ValGanciclovir Versus ValAcyclovir for Viral Prophylaxis in Kidney Transplantation
Phase: PHASE2
Conditions: Transplantation Infection, Epstein-Barr Virus Infections, Cytomegalovirus Infections
Sponsor: University of Minnesota

 
 
 
 
VALACYCLOVIR VERSUS VALGANCICLOVIR FOR POST-TRANSPLANT 
CYTOMEGALOVIRUS/EPSTEIN-BARR VIRUS PROPHYLAXIS: A RANDOMIZED 
CONTROLLED TRIAL 
 
 
 
 
Regulatory Sponsor: 
Henry H Balfour Jr, MD 
Department of Pediatrics 
Lab Medicine & Pathology 
Division of Pediatric Infectious Diseases & 
Immunology 
15-144 PWB 
516 Delaware St SE 
Minneapolis, MN 55455 
612-625-3998 
Funding Sponsor: 
University of Minnesota Department of Surgery 
Minneapolis, MN 
Study Product: 
Valacyclovir 
TASCS Number: 
130162 
IND/IDE Number: 
FDA Exempt 
 
 
Version 11.0: 
 
 
       December 19, 2019 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Minnesota.  
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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Table of Contents 
STUDY SUMMARY .................................................................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................................................... 6 
1.1 
BACKGROUND .............................................................................................................................................. 7 
1.2 
INVESTIGATIONAL AGENT............................................................................................................................. 7 
1.3 
PREVIOUS CLINICAL EXPERIENCE ............................................................................................................... 8 
1.4 
DOSE RATIONALE AND RISK/BENEFITS ....................................................................................................... 9 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
3 
STUDY DESIGN .............................................................................................................................................. 10 
4 
SUBJECT SELECTION AND WITHDRAWAL........................................................................................... 10 
4.1 
INCLUSION CRITERIA .................................................................................................................................. 10 
4.2 
EXCLUSION CRITERIA ................................................................................................................................ 10 
4.3 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 11 
4.3.1 
Data Collection and Follow-up for Withdrawn Subjects ............................................................ 11 
5 
STUDY PROCEDURES ................................................................................................................................. 11 
5.1 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................ 11 
5.2 
RANDOMIZATION ........................................................................................................................................ 11 
5.3 
LABORATORY TESTING .............................................................................................................................. 11 
5.4 
SCHEDULE OF EVENTS .............................................................................................................................. 12 
6 
STUDY DRUG ................................................................................................................................................. 13 
6.1 
DESCRIPTION ............................................................................................................................................. 13 
6.2 
TREATMENT REGIMEN ............................................................................................................................... 13 
6.3 
DURATION OF THERAPY ............................................................................................................................. 14 
6.4 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................... 14 
6.5 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................ 14 
6.6 
KNOWN ADVERSE EFFECTS ...................................................................................................................... 14 
6.7 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 15 
6.8 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 15 
6.9 
BLINDING OF STUDY DRUG ........................................................................................................................ 15 
7 
STATISTICAL PLAN ...................................................................................................................................... 16 
7.1 
PRIMARY STUDY ENDPOINTS .................................................................................................................... 16 
7.2 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 16 
7.3 
PRIMARY SAFETY ENDPOINTS ................................................................................................................... 16 
7.4 
STATISTICAL METHODS ............................................................................................................................. 16 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 16 
8.1 
RECORDING OF ADVERSE EVENTS............................................................................................................ 19 
8.2 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................ 19 
8.2.1 
Study Sponsor Notification by Investigator ................................................................................. 19 
8.2.2 
IRB Notification by Investigator .................................................................................................... 19 
8.2.3 
FDA Notification by Sponsor ......................................................................................................... 20 
8.3 
STOPPING RULES ...................................................................................................................................... 21 
8.4 
MEDICAL MONITORING............................................................................................................................... 21 
8.4.1 
Internal Data and Safety Monitoring Board ................................................................................. 21 
9 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 21 
9.1 
CONFIDENTIALITY ....................................................................................................................................... 21 
9.2 
SOURCE DOCUMENTS ............................................................................................................................... 21 
9.3 
CASE REPORT FORMS ............................................................................................................................... 22 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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9.4 
RECORDS RETENTION ............................................................................................................................... 22 
10 
STUDY MONITORING, AUDITING, AND INSPECTING.......................................................................... 22 
10.1 
STUDY MONITORING PLAN ........................................................................................................................ 22 
10.2 
AUDITING AND INSPECTING ........................................................................................................................ 23 
11 
ETHICAL CONSIDERATIONS ..................................................................................................................... 23 
11.1 
INFORMED CONSENT ................................................................................................................................. 23 
12 
STUDY FINANCES ......................................................................................................................................... 23 
12.1 
FUNDING SOURCE...................................................................................................................................... 23 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 24 
13 
PUBLICATION PLAN .................................................................................................................................... 24 
14 
REFERENCES ................................................................................................................................................ 25 
 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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List of Abbreviations 
 
 
AE 
 
Adverse Event 
BID 
 
twice daily 
BMP  
basic metabolic panel 
CBC  
complete blood count 
CFR  
Code of Federal Regulations 
CMV  
cytomegalovirus 
CRF  
Case Report Form 
DSMB  
Data and Safety Monitoring Board 
DSMP  
Data and Safety Monitoring Plan 
EBV  
Epstein-Barr virus 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
 
International Conference on Harmonization 
IDS 
 
Investigational Drug Services 
IRB 
 
Institutional Review Board 
KTx 
 
kidney transplant 
PCR  
Polymerase Chain Reaction 
PHI 
 
Protected Health Information 
SAE  
Serious Adverse Event 
QD 
 
once daily 
QOD  
every other day 
valA  
valAcyclovir 
valG  
valGanciclovir 
 
 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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Study Summary 
Title 
Valacyclovir versus Valganciclovir for Post-transplant 
Cytomegalovirus/Epstein-Barr Virus Prophylaxis: A 
Randomized Controlled Trial 
Short Title 
ValA vs ValG for Post-transplant CMV/EBV Prevention 
Protocol Number 
11.0 
Phase 
Pilot 
Methodology 
Randomized Control Trial 
Study Duration 
36 months 
Study Center(s) 
Single-Center 
Objectives 
To compare the effectiveness of valacyclovir (valA) to 
valganciclovir (valG) in the prevention of EBV and CMV viremia 
post-kidney transplant.  
Number of 
Subjects 
Total of 200 
Diagnosis and 
Main Inclusion 
Criteria 
Adult and pediatric kidney transplant recipients 
Study Product, 
Dose, Route, 
Regimen 
Valacyclovir 
Dose: 500-1500mg bid  
Oral 
Duration of 
administration 
3-12 months dependent on treatment assignment and donor and 
recipient viral serostatus in accordance with standard of care.  
Reference therapy 
Valganciclovir 
Oral 
 
Statistical 
Methodology 
Incidence of viremia will be compared using a two-sided Fisher 
exact test and viral load-time curve areas will be compared 
using a Mann-Whitney test. A p-value of <0.05 will be 
considered significant.  
 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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1 
Introduction 
Infections are now a leading cause of death and morbidity in kidney transplant 
recipients. Herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus 
(CMV) are particularly troublesome.  
 
At the present time, valganciclovir (valG) is the primary prophylactic agent against CMV 
in kidney transplant (KTx) recipients. Although many centers try to prevent CMV 
disease by placing all or in some centers, only the high risk patients (defined as CMV 
antibody negative patients receiving organs from CMV antibody positive donors) on 
antiviral prophylaxis with valG for three to 12 months post-KTx, there continue to be 
patients with break-through infections. CMV viremia has been noted in 22% of pediatric 
post-KTx recipients, and the incidence at the University of Minnesota (UMMC) in all KTx 
recipients is as high as 17% despite valG prophylaxis. CMV disease post-KTx can 
manifest as fever, leucopenia, or mild to severe organ involvement. While an effective 
anti-CMV drug, valG has a number of adverse effects including leucopenia, also a side 
effect of mycophenolate mofetil (MMF), one of the cornerstones of current anti-rejection 
regimens.  Combined therapy with MMF and valG frequently results in leucopenia 
associated infection or leucopenia necessitating reduction in MMF doses, increasing the 
risk of rejection. In addition, valG is prohibitively expensive. Therefore, rather than 
prophylaxis, many centers adopt a pre-emptive therapeutic approach whereby post-Ktx 
patients are screened for CMV, and at new onset viremia, valG is initiated. This 
approach has been associated with increased CMV infections and resistant viral strains.  
 
Therefore, there is need for an alternate drug with a more benign side effect profile and 
equal effectiveness against CMV. Valacyclovir (valA) was shown to reduce the 
incidence and delay the onset of CMV disease in both CMV seronegative patients 
(P<0.001) and CMV seropositive patients (P=0.03) and has fewer severe adverse 
events. In fact, very high doses of valA (8g/day), for post-KTx CMV prophylaxis were 
shown to have no severe or treatment-limiting side effects compared to placebo.  
 
Currently, prevention of EBV infection is conducted by close monitoring of patients and 
immunosuppression reduction at the discovery of EBV viremia.  A recent study 
suggested that valG prophylaxis post-KTx is protective against EBV infection, but it had 
design flaws and the number of subjects was limited. Therefore to date, the anti-EBV 
effect of valG is poorly defined. EBV can present post-KTx as infectious mononucleosis 
syndrome, hepatitis and, most importantly, can initiate potentially fatal 
lymphoproliferative disorders (PTLD). Between October 2003 and December 2009, EBV 
viremia occurred in 20% of adults and 50% of pediatric KTx recipients (60/120) at 
UMMC, and, PTLD occurred in 6% (7/120) of pediatric recipients. Effective anti-EBV 
prophylaxis could substantially improve KTx outcomes. ValA therapy resulted in a 
statistically significant reduction in oral EBV shedding, accompanied by a clinical 
benefit, and valA is currently used for the therapy of severe cases of infectious 
mononucleosis in the community.  
 
This document is a protocol for a human research study. This study will be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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312 or 812 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures.  
1.1 Background 
 
Therefore as stated above CMV and EBV remain critical posttransplant complications 
that can significantly and negatively impact patient and kidney transplant survival. In 
addition to overt CMV and EBV related issues detailed above, subclinical CMV and/or 
EBV viremia have been associated with deterioration in kidney function in KTx 
recipients. The significance of this research also includes the potential for substantial 
cost-savings. At UMMC, even with discounted pricing due to the University status and 
bulk ordering, a 90 day supply of 450mg doses of valG administered twice daily is 
approximately $11,000 compared to $3250 for 1.5g tablets twice daily of valA. At least 
200 patients receive kidney transplants each year at UMMC, making the impact of a 
successful outcome from this research a saving of at least $1.55 million per year in 
addition to the cost-saving of reducing viral infection or rejection related admissions and 
expenses.  
 
UMMC conducts surveillance biopsies at 3 and 12 months post-KTx on some adult 
transplant recipients, providing an ideal opportunity to assess kidney tissue for EBV and 
CMV via molecular and immunological assays. We think it likely that post-KTx, kidneys 
exposed to an immunosuppressed milieu allowing viral multiplication will increase the 
likelihood of isolating the virus from infected recipients; a pivotal step in our 
understanding of the mechanisms of CMV and EBV infection post-KTx.  
 
In summary, valA is less expensive, with fewer adverse effects, and less likelihood of 
causing leucopenia than valG.  If this agent has equivalent efficacy in CMV and any 
efficacy in EBV prophylaxis, the use of valA will result in significant financial savings, a 
reduced risk of leucopenia-associated infection, and a lower incidence of rejection by 
allowing the use of standard MMF doses. 
 
1.2 Investigational Agent 
Valacyclovir (valacyclovir hydrochloride) is the hydrochloride salt of the L-valyl ester of 
the antiviral drug acyclovir. Caplets are for oral administration. Each caplet contains 
valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive 
ingredients carnauba wax, colloidal silicon dioxide, crospovidon, FD&C Blue No. 2 Lake, 
hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, 
polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are 
printed with edible white ink.  
 
Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared 
extemporaneously from 500 mg VALTREX Caplets for use in pediatric patients for 
whom a solid dosage form is not appropriate. 
 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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The chemical name of valacyclovir hydrochloride is L-valine, 2[(2-amion-1,6-dihydro-6-
oxo-9H-purin_9_yl)methoxy]ethyl ester, monohydrochloride.  
 
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir 
hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity 
against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo. 
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme 
thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir 
into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further 
converted into diphosphate by cellular guanylate kinase and into triphosphate by a 
number of cellular enzymes.  
 
Valganciclovir (valganciclovir hydrochloride) contains valganciclovir hydrochloride 
(valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as 
a mixture of two diasteromers. Ganciclovir is a synthetic guanine derivative active 
against CMV.  
 
Tablets are available as 450 mg for oral administration. Each tablet contains 496.3 mg 
of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactivie 
ingredients microcrystalline cellulose, povidone K-30, crospovidone and stearic acid. 
The film-coat applied to the tablets contains Opadry Pink.  
 
For pediatric patients, valganciclovir HCl is available in an oral solution that must be 
prepared by a pharmacist prior to dispensing. Valganciclovir HCl for oral solution (50 mg 
per mL) is supplied as a white to slightly yellow powder for constitution, forming a 
colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles 
containing approximately 100 mL of solution after constitution. 
 
Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two 
disteromers. After oral administration, both diastereomers are rapidly converted to 
ganciclovir by intestinal and hepatic esterases.  
1.3 Previous Clinical Experience 
The anti-EBV effect of valG has not been conclusively demonstrated or proven. On the 
other hand, data from infectious mononucleosis intervention trials document that two 
weeks of valA therapy resulted in a statistically significant reduction in oral EBV 
shedding, accompanied by a clinical benefit (1, 2), and valA is currently used for the 
therapy of severe cases of infectious mononucleosis in the community (1, 3).  
Oral acyclovir has been shown to prevent CMV disease in post-KTx recipients (4-7) and 
valA in particular has been shown to reduce the incidence and delay the onset of CMV 
disease in both CMV seronegative patients (P<0.001) and CMV seropositive patients 
(P=0.03) (8). But since that trial did not include a comparison arm with the current 
standard of care which is valG and did not provide information on the anti-EBV effect of 
the valA, our study is critical in proving the effectiveness of valA for CMV and EBV 
prophylaxis. 
 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
Page 9 of 25 
 
ValG is associated with adverse events including diarrhea, fever, nausea, vomiting, 
tremor, leucopenia, neutropenia, anemia and thrombocytopenia in ≥20% of patients 
based on their package insert which we have attached. ValG induced leucopenia often 
necessitates a reduction in immunosuppressive therapy, increasing the risk of allograft 
rejection. Fewer severe adverse events are related to valA, including rash (8%), 
abdominal pain (1% to 11%), nausea (5% to 15%), vomiting (less than 1% to 6%), 
headache (13% to 38%) and fatigue (8%). Very high doses of valA (8g/day) for post-
KTx CMV prophylaxis was shown to have no severe or treatment-limiting side effects 
compared to placebo (8).  
1.4 Dose Rationale and Risk/Benefits 
Prior research at the University of Minnesota has shown that valacyclovir 1g every 8 
hours for a total daily dose of 3g is well tolerated and was associated with a reduction in 
EBV excretion (1) in patients with infectious mononucleosis. Subsequently a study done 
at the University of Minnesota to characterize the pharmacokinetics and explore the 
pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects with EBV 
infectious mononucleosis receiving the same daily dose of valacyclovir (3g) as a twice 
daily dosing of 1500 mg twice daily demonstrated safety and showed that the quantity of 
EBV DNA in oral washings and blood, and the severity of illness, measured by a graded 
scale, decreased during treatment (9).  
Therefore in order to increase the likelihood of compliance in our patients, we have 
decided to utilize 1.5g twice a day dosing of valacyclovir and since it was shown to be 
effective as therapy in the above study, we hypothesize that it will be adequate for anti-
viral prophylaxis as intended in this study. The dose will of course be adjusted based on 
GFR and in pediatric patients based on their weight as detailed in package insert and 
below. 
 
No major side effects are anticipated since even very high doses of valA (8g/day), for 
post-KTx CMV prophylaxis were shown to have no severe or treatment-limiting side 
effects compared to placebo (10).  
  
2 
Study Objectives 
 
Primary Objectives: 
To compare the effectiveness of valacyclovir (valA) compared valganciclovir (valG) in 
the prevention of EBV and CMV viremia post-KTx.  
 
To compare the proportion of patients requiring dose reduction or cessation of valA 
compared to valG due to adverse drug side effects.  
 
Secondary Objective: 
To identify the presence and quantity of EBV and CMV in renal tissue biopsies from 
kidney transplant recipients.  

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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3 
Study Design 
This is a single-center, prospective, randomized, pilot study of up to 200 kidney 
transplant recipients from the University of Minnesota Medical Center. Randomization of 
subjects will be in a 1:1 ratio to receive either ValA or standard of care regimen of ValG. 
Duration of therapy will be 3-13 months.  
 
Subjects will be assessed weekly then monthly for medication compliance, as well as 
assessing adverse events.  Subjects will be assessed at their routine clinic visits, or via 
email/telephone.  Subjects will be followed for a total of 12-13 months, or for an 
additional 30 days after stop of the drug for adverse events. 
 
Blood samples will be collected by using left-over standard of care samples for 
immunosuppression drug analysis. From these samples, qualitative PCR assay (qPCR) 
will assess CMV and EBV for up to six months post study drug cessation.  Complete 
blood count and metabolic panels will be collected clinically, and results recorded for 
this study. CMV and EBV IgG and IgM levels will be measured bi-annually until 
seroconversion. In the cases where blood is not drawn for clinical purposes at least 
once a month, 10-15ml of the subject’s blood may be collected for this testing for 
research purposes. Surveillance kidney transplant biopsies are obtained at the time of 
transplant, 3 months post-transplant, 12 months post-transplant, and as clinically 
indicated. For the duration of subject study participation, kidney tissue (two to three 
cores) from any biopsy will be shared with the research team.  
 
Subjects will be followed-up regularly by the research team during the first year post 
transplant. During these follow-up assessments, the research team will assess drug 
adherence as well as evaluate side effects. If subjects are seen during a standard of 
care visit, laboratory values and a review of medical records will also be performed to 
assess any potential adverse events.  
  
 
4 
Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
• Adult or pediatric kidney transplant recipients   
o Adult cases are defined as patients transplanted and cared for at the 
University of Minnesota Medical Center, East Bank campus. 
o Pediatric cases are defined as patients transplanted and cared for at the 
University of Minnesota Masonic Children’s Hospital.   
• Consent to participate in the study. 
4.2 Exclusion Criteria 
• Documented allergy to valA or valG 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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• Recipients that are unable to independently understand the consent form.  
• Pregnant 
  
4.3 Early Withdrawal of Subjects from the Study 
Subjects may withdraw from the study at any time. If a subject withdraws consent, all 
follow up will stop, however data collected up to that point will still be used. Subjects 
may be withdrawn from the study for the following reason: 
• Patient chooses to withdraw consent 
 
4.3.1 Early Withdrawal of Subjects from Drug 
Subjects may be withdrawn from drug early for the following reasons: 
CMV disease requiring therapy with valG. Cytomegalovirus disease will be 
defined as CMV DNA in the blood (viremia) on two or more occasions with 
clinical and/or pathological confirmation of CMV end-organ disease. 
• PI decides that further treatment in not in the best interest of the subject 
• Graft failure 
• Pregnancy 
• Treatment related anaphylaxis 
4.3.2 Data Collection and Follow-up for Withdrawn Subjects 
Subjects will be followed for 12-18 months post-transplant procedure. Please refer to 
Table 1 for data points and frequency.  
5 Study Procedures 
5.1 Subject Recruitment and Screening 
Initial contact regarding the research study will be done by the transplant clinical team 
or clinical research team once notification of treatment date is set.  For potential 
subjects that are receiving a transplant from a living donor, the study team will approach 
for informed consent prior to transplant surgery. For subjects that receive a transplant 
from a deceased donor, because of time constraints, the study team may approach the 
patient after they are placed on the transplant list to introduce the study.  Informed 
consent will then be obtained up to 7 days post-operatively. 
5.2 Randomization 
The randomization will be done in a 1:1 fashion and will be computer generated.  
 
5.3 Laboratory Testing 
Blood is collected in accordance to standard of care procedures for these patients. Left-
over blood from the clinical laboratories of subjects will be obtained and tested for CMV 
and EBV quantitative PCR assay (qPCR), at minimum weekly for the first month and 
monthly for the first year to year and a half post-KTx. Acyclovir levels will be measured 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
Page 12 of 25 
 
at 1 month in patients randomized to valA. CMV and EBV IgG and IgM levels will be 
measured bi-annually for patients who are seronegative until seroconversion after which 
they will no longer be checked. Safety labs include complete blood counts and basic 
metabolic panels which will be done for recipients randomized to valA monthly while 
participating in the study.  
 
If the labs are not being collected at a minimum of weekly for the first month and then 
monthly for the first year, the study team will collect 10-15mL of blood from the subjects 
for research procedures.  
 
Half to one core of kidney tissue will be obtained, if available, from all kidney transplant 
biopsies performed during the first year post-KTx.  
 
5.4 Schedule of Events 
All assessments will be completed during routine clinical visits when feasible.  If the 
participant does not have a scheduled clinic visit, the participant or parent/guardian can 
choose to receive an email or phone call follow-up of drug adherence and adverse 
events.  Assessments will continue until at least 30 days after last dose of anti-viral. 
Visit Schedule 
Pre-KTx 
KTx 
Weekly        
During Month 
1 
Monthly                
through End of Study 
Period 
CBC and BMP1                  
(routine clinical lab) 
X 
 
X 
 X 
CMV PCR, EBV PCR2       
(Balfour research lab) 
X 
 
X 
X 
CMV IgG, EBV IgG & 
IgM2                        
(Balfour research lab) 
X 
 
  
X3  
Acyclovir levels 
 
 
 
X4 
Kidney bx tissue5 
 
X 
  
X3 
Medication compliance 
  
 
X 
X6 
Adverse Events 
assessment 
  
 
X 
X6 
 
1 CBCs and BMP are performed routinely in post-transplant patients.  If these are 
not done clinically, we will collect and perform for research safety monitoring 
 
2 PCRs will be run using leftover blood collected clinically.  If no leftover blood is 
available, we will collect a research specimen. 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
July 5 2018 
 
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6 
Study Drug  
6.1 Description 
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor capsule of 500 mg. 
 
Valganciclovir is a cytomegalovirus nucleoside analogue DNA polymerase inhibitor 
tablet of 450 mg.  
 
6.2 Treatment Regimen 
 
Dosing of valG and valA will be based on level of renal function assessed by glomerular 
filtration rate (GFR).  
 
Table 2: valA (valAcyclovir) dosing based on GFR 
GFR 
> 50ml/min 
30-49ml/min 
10-29ml/min 
< 10ml/min 
Adults 
1500mg BID 
1000mg BID 
500mg BID 
500mg QD 
Children 
20mg/kg BID 
15mg/kg BID 
7.5mg/kg BID 
7.5mg/kg QD 
 
 
 
Table 3: valG (valGanciclovir) dosing based on GFR 
GFR 
> 60ml/min 
40-59ml/min 
25-39ml/min 
10-24 ml/min 
 
< 10ml/min 
Adults 
900mg QD 
450mg QD 
450mg QOD 
450 mg twice 
weekly 
Hold dose 
Children 
7 x BSA x Creatinine Clearance (CrCl)                                       
(calculated by modified Schwartz formula and Cockroft-Gault 
for less than and equal to 17 years of age respectively; max 
900 QD; max CrCl 150 mL/min/1.73 mL/m2) 
Hold dose 
 
3 Month 6 only  
4. Month 1 only if randomized to valA 
5. Kidney biopsies are performed routinely during the first year post-transplant.  
Paraffin-embedded scrolls will be requested from leftover tissue. 
6. Completed monthly until 1 month after cessation of the treatment 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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6.3 Duration of Therapy 
Duration of therapy is dependent on donor and recipient antibody status.  
 
Adult subjects will be treated with their assigned study drug (ValA or ValG) for three 
months,  unless the donor is antibody positive and the recipient is antibody negative 
(D+R-) to CMV/EBV, then patient will get six months of prophylaxis.   
 
Pediatric transplant recipients will be treated for twelve months except  if both the 
donor and the recipient are antibody negative (D- R-) for both CMV and EBV, subjects 
will be treated for three months.   
 
Patients that are randomized to ValA that develop CMV disease or CMV viremia X2 
may discontinue ValA and begin standard of care treatment with ValG. At that time they 
will continue research related follow up but valA use is up to the discretion of the 
treating physician. At that time all protocol directed safety follow up with be 
discontinued; however, outcomes will be followed until month 12.  
6.4 Method for Assigning Subjects to Treatment Groups 
Subjects will be randomized by the IDS pharmacy in 1:1 fashion using computer 
allocation to receive either valA or valG, and will notify the study team of the 
randomization assignment   
6.5 Preparation and Administration of Study Drug 
After randomization, the treating investigator will order the treatment following this 
protocol dosing schema (see Tables 2 and 3).  Commercial supply of ValA and ValG will 
be dispensed to the subjects. 
6.6 Known Adverse Effects 
As extracted from the package inserts for the study drugs, these are the known adverse 
effects for this protocol. 
Val G 
Val A 
COMMON Side Effects        
headache 
headache 
nausea 
nausea 
abdominal pain 
abdominal pain 
hematologic toxicity 
  
diarrhea 
  
fever 
  
tremor 
  

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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graft rejection 
  
vomiting 
  
hypertension 
  
upper respiratory infection 
  
urinary tract infection 
  
insomnia 
  
RARE adverse reactions 
acute renal failure 
acute renal failure 
allergic  reaction 
allergic reaction 
bleeding complications 
bleeding complications 
nervous system effects: agitation, 
hallucinations, confusion, 
delirium, seizures, swelling of the 
brain 
nervous system effects: agitation, 
hallucinations, confusion, 
delirium, seizures, swelling of the 
brain 
general pain, fatigue, weakness, 
edema 
  
abnormal lab results that might 
indicate abnormal organ function 
  
skin rash 
  
cough 
  
shortness of breath 
  
 
 
6.7 Subject Compliance Monitoring 
Subjects will be asked to adhere to their prescribed treatment and dosage.  Medication 
adherence will be assessed by the study team during routine visits, by reviewing the 
medical record, and by communication with the subject or guardian (table in section 
5.4). 
6.8 Prior and Concomitant Therapy 
All prior and concomitant therapies will be documented and allowed as per standard of 
care procedures. Provided there are no direct interactions with the randomized 
medication, all medications will be prescribed as standard of care. Management of all 
viral disease is as per physician and will not be protocoled by research procedures.  
 
6.9 Blinding of Study Drug 
Not applicable.  

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7 
Statistical Plan 
7.1 Primary Study Endpoints 
The primary study endpoints are as follows: 
1. Incidence and duration of CMV and EBV viremia and magnitude of viremia as 
measured by area under the viral load-time curve of recipients who become 
viremic with CMV and/or EBV in the first year post-Ktx.  
2. Incidence of subjects developing drug related side effects requiring dose 
reduction or cessation. 
3. Presence of EBV and or CMV in renal tissue (protocol biopsies).   
7.2 Secondary Study Endpoints 
Organ donor and recipient demographics, transplant characteristics, donor/recipient 
infection history (pre-transplant EBV and CMV IgE antibody status and qPCR in donors 
and recipients.  
7.3 Primary Safety Endpoints 
Interim analysis will be done after the enrollment and completion of therapy with study 
drug valA or standard of care drug valG in 6 patients. If there is >= 20% increased 
incidence of CMV / EBV viremia in the valA cohort compared to the valG cohort then 
study will be stopped. 
7.4 Statistical Methods 
As per Lowance et al., 80% of the recipients that are randomized to the valA cohort will 
be CMV viremia free at 6 months. Therefore, to establish non-inferiority of valA as 
compared to valG, if I consider a difference less than 10% of no clinical importance, the 
required sample size with equal allocation between valA and valG to achieve an 80% 
power (β=0.2) at α=0.05 we would need 54 recipients. 
 
 
CMV viremia 
free proportion 
N in valA grp 
N in valG grp 
Total=119 
CMV Ab+ R 
80% 
43 
43 
86 
CMV Ab- R 
84% 
61 
16 
32 
 
Since the anti-EBV effect of valG is unknown, a power calculation is impossible. 
Therefore we plan to include 200 recipients based on above sample size calculation 
and accounting for patient attrition etc. 
 
8 
Safety and Adverse Events 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or 
injuries will be regarded as adverse events.   

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse 
event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs a hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.   They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
 
Known side effects of the study drug and of kidney transplant will not be 
treated as serious adverse events for this study unless they are life-
threatening or fatal. See section 5.5 for a list of the known adverse effects of the 
study drugs. The known adverse effects of kidney transplant include: 
• Graft dysfunction, including: 
o Delayed graft function 
o Failure of donor kidney 
o Rejection of the new kidney 
o Vascular thrombosis 
• Recurrence of primary kidney diagnosis 
• Severe infections 
• Surgical complications 
• Risks related to immunosuppression 
• Risks related to steroids 
• Hypertension 
• Cardiovascular disease 
• Diabetes 
• Malignancy 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 30 days following the last administration of study treatment.  
Preexisting Condition 

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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event will also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events 
are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the investigator will instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.   
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be 
documented as an adverse event if the condition meets the criteria for an adverse 
event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 

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8.1 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results will be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
8.2 Reporting of Serious Adverse Events 
8.2.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the Principle Investigator within 24 hours 
of finding out of the event.  Within the following 48 hours, further information on the 
serious adverse event must be documented in the form of a written narrative.  This 
should include a copy of the completed Serious Adverse Event form (see Appendix), 
and any other diagnostic information that will assist the understanding of the event.  
Significant new information of ongoing serious adverse events should be provided 
promptly to the PI. The PI will keep a copy of this SAE form on file at the study site.  
Report serious adverse events by phone and facsimile to: 
 
Henry Balfour Jr, MD 
612-625-3998 
balfo001@umn.edu 
 
At the time of the initial report, the following information should be provided: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event 
and study treatment 
 
 
8.2.2 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the IRB within 5 working days if it falls under the expedited reporting 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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guidelines.  Copies of each report and documentation of IRB notification and 
receipt will be kept in the Clinical Investigator’s binder. 
8.2.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with the use of 
the drug as soon as possible but no later than 7 calendar days from the 
sponsor’s original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a 
written report to the FDA as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
 
Agency Criteria for 
Reporting 
Timeframe 
Form to Use  Submission address/fax 
numbers  
U of 
MN IRB 
Unanticipated 
death of a locally 
enrolled subject(s); 
New or increased 
risk; Any adverse 
event that requires 
a change to the 
protocol or consent 
form- refer to the 
IRB website for 
complete details 
5 working days 
 UMN IRB 
Report Form 
email to irb@umn.edu  
Other Problems 
or Events meeting 
the definition of 
Prompt Reporting 
per the IRB’s 
website 
5 working days 
UMN IRB 
Report Form 
email to irb@umn.edu 
FDA 
SAE: fatal, life-
threatening, 
unexpected, at 
least possible 
related 
7 calendar 
days  
FDA 
MedWatch  
– MedWatch Online Voluntary 
Reporting Form 
(www.accessdata.fda.gov/scri
pts/medwatch  
SAE: serious, 
unexpected, at 
least possibly 
related 
15 calendar 
days 
 
 

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8.3 Stopping Rules  
This study may be terminated by the PI or DSMB at any time. Reasons for terminating 
the study may include the following: 
• The incidence or severity of AEs in this or other studies indicates a 
potential health hazard to subjects. 
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
8.4 Medical Monitoring 
The PI will oversee the safety of the study, including careful assessment and 
appropriate reporting of AEs. Medical monitoring will include a regular assessment of 
the number and type of SAEs.  
8.4.1 Internal Data and Safety Monitoring Board 
The study’s Data and Safety Monitoring Plan will be compliance with the UMN Clinical 
and Translational Scientific Institute’s Data & Safety Monitoring Plan (DSMB).  
 
A DSMB will meet twice per year, with the first meeting occurring once approximately 
25% of target enrollment has been accrued. The DSMB will review recruitment, 
participant status and subject safety associated with the trial and create a report for the 
Principal Investigator with their recommendations, if any, to the PI for the conduct of 
the study. 
9 
Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
Data generated by the methods described in the protocol will be recorded in the 
subjects' medical records and/or study progress notes. Data may be transcribed legibly 
on CRFs supplied for each subject or directly inputted into an electronic system or any 
combination thereof. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  
If a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write 
“N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO 
NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 6 
years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or at least 6 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents will be retained for a longer period if required 
by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to FDA/GCP guidelines.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 

ValA vs ValG for CMV/EBV Prophylaxis post KTx 
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10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
11 Ethical Considerations 
To avoid participants forgetting their participation in the study, those subjects who begin 
active participation more than two months after their original consent will be contacted 
to confirm their interest in participation before they are randomized. 
 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator and a 
copy of this decision will be provided to the sponsor before commencement of this 
study.  The investigator should provide a list of IRB members and their affiliate to the 
sponsor. 
 
11.1 Informed Consent 
All subjects’ will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation 
in this study. The consent form will be submitted with the protocol for review and 
approval by the IRB for the study. The formal consent of a subject using the IRB-
approved consent form must be obtained before that subject is submitted to any study 
procedure. This consent form must be signed by the subject or legally acceptable 
surrogate and the Investigator-designated research professional obtaining the consent. 
A blank copy of the IRB-approved form must be kept on-site by the Investigator. 
 
12 Study Finances 
12.1 Funding Source 
Study funding source is the Department of Surgery at the University of Minnesota.  

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12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must refer to the Regents Policies on Individual Conflict of Interest Policy or Institutional 
Conflict of Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial interests related to 
his or her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that 
presents a potential conflict of interest is anticipated, or when submitting an application 
for research support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators will follow the 
University conflict of interest policy. 
13 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor.  Any investigator involved with this study is obligated to 
provide the sponsor with complete test results and all data derived from the study. 
 
 

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virology : the official publication of the Pan American Society for Clinical Virology. 
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2. 
Tynell E, Aurelius E, Brandell A, Julander I, Wood M, Yao QY, et al. Acyclovir and 
prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-
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3. 
Michael W. Simon RGD, Britt Shahan The Effect of Valacyclovir and Prednisolone in 
Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study. 
International Pediatrics. 2003;18(3). 
4. 
Reischig T, Opatrny Jr K, Treska V, Mares J, Jindra P, Svecova M. Prospective 
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5. 
Reischig T, Jindra P, Hes O, Svecova M, Klaboch J, Treska V. Valacyclovir prophylaxis 
versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal 
transplantation. Am J Transplant. 2008;8(1):69-77. 
6. 
Reischig T, Opatrny K, Jr., Bouda M, Treska V, Jindra P, Svecova M. A randomized 
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cytomegalovirus disease after renal transplantation. Transpl Int. 2002;15(12):615-22. 
7. 
Balfour HH, Jr., Chace BA, Stapleton JT, Simmons RL, Fryd DS. A randomized, 
placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in 
recipients of renal allografts. The New England journal of medicine. 1989;320(21):1381-7. 
8. 
Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, et al. 
Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. 
International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. The New 
England journal of medicine. 1999;340(19):1462-70. 
9. 
Vezina HE, Balfour HH, Jr., Weller DR, Anderson BJ, Brundage RC. Valacyclovir 
pharmacokinetics and exploratory pharmacodynamics in young adults with Epstein-Barr virus 
infectious mononucleosis. Journal of clinical pharmacology. 2010;50(7):734-42. 
10. 
Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, et al. 
Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. 
International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. The New 
England journal of medicine. 1999;340(19):1462-70.