on specimen preparation, handling and shipping will be provided in 
the Manual of Procedures for this study. 


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9 
ASSESSMENT OF SAFETY 
 
 
 
 DMID Safety Reporting and Safety Monitoring 
 
 
Regulatory requirements including the Food and Drug Administration (FDA) 
regulations, International Conference on Harmonisation (ICH) Guidelines for Good Clinical 
Practice (GCP), and European Union (EU) Clinical Trials Directive set forth safety monitoring 
and reporting responsibilities of sponsors and investigators to ensure the safety and protection 
of human subjects participating in clinical trials. 
 
 9.1 Responsibilities 
Investigators participating in this clinical trial are responsible for and will: 
• 
Evaluate subject safety including assessment of adverse events (AEs) for 
seriousness, severity, expectedness, and causality; 
• 
Notify the sponsor (DMID) of protocol defined serious adverse events (SAEs) with-in 
the protocol defined reporting requirement. 
• 
Provide detailed written reports, including necessary documentation requested by 
the sponsor or institutional review board (IRB)/independent ethics committee (IEC), 
promptly following initial reports 
• 
Inform the IRB/IEC of AEs as required by applicable local regulatory requirements. 
9.2 
Adverse Event (AE) Definitions 
9.2.1 ICH E6 Definition  
 
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product regardless of its causal 
relationship to the study treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of medicinal (investigational) product. The 
occurrence of an AE may come to the attention of study personnel during study visits 
and interviews of a study recipient presenting for medical care, or upon review by a 
study monitor. (Please note: for the CAPSIL study AEs are reportable only if study 
related or unexpected, please see definition of reportable event for CAPSIL study 9.2.3)   
 
 


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9.2.2 FDA Definition 
 
 
The FDA defines an AE as any untoward medical occurrence associated with the use  
 
of a drug in humans, whether or not considered drug related. (Please note: for the  
 
CAPSIL study AEs are reportable only if study related or unexpected, please see  
 
definition of reportable event for CAPSIL study 9.2.3)   
 
9.2.3 CAPSIL Definition 
 
 
For the CAPSIL study, a reportable adverse event is defined as:  
 
 
1. Any clinically important untoward medical occurrence in a subject receiving study 
drug that is different from what is expected in the clinical course of a patient with 
a liver transplant (see appendix C for events considered to be part of the 
expected course of liver transplant). 
 
 
 
OR 
 
 
2. Any clinically important, untoward medical occurrence that is thought to be 
related to the study drug, regardless of the “expectedness” of the event for the 
course of a patient with a liver transplant. Expected events for liver transplant are 
untoward clinical occurrences that are deemed by the investigator to occur with 
reasonable frequency in the day-to-day care of patients with a liver transplant 
(see appendix C for events considered to be part of the expected course of liver 
transplant). 
9.3 
Documentation of Reportable AEs  
 
All reportable AEs should be captured on the eCRF. Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, and relationship to study 
product or procedure (assessed only by those with the training and authority to make a 
diagnosis, which would include MD, PA, Nurse Practitioner, DO, or DDS), and time of 
resolution/stabilization of the event. Reportable AEs occurring while on study must be 
documented appropriately and will be followed to resolution or stabilization. AE events that are 
assessed as Serious require additional reporting as described in section 9.4.1.1. 
Any medical condition that is present at the time that the subject is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time during 
the study and meets reportable criteria it should be recorded as an AE. 
9.4 
Investigator’s Assessment of Adverse Events  
 


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Complete review of each subject’s medical records will take place on an ongoing basis 
by the site investigator while hospitalized at the transplant center. Although only AEs meeting 
reportable criteria will be documented in the eCRF, after discharge, the site investigator will 
assess all subjects’ records at each study visit to verify that all adverse events that meet 
reportable AE criteria have been documented in the eCRF and reported per reporting guidelines 
discussed below. The investigator will provide documentation in the subject’s study file 
confirming that all AEs have been assessed and those meeting reportable criteria have been 
reported and documented as required. 
 
 
For reportable adverse events, the investigator is required to provide source 
documentation for the serious criteria, severity, relatedness, action taken, and outcome of each 
event. 
 
 
The determination of seriousness, severity, and causality will be made by an on-site 
investigator who is qualified (licensed) to diagnose AE information, provide a medical evaluation 
of AEs, and classify AEs based upon medical judgment. This includes but is not limited to 
physicians, physician assistants, and nurse practitioners.  
 
 9.4.1 Serious Adverse Events (Assessment of Seriousness) 
 
An adverse event is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• 
Death 
• 
A life-threatening adverse event* 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
 
normal life functions 
• 
Congenital anomaly/birth defect.   
• 
Important medical events that may not result in death, be life-threatening, or require 
 
hospitalizations may be considered serious when, based upon appropriate medical 
 
judgment they may jeopardize the subject or/ and may require medical or surgical 
 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
 
medical events include allergic bronchospasm requiring intensive treatment in an 
 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death.  It does not include an adverse event, had it occurred in a 
more severe form, might have caused death. 
9.4.1.1         Reportable SAEs for CAPSIL study 
 


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Liver transplant recipients represent a critically-ill population in whom a high rate of 
untoward medical events are commonly seen during the routine post-transplant course as part 
of their underlying medical condition, transplant surgery or postoperative state. In an effort to 
document only clinically-relevant untoward medical events that have a greater likelihood of 
being study-related (rather than the normal course of liver transplantation), study endpoints 
(CMV disease, opportunistic infections, rejection, graft loss, mortality, and hematologic toxicity) 
and certain pre-specified expected events commonly seen in this population (see appendix C 
for list of expected events for liver transplant patients) will not be reported as serious adverse 
events SAEs even if they meet the serious event criteria listed in 9.4.1. Reportable SAEs for 
CAPSIL study will be adverse events that are serious and unexpected [not expected to occur 
with a reasonable frequency in the typical clinical course of a patient following liver transplant 
(appendix C)]. 
Death will be recorded in the CRF although it will not be a reportable SAE as it is an 
endpoint for the CAPSIL study unless it meets the CAPSIL reportable criteria of related and/or 
unexpected (see appendix C for list of expected events for liver transplant patients) 
Reportable SAEs will be: 
• 
Recorded on the appropriate CRF 
• 
Followed through resolution by a study clinician 
• 
Reviewed and evaluated by a study clinician 
9.4.1.2        Notification of the Sponsor, Coordinating Center and    
Local IRB of Serious Adverse Events (SAE) 
 
A Reportable AE that meets the protocol-defined serious criterion must be 
reported with a completed SAE report within 24 hours of site awareness to the DMID 
pharmacovigilance contractor, at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20814, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
A copy of the DMID SAE form will also be faxed to the Coordinating Center: 
Attention: CAPSIL Study Manager: Mary Stefanick, BSN RN CCRC. FAX: 412-
647-6872 
 
 
Other supporting documentation of the event may be requested by the DMID 
 
pharmacovigilance contractor and should be provided as soon as possible.  The DMID 
 
pharmacovigilance contractor will notify the DMID medical monitor and clinical 


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protocol manager. The DMID medical monitor will review and assess the SAE for 
 
regulatory reporting and potential impact on study subject safety and protocol conduct. 
 
At any time after completion of the study, if the investigator becomes aware of an SAE 
 
that is suspected to be related to study product, the investigator will report the event to 
 
the DMID Pharmacovigilance Group. 
 
 
Each individual enrolling site is responsible for adhering to the AE and SAE 
reporting requirements of their local IRB. The University of Pittsburgh will submit to the 
coordinating center IRB per their reporting requirements. 
9.4.2 Assessment of Severity 
 
Reportable AEs will be graded according to Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0, published May 28, 2009 (v.4.03 June 14, 2010). 
The severity of each event will be classified into one of five defined categories as 
follows: 
• 
Grade 1 Mild 
• 
Grade 2 Moderate 
• 
Grade 3 Severe 
• 
Grade 4 Life Threatening or Disabling 
• 
Grade 5 Death 
. 
9.4.3 Assessment of Relationship to Study Product or Procedure 
 
Relationship to Study:  The clinician’s assessment of an AE's relationship to study 
product or study procedures is part of the documentation process and may determine 
what is or is not reported in the study (Please see CAPSIL definition of an AE).  If there 
is any doubt as to whether a clinical observation is a reportable AE, the event should 
be reported. Reportable AEs must have their relationship to study product or 
procedure assessed using the terms: related or not related. To help assess, the 
following guidelines are used. 
 
• 
Related – There is a reasonable possibility that the study product or study 
procedure caused the adverse event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study product or study 
procedure and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the study product or 
study procedure caused the adverse event. 
The investigator must provide an assessment of relationship of AEs to the study 
product based on: 
•  
Temporal relationship of the event to the administration of study product or  
   
procedure 
•  
Whether an alternative etiology has been identified 


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•  
Biological plausibility 
•  
Existing therapy, and/or concomitant medications.  
9.5 
Reporting Interval 
 
Site investigators will be responsible to monitor, document reportable AEs and SAEs, 
through study intervention period of the CAPSIL study plus one week. This is anticipated to be 
study day107 in the prophylaxis group and may vary in the preemptive group depending on 
treatment for viremia detected during study days 1-100. 
 
 
Reportable AEs and SAEs will be followed until resolution, even if this extends beyond 
the study-reporting period. Resolution of an AE is defined as the return to pretreatment status or 
stabilization of the condition with the expectation that it will remain chronic.  
 
 
At any time after completion of the study, if the investigator becomes aware of an SAE 
that is suspected to be related to study product, the investigator will report the event as a SAE. 
 
9.6 
Regulatory Reporting for Studies Conducted Under 
DMID-Sponsored IND 
 
 
 
Following notification from the investigator, DMID, the IND sponsor, will report any 
suspected adverse reaction that is both serious and unexpected.  DMID will report an adverse 
event as a suspected adverse reaction only if there is evidence to suggest a causal relationship 
between the drug and the adverse event.  DMID will notify FDA and all participating 
investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or 
under any investigator’s IND) in an IND safety report of potential serious risks from clinical trials 
or any other source, as soon as possible, but in no case later than 15 calendar days after the 
sponsor determines that the information qualifies for reporting as specified in 21 CFR Part 
312.32. DMID will also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor’s initial 
receipt of the information.  Relevant follow-up information to an IND safety report will be 
submitted as soon as the information is available. Upon request from FDA, DMID will submit to 
FDA any additional data or information that the agency deems necessary, as soon as possible, 
but in no case later than 15 calendar days after receiving the request. 
 
All reportable serious events designated as “not related” to study product(s), will be reported to 
the FDA at least annually in a summary format. 
 
9.7 
Reporting of Pregnancy  
 
 


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If pregnancy is discovered during the follow-up period the investigator must report 
information using the Pregnancy Report Form to the Coordinating Center. All pregnancies will 
be followed up to final outcome, using the pregnancy follow-up form. At that time, the status of 
the mother and infant will be noted, including the date of delivery and the infant’s gender and 
weight. 
 
 
The outcome, including any premature termination, must be reported to the Coordinating 
Center within calendar 5 days awareness of pregnancy on a pregnancy notification form. The 
pregnancy is not considered an AE; however pregnancy complications, including miscarriage or 
spontaneous abortion, are considered AEs. The report of any pregnancy and the outcomes of 
pregnancy as outlined above will be reported by the Coordinating Center to the DMID Medical 
Monitor within 7 business days of receiving pregnancy report form from the site.  
9.8 
Safety Monitoring By the DMID Safety Oversight Mechanism 
9.8.1 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established by the DMID. The 
DSMB members will consist of persons independent of the investigators or study team 
with no financial, scientific or other conflict of interest with the study and will be selected 
by the NIH.  The initial responsibility of the DSMB will be to review and make 
recommendations regarding the initiation of the study. After the initiation of the study and 
during the course of the study at intervals determined by the DMID, the DSMB will: 
 
1. Review the research protocol, template informed consent document and plans for data 
and safety monitoring. 
2. Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that can affect study outcome. 
3. Review study endpoints for differences between groups  
4. Consider factors external to the study when relevant information becomes available,  
5. Monitor the confidentiality of the study data and the results of monitoring.  
  
The coordinating center will provide all data, tables, unique and repeated listings, 
figures, descriptive statistics, and tests of significance requested by the NIH for all DSMB 
meetings, interim analysis plan and final analysis.  
9.8.2 Discontinuation of Study Enrollment and Study Product 
Administration for all Subjects in the Study 
 
DMID, when it is the study sponsor, may interrupt study dosing and/or study entry at any 
time if medically indicated. To minimize risk, the medical monitor and the DSMB will review 
cumulative safety data. The study enrollment and dosing will be stopped, and an ad hoc review 
will be performed if halting rules are met. 
 


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9.8.3   Halting rules 
 
 1. All-cause mortality compared at interim analysis will be used as safety parameter for 
halting the trial. With 60 subjects enrolled, a difference in survival probability of greater than 
37% would be detected at the .05 level with 90% power. Thus an important difference in 
mortality between the two groups if documented will be detected at interim analysis and DSMB 
recommended action can be undertaken. The table below depicts minimal detectable hazard 
ratio with sample size of 60. 
 
 
2. Halting for a difference in reportable SAEs will be done upon the recommendation of 
the DSMB if there is a statistically significant difference in reportable SAEs at the .05 level after 
at least 20 subjects are enrolled.  
3. A statistically significant difference (p=0.001) of more than 50% between the two 
groups in the incidence of CMV disease after 1 year follow of 60 subjects. 
 
Safety endpoint 
At interim-Minimal detectable hazard ratio with sample size of 60 at alpha=.05, power=.9: 
Probability of survival 
(inferior regimen) 
Probability of survival  
(superior regimen) 
Events Hazard ratio 
.600 
.976 
13 
.048 
.550 
.950 
16 
.089 


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10 END-POINTS COMMITTEE (EPC)  
 
10.1 Composition  
 
An EPC will be established comprising three individuals with expertise in CMV and 
transplantation to adjudicate CMV disease events. The members of the EPC will be 
independent of the study investigators and will be selected by the DMID. The function of the 
committee will be to review the supporting clinical and laboratory data from all subjects identified 
as having developed CMV disease by the site investigators. Based on their review of the 
protocol definition of CMV disease and the clinical and laboratory documentation, the committee 
will identify those CMV disease events that should be included in the primary efficacy analysis. 
The EPC members will receive no financial incentives for their participation, but may be 
reimbursed for customary consultative or administrative support fee as determined appropriate 
by the DMID. 
10.2 Responsibilities and Data Flow 
The role of the EPC will be to evaluate and determine if the cases reported as having 
CMV disease by the investigators meet the protocol definition of CMV disease. In order to do 
so, the EPC will review all supporting clinical and laboratory data from such cases. The 
committee members will be blinded to the treatment allocation of all subjects in the study, 
including the subjects on which they are adjudicating. Subjects will be identified only with their 
study number. For the purposes of review, the following specific information will be provided to 
the EPC for the cases: 
• 
Narrative summary that includes description of all signs and symptoms of the illness, 
and the reasons that the investigator diagnosed or suspected CMV disease. 
• 
Type of CMV disease (viral syndrome or tissue invasive disease) 
• 
Sites of CMV organ disease. 
• 
Laboratory assay(s) that detected CMV disease 
• 
Biopsy findings (if applicable) 
• 
Other relevant laboratory, imaging studies or diagnostic procedures 
• 
Outcome of disease and treatment employed. 
The coordinating center will provide the required documents to the EPC. The EPC event 
adjudication will occur prior to interim analysis and prior to close out. It is anticipated that there 
will be approximately 30 CMV disease events to be reviewed. 
The EPC will provide the coordinating center and the DMID with the conclusion for all cases 
that it has reviewed and whether the event meets the protocol definition of CMV disease (yes or 
no). When a unanimous decision cannot be made on the adjudication of the case by the three 
committee members, a vote will be taken and the majority vote will hold. 


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11   
SITE MONITORING PLAN 
 
Site monitoring will be conducted to ensure that human subject protection, study 
procedures, laboratory procedures, study intervention administration, and data collection 
processes are of high quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that 
the study is conducted in accordance with the protocol and sponsor standard operating 
procedures.  DMID, the sponsoring agency, or its designee will conduct site-monitoring visits as 
detailed in the monitoring plan. 
 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, CRFs, informed consent forms, medical and laboratory 
reports, source documents, data collection forms , medical records and protocol compliance. 
Study monitors will meet with investigators to discuss any problems and actions to be taken and 
document visit findings and discussions. 


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12 
 
STATISTICAL CONSIDERATIONS 
 
12.1   Sample size calculations 
 
The primary endpoint is the incidence of CMV disease within 12 months post 
transplantation. The null hypothesis is that the incidence of CMV disease in the prophylaxis 
group is equal to that in the preemptive therapy group. The null hypothesis will be rejected 
if there is a significant difference between the two groups at 0.05. The sample size 
estimates have been calculated based on the numbers required to detect a disparity in two 
survivor functions using a two-sided log-rank test [stpower logrank, STATA version 
10.1].The calculations are based on a realistic and conservative expectation in differences 
in event (CMV disease), feasibility and clinically relevant effect size. The mean CMV 
disease rate (weighted for study size) for prophylaxis and preemptive therapy studies 
(depicted in the Tables in the Background section of the protocol) is 30.6% (95% CI 24.1-
37.1) and 0.78% (95% CI: 0-2.4%), respectively. Based on power calculations that coincide 
with the lowest observed rate for CMV disease in prophylaxis studies and highest rate 
observed in preemptive therapy studies, we assume that CMV disease will occur in 20% of 
the subjects in the prophylaxis and 5% in the preemptive therapy group. A sample size of 
160 study subjects (80 per group) will detect this difference with power of 80% and alpha 
=0.05 using two-sided Fisher’s exact test for two independent proportions. The Table below 
provides sample size estimates for CMV disease rates of 20-25% in the prophylaxis and 5-
7% in the preemptive therapy group.  
 
       Prophylaxis group 
 
Preemptive therapy 
group 
Hazard 
ratio 
Power 
Estimated 
events 
Sample  
size 
each  
group 
Total 
sample 
Estimated 
disease 
rate 
Disease  
free  
survival 
Estimated 
disease  
rate 
Disease  
free  
survival 
25% 
.75 
7.1% 
.929 
.254 
.83 
25 
75 
150 
 25% 
.75 
7.1% 
.929 
.257 
.85 
26 
80 
160 
22% 
.78 
7.0% 
.930 
.291 
.80 
27 
90 
180 
20% 
.80 
5.0% 
.950 
.229 
.80 
20 
80 
160 
20% 
.80 
6.0% 
.941 
.273 
.80 
25 
93 
186 
20% 
.80 
5.4% 
.946 
.247 
.80 
22 
85 
170 
20% 
.80 
7.0% 
.930 
.325 
.80 
31 
112 
224 
 


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Non-inferiority: Although the study sample size is powered to detect the superiority of one 
preventive strategy compared to the other, it is possible that the two approaches may be similar 
in efficacy with respect to CMV disease. Therefore a non-inferiority assessment will be done 
using a non-inferiority margin of 5%. This margin is based on what is known about the 
effectiveness of the two approaches in the literature and the potential that the two strategies 
may be equally efficacious in preventing CMV disease. As noted above, the success rate for the 
prophylaxis group is estimated at 75 to 80% based on previous studies with comparable 
success rates for the preemptive group. The null hypothesis for non-inferiority is that the 
success rate (percent of subjects remaining CMV disease free) for subjects in the prophylaxis 
group is better than the success rate for those in preemptive therapy group by 5%. The null 
hypothesis will be rejected and the preemptive therapy will be considered to be non-inferior if 
the success rate in the prophylaxis group is less than 5% greater than that in the preemptive 
therapy group. Sample size estimates for non-inferiority are given below at alpha=.05 
 
Success in 
prophylaxis 
group 
Success in  
preemptive therapy 
group 
Non 
inferiority 
margin 
 
Sample size each 
group 
[total sample] 
Power 
80% 
85% 
10% 
80   [160] 
80 
80% 
85% 
8% 
106 [212] 
80 
80% 
90% 
5% 
96   [192] 
90 
80% 
90% 
5% 
70   [140] 
80 
80% 
89% 
5% 
80   [160] 
80 
80% 
85% 
5% 
178 [356] 
80 
75% 
85% 
5% 
87   [174] 
80 
75% 
90% 
5% 
76   [152] 
95 
75% 
90% 
2% 
83   [166] 
90 
75% 
88% 
5% 
78   [156] 
90 
80% 
80% 
5% 
792 [1584] 
80 
Note: for "equivalence" at 80% success rate in each group and a 5% equivalence limit, a sample of 1097 in each 
group would be required [2194 total subjects] at alpha=.05 and power=.80.  
 
Our sample size is adequate to assess both superiority and non-inferiority (with a margin 
of 5%) without statistical penalty. In a sample size of 160 subjects, if there is a true difference of 
9% in favor of the preemptive therapy group [9% higher success rate for CMV disease 
prevention]; we can be certain (with power equal to 80%) that the upper limit of a one-side 95% 
confidence interval will not include a difference of more than of 5% (non-inferiority margin) in 
favor of the prophylaxis group. 
 
12.2 Treatment groups 
 
 
Subjects will be randomized into one of the two groups in 1:1 ratio. Prophylaxis group 
will receive VGCV for 100 days and preemptive therapy group will undergo weekly CMV PCR 
screenings and receipt of VGCV following a positive CMV PCR test. A stratified, blocked 
randomization scheme will be utilized in order to keep the sample sizes similar in both groups. 


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Subjects at each site will be stratified by receipt of anti-lymphocyte induction therapy and renal 
dialysis at the time of randomization. Subjects will be consecutively entered. 
 
12.3 Populations for analysis 
 
 
There will be two analysis populations: Intent-to-treat (ITT) and a modified ITT.  Limited 
summary information will be provided for screen failures. An ITT analysis will be conducted for 
the primary endpoint. 
 
12.3.1 Intent-to-treat (ITT) population 
 
 
All subjects who meet all eligibility criteria, sign an informed consent form, and are 
randomized to one of the treatment groups constitute the ITT population regardless of whether 
they received valganciclovir or had any post-baseline evaluations. 
  
12.3.2 Modified intent-to-treat population 
 
 
The modified ITT population will consist of those subjects in ITT population who were 
randomized and received at least one dose of valganciclovir in the prophylaxis group or had at 
least one CMV PCR test post-randomization in the preemptive therapy group. 
 
12.3.3 Screen failures 
 
Subjects that were screen failures will be summarized as to the reason for screen failure 
with no further characterization. Screen failures will include patients that never signed consent 
as well as those that signed consent but did not meet eligibility criteria and therefore were never 
randomized  
 
12.4 Data Analyses 
 
12.4.1 General considerations 
 
All statistical analyses will be performed using STATA version 10.1 or later [Stata Corp, 
College Station, TX] or SAS version 9.2 or later [SAS Institute Inc., Cary, NC].  Cost efficacy 
analysis will use TreeAge Pro 2011 or later [TreeAge software, Williamstown, MA]. Tests of 
statistical significance will be two sided at an alpha of 0.05 unless otherwise specified. 
 


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12.4.2 Missing data 
 
Sensitivity analysis employing imputation of missing values will be carried out for efficacy 
and safety endpoints as appropriate. The type of imputation is specified under the analysis 
section for each end point where imputation is employed. In addition, imputation will be 
employed for missing or incomplete dates for the onset of adverse events.  For selected 
analyses, a complete date is necessary to determine whether or not an adverse event began 
after study treatment.  In cases where an incomplete onset date is provided in the case report 
form (CRF), the missing components will be defined as follows: 
• 
Missing day, month and year present:  If month and year are the same as the first 
treatment dose month and year, the day will be assumed to be the same as the first dose day. 
Otherwise, the day will be assumed to be the 15th. 
• 
Missing day, month and year:  The date will be assumed to be the same as the first 
treatment dose date. If the imputed date is after the resolution date, the imputed onset date will 
be assumed to be the same as the resolution date. 
• 
Severity and causality of adverse events occurring on or after the start of study drug are 
imputed when missing events for which causality was unknown or not recorded will be included 
in the summary of study drug related events. 
12.4.3 Disposition of subjects 
 
The number and percentage of subjects who were screened, enrolled, and completed 
the arm specific protocol, as well as the reason for discontinuation or withdrawal from the study 
will be presented in summary tables by treatment group and total subjects.   
 
12.4.4 Baseline assessments 
 
Baseline assessment summary tables will be presented by treatment group and total 
subjects for the ITT populations. Baseline demographics include age, gender, ethnicity, race, 
and transplant information including receipt of induction therapy. Baseline laboratory 
assessments include hematologic, renal and liver function tests.  Continuous data will be 
presented with descriptive statistics—N, mean, standard deviation, median, range 
and interquartile range.  Categorical data will be summarized by frequency distributions. 
 
12.4.5 Duration of treatment, compliance, and participation 
 
Duration of valganciclovir, length of study participation (while on therapy and during 
follow up), compliance as well as a distribution of the number of days from the date of 
transplantation to the date of the first dose of valganciclovir [prophylaxis arm] or date of first 
CMV PCR test [preemptive arm] will be summarized for the modified ITT population using 
descriptive statistics, including frequency distributions. For the preemptive arm the number of 
PCR tests, number of days between positive PCR test and the initiation of valganciclovir as well 
as well as the exposure to valganciclovir will be summarized. 


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Duration of valganciclovir is (date of the last dose of drug minus the date of first dose of drug 
plus 1 day). 
Study participation as defined by the duration of the overall CMV evaluation period (while on 
therapy and during follow-up) will be summarized for the ITT and modified ITT populations.  
Evaluation period length for CMV disease assessment is (date of last study contact minus the 
date of randomization plus 1 day). 
Receipt and duration of generic or nongeneric valganciclovir will be recorded and summarized 
for each study population.  
 
 
12.5 Primary outcome measures  
 
12.5.1 Definition  
 
The primary endpoint is the incidence of CMV disease within 12 months post-transplant. 
This endpoint will include all reported occurrences of CMV disease as adjudicated by the 
endpoint committee and/or investigator-determined CMV disease. The latter endpoint will 
include all reported occurrences if CMV disease by the investigator, regardless of whether they 
met the protocol definition of CMV disease. 
 
12.5.2  
Missing with respect to the primary endpoint 
 
A subject in the ITT population will be defined as missing with respect to the primary 
endpoint (lost to follow up for the purposes of analysis of the primary endpoint) if the subject 
withdrew,  discontinued consent or was lost to follow up prior to 3 month window for CMV 
disease without having reached the primary endpoint. 
 
12.5.3 Primary outcome analysis 
 
12.5.4 Primary end point-CMV disease [ITT group] includes all randomized 
subjects] 
 
The primary endpoint is CMV disease. The primary analysis is the Cochran-Mantel-
Haenszel [CMH]. Incidence rates will be compared and point estimates and confidence intervals 
for the incidence-rate ratio and difference, along with attributable or prevented fractions will be 
calculated for the two regimens. The analysis will be repeated, controlling for induction 
antilymphocyte therapy. Within-stratum statistics will be shown as well as the combined with 
Mantel-Haenszel estimate.  Subjects that die or are lost to follow up without evidence of CMV 
disease will be considered as 'no disease' for this analysis. All randomized subjects will be 


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included in the denominator.  An additional analysis will be performed in which all lost to follow 
up subjects will be considered as 'CMV disease'.  
 
12.5.5 Primary end point-CMV disease [modified ITT group] 
 
The primary analysis will be repeated in the modified ITT group [excludes subjects that 
withdrew prior to receipt of valganciclovir if in preemptive arm and subjects that have no post 
randomization PCR testing in the preemptive group]. An additional disease free survival model 
will be presented with censoring at retransplantation [return to standard care] if retransplantation 
occurs greater than 30 days post enrollment. 
 
12.5.6 End point committee and investigator-determined CMV disease 
 
The primary analysis will be repeated separately utilizing the adjudicated incidence of 
CMV disease and the investigator-determined CMV disease as the end point. 
 
 
12.6 Secondary outcome measures  
 
12.6.1  
Clinical outcomes 
 
12.6.1.1           
Incidence of late onset CMV disease [adjudicated] 
 
The incidence of adjudicated CMV disease will be determined at the 3 and 12-month 
time points (late-onset CMV disease) using an analysis similar to that specified for the primary 
analysis of the primary endpoint and, in addition, will include separate subset analyses for CMV 
syndrome  and CMV tissue invasive  disease. The analysis will be a Cochran-Mantel-Haenszel 
test of the significance of the odds ratio, while controlling for the use of induction antibody therapy 
and renal dialysis. In addition potential prognostic factors, such as allograft rejection will be 
examined with a Cox proportional hazards model applied to the ITT and modified ITT 
populations.  This analysis will be used to test the presence of a treatment effect while 
controlling for the various prognostic factors entered into the model. Results will be reported as 
the hazard ratio comparing two groups. 
 
 
12.6.1.2            Incidence of late onset of CMV disease [adjudicated and 
investigator-determined] 
 


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The above analysis will be repeated separately utilizing adjudicated CMV disease and 
investigator determined CMV disease as the respective endpoint. 
 
 
12.6.1.3 
Bacterial, fungal and non-CMV viral infections 
 
Invasive fungal infections, major bacterial infections and non-CMV viral infections will be 
analyzed. These infections are outlined in the manual of operations. The analysis of incidence 
of an opportunistic infection will be performed using a Chi Square test or Fisher Exact in the 
modified ITT population. Results will be reported as the p-value and the 95% confidence interval 
for the difference in the rates of invasive fungal, major bacterial or viral infections; the analysis 
will be repeated using a CMH test stratified by receipt of induction therapy.  The analysis will 
include an assessment of baseline comparability of the comparison groups and will incorporate 
variables not adequately controlled by randomization. The initial episode of major infection will 
be evaluated in a time dependent Cox model with the end point being the date of first major 
infection. The starting point will be date of transplantation and the infection free survival 
functions will be compared between the two regimens adjusted for cluster [site].  Subjects will 
be censored at death and study termination/withdrawal.  Multiple infection episodes will be 
evaluated by comparing the total 1 year episodes per person day of follow up between the two 
regimens. The analysis will be repeated controlling for receipt of anti-lymphocyte induction and 
renal dialysis. The type of infection (major bacterial, fungal, non- CMV viral) will be compared 
between the two regimens using a CMH test, non-stratified and controlled for induction 
antilymphocyte therapy and renal dialysis. Summary tables listing the type of opportunistic 
infections for each regimen will be presented. 
      
12.6.1.4  
Allograft rejection  
 
Rejection will be evaluated by several methods. Rejection rates at one year, between 
the two groups will be evaluated with a CMH test, both non-stratified and adjusted for receipt of 
antilymphocyte induction and renal dialysis. Initial rejection will be evaluated in a time 
dependent Cox model with the end point being the date first rejection episode. The starting point 
will be date of transplantation and the rejection free survival functions will be compared between 
the two regimens adjusted for cluster.  Multiple rejection episodes will be evaluated by 
comparing the total 1 year episodes of rejection between the regimens using a regression 
model with the endpoint total number of rejection episodes, clustered by site, and adjusted for 
receipt of antilymphocyte induction therapy and renal dialysis.  An additional model may be 
developed to adjust for inequalities not adequately controlled by the randomization process. 
Incidence of chronic graft rejection will be compared between the two study groups using a 
CMH test stratified for receipt of induction lymphocyte depleting therapy and controlling for renal 
dialysis. 
 
Rejection episodes  
  
Incidence rates will [number of rejection episodes per patient days of follow up] will be 
calculated and compared between the two groups. Patient days will be counted from the day of 


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randomization until the date of death, one year or last known follow up if subject is unable to be 
followed for one year.  
 
 
12.6.1.5 
Graft loss (loss due to retransplantation) 
 
The incidence of retransplantation will be determined at the 3 and 12 month time points. 
The date of retransplantation will be considered the date of occurrence of the event. A Cochran-
Mantel-Haenszel test stratified for receipt of antilymphocyte therapy and controlling for renal 
dialysis will be used to test the significance between the two treatment regimens.  
 
 
12.6.1.6 
All-cause mortality 
 
A Kaplan-Meier survival probability will be calculated for each regimen. The starting 
point will be the date of randomization and the end point will be date of death.  Subjects will be 
censored at date of last follow up if lost to follow up, or at one year post-transplant. The equality 
of the two survivor functions will be compared using a rank sum test for both the non-stratified 
data as well as the stratified log rank test for each stratum separately (receipt of lymphocyte 
depleting induction therapy and renal dialysis). Graphs of the Kaplan-Meier curves will be 
presented.  
 
12.6.2 Hematologic toxicity 
  
12.6.2.1 
Incidence of neutropenia 
 
The incidence of neutropenia will be summarized for each of the following definitions of 
neutropenia:  ANC values < 1000/µL and < 500/µL.  Incidence will be determined based on 
safety labs performed per protocol.  The analysis will be a CMH test of the significance of the 
odds ratio, while controlling for anti-lymphocyte antibody induction and renal dialysis with the 
levels of stratification determined at the time of randomization, using the modified ITT 
population.  Results will be reported, as the MH odds ratio with 95% confidence intervals in the 
modified ITT population.  The analysis will include assessment of baseline comparability of the 
comparison groups and will incorporate relevant items not adequately controlled by 
randomization in additional models.  
 
12.6.3  
Adverse events 
 
Severe, unexpected drug related adverse events will be compiled and compared 
between the two groups. Adverse events will be evaluated by comparing the total number of 
reportable adverse events per person day of follow up between the two regimens. The analysis 


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will be repeated stratified by receipt of anti-lymphocyte induction and renal dialysis using 
Mantel-Haenzel weights. The analysis will include assessment of baseline comparability of the 
comparison groups and if necessary, will adjust for items not adequately controlled by 
randomization in additional models. 
 
 
12.7 Exploratory end-points   
    
12.7.1 Clinical outcomes 
 
12.7.1.1 
Time to onset of CMV disease  
 
 Disease free survival will be evaluated by calculating the Kaplan-Meier survival 
probability for each regimen. The starting point will be the day of transplant; the end point will be 
the date of onset of CMV disease.  Subjects will be censored at date of death if unrelated to 
CMV, date of last follow up if lost to follow up or at end o of study. Kaplan-Meier estimates of 
median time to onset of CMV disease and the associated 95% confidence interval will be 
presented.  In addition, the Kaplan-Meier estimates and associated confidence intervals will be 
presented for specific time points (100-day, 6-month 12-months) and quartiles (25th and 75th).  
The study groups will be compared using the non-stratified log rank test, as well as the stratified 
log rank test for each stratum separately.  Graphs of the Kaplan-Meier curves for each therapy 
group will be presented. The equality of the two survivor functions will also be compared using a 
Cox model adjusted for cluster [site] and controlled for receipt of anti-lymphocyte induction 
therapy and renal dialysis.  The primary analysis will include assessment of baseline 
comparability between the two treatment groups. If needed, additional models will be developed 
to adjust for inequalities not adequately controlled by the randomization process. Results will be 
reported as the hazard ratio comparing the 2 groups. Survival analyses will also be controlled 
for unequal follow up periods between subjects. As such, the number of subjects available at 
annual time points will be reported, along with the Kaplan-Meier probability and associated 95% 
confidence intervals. It is assumed that subjects censored early will have the same probability of 
disease at each time point as those with longer follow up. To examine this assumption, relevant 
baseline characteristics will be compared between subjects enrolled in the first half of the study 
with those enrolled later. If the 2 cohorts are similar, we can expect that the survival probabilities 
are valid even with difference in follow up. Disease free survival will also be examined between 
the two cohorts. 
 
 
Additional analysis will be presented separately for adjudicated CMV disease and 
investigator-determined CMV disease. For this analysis the entry point will be date of transplant 
and the endpoint will be the date of onset of CMV disease as determined by the endpoint 
committee and a similar comparison in which the end point is the onset of CMV disease as 
determined by the investigator. The study groups will be again be compared using the non-


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stratified log rank test, as well as the stratified log rank test for each stratum separately (receipt 
of induction antilymphocyte antibodies and renal dialysis). 
 
12.7.1.2 
  Composite disease free survival 
 
A Kaplan-Meier survival probability will be calculated for each regimen. The starting 
point will be the day of transplant; the end point will be the date of onset of CMV disease or date 
of death.  Subjects will be censored at date of last follow up if lost to follow up, withdrawal or at 
end of study. The equality of the two survivor functions will be compared using a rank sum test 
for both the nonstratified grouping and the stratified by receipt of antilymphocyte induction 
therapy and renal dialysis.  
 
12.7.1.3       
   CMV resistance 
 
 
For CMV resistance testing performed in subjects with CMV disease, the incidence of 
resistance as assessed by proportion of subjects with UL97 and UL54 mutations will be 
compared between the two study arms. The resistance will be categorized as present or absent 
and compared between the 2 groups using a Fisher exact test.  In pre-emptive therapy subjects 
showing increase or no decline in CMV PCR quantitation following receipt of valganciclovir but 
no evidence of CMV disease, the incidence of resistance (UL97 and UL54 mutations) will be 
categorized. 
 
12.7.1.4    Graft loss [retransplantation] 
 
A Kaplan-Meier survival probability will be calculated for each regimen. The starting 
point will be the day of transplant; the end point will be the date of retransplant. Subjects will be 
censored at date of last follow up if lost to follow up, at date of death, or at study closure (and no 
longer than 7 years after enrollment). The equality of the two survivor functions will be 
compared using a rank sum test. Additional models will include adjustment for cluster [site] and 
receipt of antilymphocyte induction therapy and renal dialysis.  The analysis will include 
assessment of baseline comparability between the two treatment groups. If needed, additional 
models will be developed to adjust for inequalities not adequately controlled by the 
randomization process. 
 
12.7.1.5    Graft loss [death] 
 
A Kaplan-Meier survival probability will be calculated for each regimen. The starting 
point will be the day of transplant; the end point will be the date of retransplant or date of death 
if no retransplantation occurs.  Subjects will be censored at date of last follow up if lost to follow 
up, or at study closure (and no longer than 7 years after enrollment). The equality of the two 
survivor functions will be compared using a Cox model.  The survival functions will also be 
presented adjusted for cluster [site] and stratified by receipt of antilymphocyte induction therapy 
and renal dialysis.  The analysis will include assessment of baseline comparability between the 


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two treatment groups. If needed, additional models will be developed to adjust for inequalities 
not adequately controlled by the randomization process 
 
12.7.1.6 
All-cause mortality  
 
A Kaplan-Meier survival probability will be calculated for each regimen. The starting 
point will be the date of randomization and the end point will be date of death.  Subjects will be 
censored at date of last follow up if lost to follow up, or at study closure (and no longer than 7 
years after enrollment).The equality of the two survivor functions will be compared using a rank 
sum test for both the non-stratified data as well as the stratified log rank test for each stratum 
separately (receipt of lymphocyte depleting induction therapy and renal dialysis). The number of 
subjects available at annual time points will be reported, along with the Kaplan-Meier probability 
and associated 95% confidence intervals. To validate the assumption of that all subjects have 
similar probability of survival at each time point despite different follow up, relevant baseline 
characteristics will be compared between subjects enrolled in the first half of the study with 
those enrolled later. If the 2 cohorts are similar, we can expect that the survival probabilities 
are valid irrespective of variable follow up. Survival will also be examined between the two 
cohorts. 
 
12.7.1.7 
Opportunistic infections 
 
Incidence rates [number of infections per patient days of follow up] will be calculated. 
Patient days will be counted from the day of randomization until the date of death, end of study 
or last known follow up if subject is lost to follow up. The rates will be compared between the 
two groups using both the ITT population and modified ITT populations. The incidence rate will 
be calculated for all OI combined. Separate rates will also be calculated for bacterial and fungal 
infections. Similar analyses will be done using the date of study closure as the endpoint.  
 
12.7.1.8 
Need for dialysis  
 
 
Renal failure will be evaluated between the 2 groups using both the ITT and modified 
ITT populations. Subjects requiring renal replacement therapy [RRT] more than 7 days post-
transplant will be considered in the comparison.  The proportions of subjects with RRT will be 
compared stratified by pre-transplant renal status. Timing to start of RRT will also be compared 
using a Kaplan-Meier probability function.   
 
12.7.1.9 
Post-transplant malignancies  
 
 
Post-transplant malignancies will be compared in both the ITT and modified ITT 
populations. The timing to diagnosis will be compared using a Kaplan-Meier probability function 
and will be stratified by recurrence and new diagnosis. Descriptive statistics will be given on the 
location/type of malignancy in each study group.  
 


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12.7.2  
Use of hematopoietic growth factors 
 
12.7.2.1 
Frequency of use 
 
 
The number and percentage of subjects in the modified ITT population receiving any 
hematopoietic growth factor (e.g., G-CSF) during the study treatment period will be tabulated, 
by study group. The study groups will be compared using a CMH test of the odds ratio 
controlling for anti-lymphocyte induction and renal dialysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.7.2.2  
Number of dosages  
 
 
 
 
 
 
 
 
 
 
 
 
Total doses of will be compared between the study groups using a Mann Whitney test.  
Time to use of G-CSF will also be evaluated with the starting point as date of randomization and 
the end point date of use of G-CSF. A rank sum test will be used to compare the two groups.  
Summary tables will be presented with descriptive statistics for percent use, timing and total 
dosage of G-CSF for each group. 
 
 
12.7.3  
Immunologic endpoints [CMV-specific immunity] 
 
12.7.3.1  
T-cell immunity 
 
Initial sample [100 days]: The proportions of subjects with detectable CMV specific 
monofunctional  CD4+ and CD8+  T-cells  (that produce IFN-γ ) and  CMV-specific 
multifunctional CD4+ and CD8+  T-cells  ( > 2 markers that include IFN-γ + additional cytokines 
such as IL-2 and TNF-α ) will be compared between the two groups. It is hypothesized that T-
cell immune responses will be greater in preemptive versus prophylaxis group and that positive 
responses will correlate with lack of development of CMV disease overall and late-onset CMV 
disease (69).   A number of analyses will be carried out for these assessments.  Proposed 
threshold levels that confer protection against CMV in  transplant recipients are 0.4 CMV-
specific T-cells/μl for both CD4+ and CD8+ T-cells (69). The percent of responders will be 
compared between the two treatment regimens using a Mann Whitney test.  
 
The  mean, median, range of multifunctional CD4+ and CD8+ T-cells will be summarized 
between the two regimens.  The rate of CMV positive responders and the absolute number of 
CMV-specific T-cells will be compared between the subjects with adjudicated CMV disease and 
those without disease using GEE models.   A receiver operator characteristic (ROC) will be 
used to estimate a cutoff for number of CMV-specific T-cells that appear to prevent the 
development of CMV disease.  
 


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Follow up samples [6 and 12 months] for immune assays will also be evaluated as 
above. In addition, a repeated measures model will be used to evaluate the relationship of each 
type of CMV response over time and the development of CMV disease. 
 
12.7.3.2 
 Neutralization antibody 
 
This will be measured as titer of CMV neutralizing antibody [dilution factor]. Currently, 
the precise relationship between CMV neutralizing antibody and CMV disease is uncertain, 
therefore a number of exploratory analyses will be performed.  
 
Initial sample [100 days]: The percent of samples demonstrating any detectable CMV 
neutralizing antibody will be compared between the two groups using a Chi square test. This 
activity will also be quantitatively evaluated. The titers will be transformed to a log10 and the log 
mean titers will be compared between the two groups using a t-test.  A generalized estimating 
equation [GEE] regression model will be used to examine the relationship of antibody to CMV 
disease. The log transformed levels will be compared between a dichotomized grouping 
[subjects that develop CMV disease and those that remain disease free] using a t-test.  The 
timing to onset of late CMV disease will also be compared between subjects with and without 
CMV antibody activity using a Kaplan-Meier probability estimate. The two probability functions 
will be compared using a rank sum test.   
 
Follow up samples [6 and 12 months]: The follow up samples will be evaluated similarly 
to the initial sample. In addition, the log difference between the initial sample and the follow up 
sample will be calculated and compared between the two regimens using a regression analysis.  
A repeated measures model will be used to evaluate the relationship of CMV antibody activity 
over time and the development of CMV disease. 
 
 
12.7.4 Cost effectiveness analysis 
 
CMV disease and the costs associated with treating it are estimated to add $25,000 to 
$50,000 to the cost of organ transplantation (70, 71). In addition to the direct effects of CMV 
disease, CMV in transplant recipients may contribute to an increased risk of rejection and 
opportunistic infection (OI).  These events add a substantial economic burden to solid organ 
transplantation related to diagnosis, treatment and increased hospital length of stay.  In addition 
to the economic considerations, CMV may also reduce graft and recipient survival. Treeage Pro 
2009 [Treeage software, Williamstown, MA] will be used to develop a decision analysis model.  
The basic model will be similar in structure to those developed by Mauskopf et.al (72) for 
evaluating CMV in renal transplantation and Annemans et.al.(73) in liver transplantation. The 
tree will be utilized to estimate the costs associated with the 2 CMV intervention strategies, 
preemptive therapy and prophylaxis. Each strategy has the principle outcome of CMV disease, 
no disease.  The disease state (CMV disease/no CMV disease) then transitions to 4 possible 
outcome states:  rejection, OI, both rejection and OI, or no complications.  Rejection can than 
transition to graft loss/no loss. Each outcome state terminates as alive/dead. Transition 
probabilities will be estimated post hoc.  The model will allow for a range of sensitivity analyses 


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in which the parameter estimates can be varied [for example at the 10th and 90th percentile of 
the observed value]. 
 
Data already collected in this study will be used for cost effectiveness analyses. These 
include length of stay, drugs received for CMV prophylaxis/preemptive therapy, CMV disease, 
treatment for leukopenia, and other outcomes including rejection and retransplantation. 
Available data already captured will be used for the analyses; no additional items will be 
collected specifically for costs efficacy analyses. Cost estimates are obtained from average 
standard costs for drugs and procedures available in the literature. No site specific costs will be 
collected. 
 
12.7.4.1 
Total costs 
 
 
Cost effectiveness will be estimated comparing the costs for each regimen. A cost-
effectiveness ratio will be calculated as [Costs associated with preemptive therapy- costs 
associated with prophylaxis]/Effect of preemptive therapy-effect prophylaxis therapy]. Where the 
costs are the total composite costs derived from the analysis tree and the effect is CMV disease 
free success. 
12.7.4.2 
Cost utility analysis 
 
 
A Cost-utility analysis will estimate the cost per quality-adjusted life-years (QALY). 
Quality of life will be estimated for possible outcomes where 0=death and 1=perfect health. The 
utility values will be estimated from the literature for patients with end stage liver disease and 
cirrhosis (74, 75).  A fully functioning graft at one year, in a recipient with no major complications 
is estimated to have a utility value of about .83.  Utility values for subjects with complications will 
be estimated from articles listed in the Cost-effectiveness analysis registry (76). Cost per QALY 
will be estimated for both regimens.    
Cost utility analysis is based on estimated utilities found in the literature for items already 
collected such as retransplantation/disease/death. No additional data items will be collected. 
 
12.8          Interim and Final Analysis 
 
12.8.1 Interim analysis 
 
 There will be a single planned interim analysis for the primary endpoint of CMV disease. 
This analysis will be done after 1/3 of the subjects or 60 subjects have been enrolled and 
followed for 1 year. Additional endpoint analysis would introduce a multiple comparison bias 
with a resultant "alpha penalty".  Each test done at alpha=.05 means that roughly 5% will 
generate a type 1 error [rejecting the null hypothesis when in fact it is true].  Repeated testing of 
interim data can therefore inflate false positive error. To account for this loss of alpha, the 
sample size would need to be up-adjusted making the study infeasible. For the planned interim 
analysis, we will use alpha preservation estimation for repeated assessments [Method of 


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Haybittle-Peto] so that the trial will be terminated only if there is a statistically significant 
difference in the incidence of CMV disease at the 0.001 level.  A statistically significant 
difference in the incidence of CMV disease at this level [.001] would be detectable after the 
enrollment of 60 subjects with 1 year follow up, if the difference in the incidence of CMV 
diseases between the two groups is greater than 50%.  
 
12.8.2 Interim analysis showing futility: 
 
 It is possible that the interim analysis could suggest the likelihood of futility i.e. the trial may 
result in equivalence or non-inferiority. However, there will be no stopping rule for futility. Even if 
the interim analysis shows that the two groups are equivalent in efficacy with regards to CMV 
disease rate, there are additional benefits of continuing the trial for example, cost effectiveness 
of the two approaches which has societal benefits and wider implications. Additionally, 
differences in immunologic parameters, opportunistic infections, survival, graft loss, and drug 
resistance have profound relevance for advancing the field.  The study will therefore continue so 
that these additional assessments can be systematically conducted. 
 
 
12.8.3 Final analysis: 
 
 This will be completed when all subjects who have not previously discontinued have completed 
the one year follow up study visit. Primary, secondary and selected exploratory analyses 
(outlined in section 12.7) will be performed after one year follow up with supplementary 
analyses of exploratory endpoints  (outlined in section 12.7) performed at study closure (and no 
longer than 7 years after first enrollment). 
 
 


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13    SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DOCUMENTS 
 
 
Source data for CAPSIL are defined as all the information related to clinical findings, 
observation, or other activities in the study, written down or electronically entered in original 
records 
 
In addition, medical records and laboratory data from all facilities (long-term nursing care 
facilities, rehab institutions, out-patient clinics) where subjects receive care throughout the study 
will be reviewed and serve as source documentation. Records to include all physician progress 
notes, laboratory results, diagnostic testing results, and medication records, will be requested 
from the institutions by the enrolling site for review and monitoring purposes.  
 
Additionally, study specific source documents have been created to record data not 
routinely documented in the subject’s medical record. Study specific documents created for the 
CAPSIL study. For each subject entered into the study, the investigator will keep a file that will 
record the specific data which are not part of the routine documentation. The investigator will 
permit trial-related monitoring, audits, IRB reviews, and regulatory inspections by providing 
direct access to source data according to the subject’s consent. 
 
 
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. 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, 
and evaluation of the study safety and progress. These representatives will be permitted access 
to all source data for CAPSIL study. Participating sites should consult the MOP and the 
DMID/NIAID Source Document Standards for specific instructions/forms. 
 
           


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14 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Following a written DMID-accepted site quality management plan, the investigational site 
is responsible for conducting routine quality assurance (QA) and quality control (QC)) activities 
to internally monitor study progress and protocol compliance.  The Principal Investigator will 
provide direct access to all trial-related sites source data/documents, data collection forms, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.  The Principal Investigator will ensure all study personnel are 
appropriately trained and applicable documentations are maintained on site. DMID-designated 
clinical monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, Good Clinical Practice, 
and the applicable regulatory requirements.  Clinical monitoring reports will be submitted to 
DMID. 
 
The Statistical and Data Coordinating Center 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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15 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of 
Human Subjects of Research of the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6; 62 Federal Regulations 25691 (1997).   
15.2 Institutional Review Board 
 
 
Reviewing IRBs will be registered with the OHRP to conduct FDA-regulated studies.  
In the United States and in other countries, only institutions and will hold a current US Federal 
wide Assurance (FWA) issued by OHRP. Notification of the IRB's composition and the 
institutions FWA number will be provided to DMID. This protocol, informed consent documents, 
relevant supporting information, and all types of volunteer recruitment or advertisement 
information will be submitted to the Institutional Review Board (IRB) for review and must be 
approved before the study is initiated.  Any amendments to the protocol must also be approved 
by the IRB prior to implementing changes in the study. The investigator is responsible for 
keeping the IRB apprised of the progress of the study and of any changes made to the protocol 
as deemed appropriate, but in any case at least once per year.  The investigator must also keep 
the IRB informed of any significant AEs. All IRB approved documents as well as relevant study 
correspondence should be copied and sent to U. Pitt (Coordinating Center). 
 
15.3 Informed Consent Process 
 
The process of obtaining informed consent must be documented in the medical records, 
clinic chart, and/or research chart.  The consent form must be signed and dated by the study 
participant or legal guardian before participation in the study.  A copy of the signed consent form 
must be provided to the study participant or legal guardian.  Signed consent forms must remain 
in each study participants study file and must be available for verification by study monitors at 
any time.  
 
The investigational nature and research objectives of this trial, the procedure, and its 
attendant risks and discomforts will be carefully explained to the study participant or legal 
guardian.  A signed informed consent document will be obtained from each study participant or 
legal guardian prior to entry into this study.  At any time during participation in the protocol, if 
new information becomes available relating to risks, AEs, or toxicities, this information will be 
provided orally or in writing to all enrolled or prospective study participant or legal guardian. 


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Documentation will be provided to the IRB and, if necessary, the informed consent will be 
amended to reflect any relevant information. 
 
An investigator shall seek such consent only under circumstances that provide the 
prospective subject or the representative sufficient opportunity to consider whether or not to 
participate and that minimize the possibility of coercion or undue influence. The information that 
is given to the subject or the representative shall be in language understandable to the subject 
or the representative. 
 
The participant or legal guardian will sign the informed consent document prior to any 
procedures being done specifically for the study.  The participant or legal guardian should have 
the opportunity to discuss the study with their family, friends or personal physician, or think 
about it prior to agreeing to participate.  The participant or legal guardian may withdraw consent 
at any time throughout the course of the trial.  A copy of the informed consent document will be 
given to the participant or legal guardian for their records.  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. 
For non-English speaking subjects, a translated informed consent form will be used according to 
institutional IRB specific procedures. 
15.4 Exclusion of Women, Minorities and Children (Special 
Populations) 
 
 
Subjects will be eligible for participation in the study, regardless of gender, race or 
ethnicity. All patients undergoing liver transplant are potentially eligible for inclusion.  The 
expected percentage of women and minorities enrolled will reflect the local demographics of the 
liver transplant population.  Only individuals who are greater than or equal to 18 years old will be 
included at this time. 
 
 
Children will not be included in the trial because there are significant problems and 
concerns with the use and appropriate dosing of valganciclovir in pediatric setting. Unlike adult 
transplant recipients, the oral bioavailability of valganciclovir is considerably lower in children 
(77).  Its use in pediatric patient population has been limited by low bioavailability necessitating 
large and frequent doses, a problem compounded by the increased weight-adjusted clearance 
of ganciclovir in children (78). Consequently, unexpectedly high inter- and intrapatient variability 
in ganciclovir levels has been observed (77) and dosing recommendations based on adult 
guidelines have the potential for overdosing in children with below normal serum creatinine, low 
body surface area or low body weight.  The potential dosing variability in pediatric subjects 
could significantly confound the study. Thus, there are significant concerns related to the 
potential for inadvertently achieving low levels and the risk of ganciclovir resistance. 
 
 
A powder for oral solution with bioequivalence to valganciclovir tablets exists 
(78). However, valganciclovir oral solution in pediatric liver and kidney transplant recipients 
using a dosing algorithm based on dose normalization for body surface area resulted in children 
aged <5 years being under exposed to ganciclovir by approximately 2-fold (79-80).  Another 
study (WV 16726 ) that included  63 pediatric transplant recipients of whom 17 were liver 


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transplant patients assessed the pharmacokinetic, safety, and efficacy study of the 
valganciclovir oral solution using dosing algorithm based on creatinine clearance and body 
surface area (81). A majority of the patients (60%) belonged to groups other than R-/D+. 
Treatment failures defined as either the development of CMV disease up to day 100 post-
transplant or discontinuation of study medication due to lack of efficacy or toxicity was observed 
in 7% of the patients; a higher number of these were liver transplant recipients. When only R-
/D+ patients were considered, treatment failure was documented in 33%. Currently, oral solution 
is not approved for use in pediatric liver transplant recipients. 
 
 
While, there are recipes available to compound liquid valganciclovir from the tablets, 
there is no standardization for these. Furthermore, unlike adult liver transplant recipients, there 
are very limited published data on the use of oral valganciclovir in children and there is no 
precedence for the use of valganciclovir as preemptive therapy in children (11). Given low 
bioavailability and the potential for erratic drug levels, use of valganciclovir for established 
viremia as in the setting of preemptive therapy is a major concern. Prolonged valganciclovir use 
in the form of prophylaxis is also theoretically worrisome given the known carcinogenicity in 
animals and unknown consequences of prolonged ganciclovir derivatives in children. 
 
 
Thus, valganciclovir use in children in context of this study poses compelling and 
significant concerns related to bioavailability (with the potential for both underdosing and 
overdosing), efficacy and toxicity such that the scientific validity of the study results and the 
safety of the subjects could be compromised. Therefore until further data becomes available 
regarding the safety and appropriate dosing of valganciclovir, inclusion of children in this study 
was not deemed prudent. 
15.5 Subject Confidentiality 
 
Once a subject is randomized in the study, they will be assigned a study number and will 
be identified only by that number for the entire study period. Identity of the research subject will 
be kept confidential and any identifying information will be kept by the study personnel at the 
local site. This confidentiality will extend to cover testing of biological samples and any clinical 
information relating to participating subjects. The study protocol, documentation, data, and all 
other information generated will be held in strict confidence.  The study monitor or other 
authorized representatives of the Institutional Review Boards of the participating Medical 
Center, National Institutes of Allergies and Infectious Disease (NIAID), U.S. Office for Human 
Research Protections (OHRP), and U.S. Food and Drug Administration (FDA) 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 in this study.  The clinical study 
site will permit access to such records. 
15.6 Study Discontinuation 
 
Under certain circumstances as noted in the protocol, the study or an individual subject’s 
participation in the study may be terminated. If the study is terminated, safety and follow up 
procedures will be continued as described in the protocol unless consent is withdrawn. 


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15.7 Future Use of Stored Specimens 
 
The investigators intend to store specimens from study participants .The prospectively 
collected samples and clinical parameters assessed in this study represent an important 
resource for future studies. Cryopreserved samples may be used to perform additional assays 
to support standardization and validation of laboratory assays, and to evaluate additional 
endpoints and associations of interest. These assays may include, but are not limited to PCR 
testing for other pathogens, additional cytokines and chemokines, proteomics, gene expression 
studies, and research related to furthering the understanding of CMV and other infections, and 
other transplant-related outcomes, to the extent authorized in each study site’s informed 
consent form, or as otherwise authorized under applicable law. The Steering Committee (Drs. 
Singh, Limaye and Boeckh) in conjunction with the DMID will evaluate proposals for substudies 
utilizing either samples or clinical data collected for the primary study. Proposals will be 
reviewed and prioritized for scientific merit and compliance with applicable regulatory/consent 
requirements.  Funding for substudies beyond those outlined in the contract will not be provided 
and will be the responsibility of substudy investigators.  
 
The specimens will be labeled with a code number and not with the study participant’s 
name or other subject-identifiable information. At the time of consent for study participation, 
study participants will have the opportunity to either agree or decline to have their specimens 
used in future research. The study participant will indicate his/her preference by initialing the 
appropriate line or checking the appropriate box of the Consent Form in the section entitled, 
“Future Use of Specimens”. Non-protocol designated, future testing of samples will be 
performed only on samples from study participants who have consented for future testing of 
samples. A repository for residual samples will be established according to OHRP guidelines 
ensuring that codes or other personally identifying links will not be distributed to future 
researchers. If the study participant has indicated in the signed consent form that he/she does 
not agree to allow the future use of specimens for future research, then his/her specimens will 
be destroyed at the end of the study. 
  


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16 DATA MANAGEMENT PLAN 
The investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data reported. 
 
16.1    
 
Data management responsibilities 
 
The University of Pittsburgh’s Center for Research on Health Care (CRHC) Data Center 
will function as the Data Coordinating Center (DCC) for the CAPSIL study and will oversee all 
aspects of data management and quality review. Analyses and reports from the study data will 
be generated by the study statistician at the Coordinating Center. Electronic Case Report Forms 
(eCRF) will be created for use in a customized web application designed to meet CAPSIL 
protocol requirements. The web application allows secured user specific access to the eCRFs. 
Menus and reporting screens allow users to randomize, track, and enter data.  To protect the 
privacy of the research subjects, only coded data will be entered. The web site will also act as a 
repository for CAPSIL study related documents including the Manual of Procedures, current 
protocol version, and additional general study information to keep sites updated on CAPSIL 
progress. Printable hardcopy versions of these forms will be available on the website in case of 
problems with the electronic system. 
 
 
All data 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 seriousness, severity and causal relationship, and reviewed by the site principal 
investigator or designee.  Data collection is the responsibility of the clinical trial staff at the site 
under the supervision of the site principal investigator. 
 
Data from all participating sites is merged upon transmission to the DCC server and will 
be used to generate files for data analysis. The DCC will also generate reports from the merged 
dataset as required by the DSMB to monitor study safety.  Measures to ensure data security, 
quality and integrity are fully described in the Data Management Plan. Specific information on 
the use of the web-based data entry system is provided in the Data management section of the 
MOP. 
 
16.2   
Data capture methods 
 
Clinical data will be abstracted from medical records and entered onto eCRFs provided 
on the study website.  All eCRFs are fully HIPAA compliant.  Data will be recorded directly from 
the subject’s medical record or study specific source documents. Data form completion 
instructions will be provided by the coordinating center and can be found in this study’s MOP. 
The data system is 21CFR part 11 compliant.  Quality control computer checks will be run 
periodically to check for data completeness, ranges of data, consistency of data between forms 


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and logic reliability.  All data changes will be automatically tracked with a change reason 
required and will be recorded on a change log. 
 
 
16.3   
Types of data 
 
 
 
 
Data for this study include safety, clinical laboratory, virologic, outcome measures 
(clinical assessments of CMV disease, mortality, allograft rejection; graft loss, hematologic 
toxicity, co-infections) and exploratory immunologic assessments. 
 
16.4   
Timing of reports 
  
The following reports will be generated during this study. 
• 
DSMB reports at a minimum annually.  Timing and frequency of these reports 
will be determined in conjunction with DMID and the DSMB, but will be generated no 
less frequently than annually.  (See Section 9.8.1) 
• 
Interim analysis will be conducted and provided to the DSMB after 60 subjects have 
been enrolled and followed for 1 year.  (See Section 10) 
• 
End point committee reports will be provided to the EPC prior to the interim analysis 
and prior to close out.   (See Section 12.8.1) 
 
16.5 Study record retention 
 
Records and documents pertaining to the conduct of this study, including eCRFs, source 
documents, consent forms, laboratory test results, and medication inventory records, must be 
retained by the investigator for 2 years .  No study records shall be destroyed without prior 
authorization from the University of Pittsburgh (Coordinating Center) and the DMID. All study 
records will be retained in compliance with CFR title 21 part 312.57 
 
 
16.6 Protocol deviations 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity.  However, if the deviation increases study 
subject risk, the reporting timeline is expedited, requiring submission of deviation within 2 
working days of identification.  All deviations must be promptly reported to the University of 
Pittsburgh (Coordinating Center). Subject specific deviations will be reported on the electronic 
protocol deviation form of the eCRF. Non-subject specific protocol deviations will require a fax 


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transmittal of a protocol deviation form to the U. of Pitt (coordinating center). This form will be 
available at the CAPSIL web portal. 
Each investigator must adhere to the protocol as detailed in this document and agree 
that any changes to the protocol must be approved by the University of Pittsburgh Coordinating 
Center and the DMID prior to seeking approval from the IRB/IEC.  Each investigator will be 
responsible for randomizing only those study participants who have met protocol eligibility 
criteria. 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual 
of Procedures requirements.  The noncompliance may be either on the part of the study 
participant, 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 
GCP: 
 
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. 
 
 
All deviations from the Protocol must be addressed in a source document.  A completed 
copy of the Protocol Deviation (PD) Form must be maintained in the Regulatory File, as well as 
in the subject's data collection forms.  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 
requirements. 
 


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17  PUBLICATION POLICY 
 
Following completion of the study, the investigators may publish the results of this 
research in a scientific journal. One year end-points will also be analyzed and reported prior to 
study closure.  Specific criteria for authorship will be reviewed and discussed with all 
investigators.  
 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a trials-registration policy as a condition for publication. This policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine (NLM). Other biomedical journals are considering 
adopting similar policies. This protocol will be registered on ClinicalTrials.gov  by the Principal 
Investigator prior to onset of subject enrollment.  
 
All investigators funded by the NIH must submit or have submitted for them to the 
National Library of Medicine’s PubMed Central 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.  The NIH Public Access Policy ensures the public 
has access to the published results of NIH funded research.  It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  Further, the policy stipulates that these papers must 
be accessible to the public on PubMed Central no later than 12 months after publication.  
Publications arising from this protocol will comply with this requirement.  
 


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35. 
La Rosa C, Limaye AP, Krishnan A, Longmate J, Diamond DJ. Longitudinal assessment 
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36. 
Reusser P, Cathomas G, Attenhofer R, Tamm M, Thiel G. Cytomegalovirus (CMV)-
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37. 
Emery VC. Prophylaxis for CMV should  not  now replace pre-emptive therapy in solid 
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38. 
Battiwalla M, Wu Y, Bajwa RP, Radovic M, Almyroudis NG, Segal BH, et al. Ganciclovir 
inhibits lymphocyte proliferation by impairing DNA synthesis. Biol Blood Marrow 
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39. 
Wade JC, Day LM, Crowley JJ, Meyers JD. Recurrent infection with herpes simplex 
virus after marrow transplantation: role of the specific immune response and acyclovir 
treatment. Journal of Infectious Disease. 1984;149:750-6. 
40. 
Lowance D, Neumayer HH, Legendre M, Squifflet JP, Kovarik J, Brennan PJ, et al. 
Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N 
Engl J Med. 1999;340:1462-70. 
41. 
Kannanganat S, Ibegbu C, Chennareddi L, Robinson HL, Amara RR. Multiple-cytokine-
producing antiviral CD4 T cells are functionally superior to single-cytokine-producing 
cells. J Virol. 2007;81(16):8468-76. 
42. 
Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al. HIV 
nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. 
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43. 
Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L, et al. Impact of 
donor CMV status on viral infection and reconstitution of multifunction CMV-specific T 
cells in CMV-positive transplant recipients. Blood. 2009;113(25):6465-76. 
44. 
Lilleri D, Fornara C, Chiesa A, Caldera D, Alessandrino EP, Gerna G. Human 
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Haematologica. 2008;93(2):248-56. 
45. 
Gerna G, Lilleri D, Fornara C, Comolli G, Lozza L, Campana C, et al. Monitoring of 
human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid 
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46. 
Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta-analysis: the efficacy of 
strategies to prevent organ disease by cytomegalovirus in solid organ transplant 
recipients. Ann Intern Med. 2005;143:870-80. 
47. 
Winston DJ, Wirin D, Shaked A, Busuttil RW. Randomized comparison of ganciclovir 
and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver transplant 
recipients. Lancet. 1995;346:69-74. 
48. 
Opelz G, Dohler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in 
solid organ transplantation: a collaborative transplant study report. Am J Transplant. 
2004;4(6):928-36. 
49. 
Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian Society of Transplantation 
Consensus Workshop on Cytomegalovirus Management in Solid Organ Transplantation 
Final Report. Am J Transplant. 2005;5:218-27. 
50. 
Emery VC, Hassan-Walker AF, Burroughs AK, Griffiths PD. Human cytomegalovirus 
replication dynamics in HCMV-naive and -experienced immunocompromised hosts. 
Journal of Infectious Disease. 2002;185:1723-8. 
51. 
Boivin G, Gilbert C, Gaudreau A, Greenfield I, Sudlow R, Roberts NA. Rate of 
emergence of cytomegalovirus (CMV) mutations in leukocytes of patients with acquired 
immunodeficiency syndrome who are receiving valganciclovir as induction and 
maintenance therapy for CMV retinitis. Journal of Infectious Disease. 2001;184:1598-
602. 
52. 
Perrottet N, Decosterd LA, Meylan P, Pascual M, Biollaz J, Buclin T. Valganciclovir in 
adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic 
characteristics and clinical interpretation of plasma concentration measurements. Clin 
Pharmacokinet. 2009;48(6):399-418. 
53. 
Sun HY, Cacciarelli TV, Singh N. Identifying a targeted population at high risk for 
infections after liver transplantation in the MELD era. Clin Transplant. 2011;25(3):420-5. 
54. 
Gonwa TA, McBride MA, Anderson K, Mai ML, Wadei H, Ahsan N. Continued influence 
of preoperative renal function on outcome of orthotopic liver transplant (OLTX) in the US: 
where will MELD lead us? Am J Transplant. 2006;6:2651-9. 
55. 
Czock D, Scholle C, Rasche FM, Schaarschmidt D, Keller F. Pharmacokinetics of 
valganciclovir and ganciclovir in renal impairment. Clin Pharmacol Ther. 2002;72(2):142-
50. 
56. 
Al Riyami D, Alam A, Badovinac K, Ivis F, Trpeski L, Cantarovich M. Decreased survival 
in liver transplant patients requiring chronic dialysis: a Canadian experience. 
Transplantation. 2008;85(9):1277-80. 
57. 
Zuckerman R, Wald A. Herpes simplex virus infections in solid organ transplant 
recipients. Am J Transplant. 2009;9 Suppl 4:S104-7. 
58. 
Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus 
in hematopoietic stem cell transplant recipients: Current status, known challenges, and 
future strategies. Biol Blood Marrow Transplant. 2003;9(9):543-58. 
59. 
Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M. Neutropenia in allogeneic 
marrow transplant ecipients receiving ganciclovir for prevention of cytomegalovirus 
disease: risk factors and outcome. Blood. 1997;90:2502-8. 


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60. 
Boeckh M, Myerson D, Bowden RA. Early detection and treatment of cytomegalovirus 
infections in marrow transplant patients: methodological aspects and implications for 
therapeutic interventions. Bone Marrow Transplant. 1994;14 Suppl 4:S66-70. 
61. 
Asberg A, Humar A, Rollag H. Oral valganciclovir is noninferior to intravenous 
ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant 
recipients. Am J Transplant. 2007;7:2106-13. 
62. 
Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, et al. Early 
treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone 
marrow transplantation. N Engl J Med. 1991;325(23):1601-7. 
63. 
Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir 
prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann 
Intern Med. 1993;118(3):173-8. 
64. 
Reusser P, Einsele H, Lee J, Volin L, Rovira M, Engelhard D, et al. Randomized 
multicenter trial of foscarnet versus ganciclovir for preemptive therapy of 
cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 
2002;99(4):1159-64. 
65. 
Winston DJ, Ho WG, Bartoni K, Du Mond C, Ebeling DF, Buhles WC, et al. Ganciclovir 
prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow 
transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med. 
1993;118(3):179-84. 
66. 
Boeckh M, Nichols G, Chemaly R, Papanicolaou G, Wingard J, Kirby KA, et al. 
Prevention of late CMV disease after HCT: A randomized double-blind multicenter trial of 
valganciclovir(VGCV) prophylaxis versus PCR-guided GCV-VGCV preemtive therapy. . 
ASBMT, 2008. San Diego CA. 
67. 
Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. 
Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus 
ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-
blind trial. Blood. 1996;88:4063-71. 
68. 
Akalin E, Sehgal V, Ames S, Hossain S, Daly L, Barbara M, et al. Cytomegalovirus 
disease in high-risk transplant recipients despite ganciclovir or valganciclovir 
prophylaxis. Am J Transplant. 2003;3(6):731-5. 
69. 
Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, et al. 
Prophylactic versus preemptive oral valganciclovir for the management of 
cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 
2006;6:2134-43. 
70. 
Manuel O, Venetz JP, Fellay J, Wasserfallen JB, Sturzenegger N, Fontana M, et al. 
Efficacy and safety of universal valganciclovir prophylaxis combined with a 
tacrolimus/mycophenolate-based regimen in kidney transplantation. Swiss Med Wkly. 
2007;137(47-48):669-76. 
71. 
Merigan TC, Renlund DG, Keay Sea. A controlled trial of ganciclovir to prevent 
cytomegalovirus disease after heart transplantation. N Engl J Med. 1993;326:1182-6. 
72. 
Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk R, Follansbee S, et al. Oral 
ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche 
Cooperative Oral Ganciclovir Study Group. N Engl J Med. 1996;334(23):1491-7. 
73. 
Gerna G, Lilleri D, Furione M, Baldanti F. Management of human cytomegalovirus 
infection in transplantation: validation of virologic cut-offs for preemptive therapy and 
immunological cut-offs for protection. New Microbiol. 2011;34(3):229-54. 


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74. 
Schnitzler MA. Costs and consequences of cytomegalovirus disease. Am J Health Syst 
Pharm. 2003;60(23 Suppl 8):S5-8. 
75. 
Kim WR, Badley AD, Wiesner RH, Porayko MK, Seaberg EC, Keating MR, et al. The 
economic impact of cytomegalovirus infection after liver transplantation. Transplantation. 
2000;69:357-61. 
76. 
Mauskopf JA, Richter A, Annemans L, Maclaine G. Cost-effectiveness model of 
cytomegalovirus management strategies in renal transplantation. Comparing valaciclovir 
prophylaxis with current practice. Pharmacoeconomics. 2000;18(3):239-51. 
77. 
Annemans L, Moeremans K, Mutimer D, Schneeberger H, Milligan D, Kubin M. Modeling 
costs and cost-effectiveness of different CMV management strategies in liver transplant 
recipients as a support for current and future decision making. Value Health. 
2002;5(4):347-58. 
78. 
Bryce CL, Angus DC, Switala J, Roberts MS, Tsevat J. Health status versus utilities of 
patients with end-stage liver disease. Qual Life Res. 2004;13(4):773-82. 
79. 
Tsevat J, Cook EF, Green ML, Matchar DB, Dawson NV, Broste SK, et al. Health values 
of the seriously ill. SUPPORT investigators. Ann Intern Med. 1995;122(7):514-20. 
80. 
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Registry. Institute for Clinical Research and Health Policy Studies, Tufts Medical Center; 
2009. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SUPPLEMENTS/APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 
 
1. Females of child bearing potential will be pregnancy tested prior to enrollment and after the end of treatment. SOC testing may be used if obtained during current hospitalization.       
The end of treatment pregnancy test may be obtained after end of treatment up to 3 months post end of treatment. 
2. Hematology sample will be collected until day 107 as part of safety labs. Additional hematology samples at 6 and 12 months will be collected for lymphocyte count assessment for 
the immune assays.  Lymphocyte count from day 98, 6 month, and 12 month sample will be recorded on the immune assay eCRF
3. Subject may opt out of genetic sampling. If consent for genetic testing is obtained, sample will be taken once at baseline. 
4. Samples will be sent to Boeckh Lab at the Fred Hutchinson Cancer Research Center 
5. Samples will be sent to the University of Washington Medical Center Virology Lab 
6. AEs and SAEs will be recorded through study intervention period plus  7 days beyond last study drug administration 
7. This sample will be collected only in subjects with suspected CMV disease (either group) 
8. Resistance testing may be performed on on subjects who fail to achieve reduction in viral load after 3 weeks of valganciclovir or iv ganciclovir  use for CMV viremia  (in preemptive 
therapy group) or in subjects  with CMV disease (in either group )  
9. Valganciclovir will be given for 100 days 
 
 
Follow-up post 
drug 
administration 
Assessments/test for ALL subjects 
B a s e l i n e 
7d 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 
107 
6mo 12mo 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ surgical  history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor/recipient CMV serology status 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/subject weight 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing (~5ml blood)¹ 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Hematology (~3ml of blood)2,12 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Chemistry  (~6ml of blood) 2,12 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
 
Genetic sample ( 10 ml of blood)3,4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Assay (~45ml of blood) 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Outcome monitoring and data collection 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AEs & SAEs 6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Suspected CMV disease sample (~8.5 ml)5,7 
----------------------x---------------------- 
CMV resistance assay (~8.5ml) 5,8 
----------------------x---------------------- 
Medication Compliance Interview 13 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
Prophylaxis group only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Valganciclovir administration 9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Preemptive  therapy  group only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV PCR assay (~8.5ml of blood)10 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Valganciclovir  administration11 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 


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10. Samples will be sent to the University of Washington Medical Center Virology Lab 
11. Study valganciclovir will only be employed upon detection of a positive CMV PCR  during study days 1-100 and will continue until two negative consecutive weekly  PCRs are  
obtained 
12.  Baseline, hematology and chemistry standard of care lab results will only be accepted if within 48 hours of enrollment. If not collected as part of standard of care within 48 hours,    
these must be drawn for research purposes. 
13. Medication compliance interview to be completed at day 30, day 60, and end of treatment with a +1


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APPENDIX B: BLOOD VOLUME COLLECTED  
 
 Preemptive Therapy Group 
  
 
 
 
 
 
        
 
Pregnancy testing  
 
 
   
10 
ml 
CMV PCR:  
(14 visits X 8.5mL)   
 
 
119 
ml 
Suspected CMV disease (only if indicated) 
 
 
8.5 
ml 
CMV Resistance testing (only if indicated) 
   
 
8.5 
ml 
Immune Assays:  (45 ml X3)  
                
135 
ml 
Genetic sample: (optional) 
 
                  
8.5 
ml 
Lymphocyte count  
 
 
 
  6 
ml 
Preemptive therapy total research blood draw  
 
~295.5 
ml/12 month (~20 tablespoons) 
 
Prophylaxis Group 
 
 
Base-
line 
7d 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 
6mo 
12mo 
Pregnancy  
test 
5ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
5ml 
 
 
CMV PCR  
 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5ml 
8.5mll 
8.5mll 
8.5mll 
 
 
CMV 
disease 
 
 
                                         -----------------------------------------------------------------------8.5ml---------------------------------------------------------------------------------- 
CMV 
resistance  
 
 
                                         -----------------------------------------------------------------------8.5ml---------------------------------------------------------------------------------- 
Immune 
Assays  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
45ml 
45m
l 
45ml 
Genetic 
testing  
8.5ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte 
count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3ml 
3ml 
 
Baseline 
7d 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 
6mo 
12mo 
Pregnancy  
test 
5ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
5ml 
 
 
Immune 
Assays  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
45ml 
45ml 
45ml 
Genetic 
8.5ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Pregnancy testing  
 
 
   
10 
ml 
Immune Assays:  (45 ml X3)  
                
135 
ml 
Suspected CMV disease (only if indicated) 
 
 
8.5 
ml 
 
CMV resistance testing: (only if indicated) 
  
 
8.5 
ml 
Genetic sample: (optional) 
 
                
8.5 
ml 
Lymphocyte count  
 
 
 
 6 
ml 
Prophylaxis total research blood draw ~ 
 
 
~176.5 
ml/12 month (~ 12 tablespoon) 
 
 
testing  
Lymphocyte 
count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3ml 
3ml 
CMV 
disease 
 
 
                                         -----------------------------------------------------------------------8.5ml---------------------------------------------------------------------------------- 
CMV 
resistance 
 
 
                                         -----------------------------------------------------------------------8.5ml---------------------------------------------------------------------------------- 


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APPENDIX C: EXPECTED EVENTS FOR LIVER TRANSPLANT 
PATIENTS 
 
Expected events for liver transplant patients: The following events are expected to occur 
with a reasonable frequency in the typical/expected clinical course of a patient following liver 
transplant: 
 
• 
Hepatobiliary: Graft rejection, non-function of liver, delayed graft function, hepatic 
artery thrombosis, hepatic necrosis, liver abscess, biliary complications, biliary stricture or 
leak, biliary stenosis, cholecystitis, pancreatitis, liver failure, hepatic necrosis, viral hepatitis, 
graft versus host disease  
• 
Surgical: Leaks (gastrointestinal, biliary or anastomotic), hemorrhage, tracheostomy, 
return to the operating room for surgery, retransplantation, vascular stenosis or thrombosis 
(inferior vena cava, portal vein), anastomotic problems, strictures, hernia, lymphocele, 
incision dehiscence, abdominal wall defect, wound infection, hernia, fluid collection, seroma, 
biloma, hematoma, abdominal wall defect, infarction of liver, vana caval tear 
• 
Gastrointestinal: Nausea, vomiting, diarrhea, dyspepsia, abdominal distension or 
bloating, abdominal pain, anorexia, perforation, ischemic bowel, reflux gastritis, dyspepsia, 
ascites, ileus, bowel obstruction, GI bleed, achlasia 
• 
Neurologic: Tremor, seizures, confusion, headache, dizziness, hallucinations, 
delusion, psychosis, insomnia, somnolence, lethargy, depressed level of consciousness, 
agitation, amnesia, anxiety, emotional lability, paralysis, vertigo, abnormal dreams, 
headache, cerebrovascular accident, subarachnoid hemorrhage, encephalopathy, posterior 
reversible encephalopathy syndrome, tacrolimus toxicity, progressive multifocal 
leukoencephalopathy, central pontine myelinolysis, neuropathy, abnormal vision, blindness, 
amblyopia, tinnitus, deafness  
• 
Neuromuscular and skeletal: Hypertonia, incoordination, leg cramps, monoparesis, 
hemiparesis, myoclonus, nerve compression, quadriparesis 
• 
Constitutional/ systemic : Fever, asthenia, failure to thrive, weight loss or weight gain, 
anasarca, embolism, multiorgan failure, malnutrition 
• 
Infection: Fever, hypothermia, rigors, chills, systemic inflammatory response 
syndrome, infection (documented or suspected), sepsis, multisystem organ failure 
• 
Pulmonary: Acute lung injury, respiratory distress syndrome, aspiration, asthma, 
atelectasis, mucus plugging, respiratory failure, dyspnea, hypoxia, pneumonia, pleural 
effusion, pneumothorax, pulmonary edema, sinusitis, need for mechanical ventilation, 
intubation or reintubation, chest tube insertion, pleural effusion, embolism, pulmonary 
hypertension 
• 
Electrolyte and metabolic: Acidosis or alkalosis, low albumin, dehydration, gout, 
elevated liver function tests (bilirubin and liver enzymes), increase or decrease in the level of


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sodium, potassium, blood urea nitrogen, creatinine, glucose, calcium, magnesium, 
phosphate, uric acid, cholesterol, lipids, iron 
• 
Hematologic: Anemia, blood loss, prolonged PT or PTT, abnormalities in coagulation 
(DIC), hematoma, hemorrhage, bleeding, venous thrombosis, 
thrombocytopenia/thrombocytosis, leukopenia/leukocytosis, thrombotic thrombocytopenic 
purpura, hemolytic uremic syndrome, pancytopenia 
• 
Cardiac: Arrythmias (atrial flutter, atrial fibrillation, ventricular fibrillation), prolonged 
QT interval, QRS or ST segment abnormal, tachycardia, bradycardia, torsade de pointes, 
hypertension, hypotension, pulmonary hypertension, myocardial ischemia or infarction, 
syncope, postural hypotension, phlebitis, thrombosis, myocardial hypertrophy, 
cardiomyopathy, anaphylaxis, shock, anaphylactoid reaction, angioedema,  arterial dissection 
• 
Renal: Acute renal failure, albuimuria, nephropathy, hematuria, renal tubular necrosis, 
interstitial nephritis, nephropathy 
• 
Genitourinary: Bladder spasm, dysuria, nocturia, incontinence, urinary frequency, 
urinary retention, hemorrhagic cystitis 
• 
Malignancies: Lymphoproliferative disorder, skin neoplasm, melanoma, hepatocellular 
carcinoma, hematologic or solid tumor. 
• 
Dermatologic: Edema at anybody site, rash (petechiae, purpura, spider angiomata), 
ecchymosis, bruising, flushing, cellulitis, dermatitis, Stevens-Johnson syndrome, toxic 
epidermal necrolysis, decubitus ulcer, photosensitivity, skin ulcer, wound healing impaired.