Clinical trial NCT03339401
Conditions: Adenovirus
Keywords: Adenovirus Pediatric Hematopoietic Cell Transplant Brincidofovir Standard of care
Sponsor: Chimerix
Start date: 2017-12-22; Completion date: 2019-05-10
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to assess the safety, overall tolerability, and antiviral activity of "short course" brincidofovir (BCV) therapy, as compared with current standard of care (SoC), for the treatment of adenovirus (AdV) infections in high-risk (i.e., T cell depleted) pediatric allogeneic hematopoietic cell transplant (HCT) recipients. A virologic response-driven approach to the duration of treatment was to be evaluated, in which subjects randomized to BCV therapy were to be treated until AdV viremia was confirmed as undetectable or until a maximum of 16 weeks of therapy, whichever occurred first. The formulation of BCV used in this study was oral tablet/suspension.

Detailed description:
This was a randomized, open-label, multi-center study of the safety, overall tolerability, and antiviral activity of BCV, as compared with SoC, in pediatric (and young adults in the United States) recipients of high-risk (i.e., T cell-depleted and/or unrelated cord blood graft, or a T cell-replete graft from ahaploidentical donor with post-transplant cyclophosphamide administration) allogeneic HCT. Subjects with AdV detected in plasma after their qualifying transplant could be screened for participation in the study. Subjects who met all applicable entry criteria were randomized in a 2:1 ratio to receive either BCV or SoC (i.e., investigator-assigned therapy). The formulation of BCV used in this study was oral tablet/suspension. Subjects were randomized within 100 days post-transplant; for study purposes, the day of randomization was defined as Day 1. During randomization, subjects were stratified based on the following variables: last AdV viremia (≥10,000 copies/mL versus \<10,000 copies/mL) measurement available from the designated central virology laboratory prior to randomization, time from transplant to randomization (≥28 days versus \<28 days), and T cell-depletion methodology (receipt of alemtuzumab or ex vivo depletion versus receipt of anti-thymocyte globulin \[ATG\] or no T cell depletion).

Arms: arm 1: Brincidofovir (BCV) for the treatment of adenovirs (AdV) infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Brincidofovir (BCV) treatment began no later than 100 days post-transplant and was to continue for a maximum of 16 weeks. Brincidofovir (BCV) was discontinued once AdV viremia was confirmed undetectable.

Subjects who did NOT receive concurrent cyclosporine on Day 1:

* If ≥48kg body weight, one 100mg oral tablet BIW (or 10mL of 10mg/mL oral suspension if unable to take tablets).
* If \<48kg body weight, 2mg/kg oral volume of 10mg/mL oral suspension BIW.

Subjects who received cyclosporine on Day 1 (or initiated cyclosporine at any time):

* 1.4mg/kg (maximum of 70mg) oral volume of 10mg/mL oral suspension BIW.
* 2mg/kg (maximum of 100mg) oral volume of 10mg/mL oral suspension BIW if discontinued cyclosporine. arm 2: Local institutional standard of care (SoC) (i.e., investigator-assigned therapy) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Management of these subjects was prescribed by the investigator as being in the best interests of the subject and may have included a "watch-and-wait" approach, with or without decreased immunosuppression (ergo, no treatment), or treatment administration with other available antivirals, most commonly cidofovir intravenously.

Decisions regarding SoC, including administration of therapy, dose and regimen of therapy, modification of immunosuppression, and monitoring was the responsibility of the clinical team caring for the subject, according to institutional guidelines, local practices, and applicable guidelines for the management of AdV infection.
Interventions: intervention 1: Standard of Care intervention 2: Brincidofovir
Intervention descriptions: intervention 1: Local institutional standard of care (SoC) (i.e., investigator-assigned therapy) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients. intervention 2: Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Protocol documents:
Prot_SAP_003.pdf: 
1 
Confidential Property of Chimerix, Inc. 
An Open-label, Randomized, Multi-center, Parallel Group, 
Two-arm Study to Assess the Safety, Overall Tolerability, 
and Antiviral Activity of Brincidofovir versus Standard of 
Care for Treatment of Adenovirus Infections in High-risk 
Pediatric Allogeneic Hematopoietic Cell Transplant 
Recipients 
Protocol Number: CXM001-999 
Protocol Version/Date: Original, dated 26 September 2017 
ClinitalTrials.gov Identifier: NCT03339401 


Protocol No. CMX001-999 
Final: 26SEP2017 
2 
Confidential Property of Chimerix, Inc. 
TITLE PAGE 
BRINCIDOFOVIR (CMX001; BCV) 
An Open-label, Randomized, Multi-center, Parallel Group, 
Two-arm Study to Assess the Safety, Overall Tolerability, 
and Antiviral Activity of Brincidofovir versus Standard of 
Care for Treatment of Adenovirus Infections in High-risk 
Pediatric Allogeneic Hematopoietic Cell Transplant 
Recipients 
PROTOCOL No. CMX001-999 
Protocol Version/Date: Original, dated 26 September 2017 
 
US IND No.: 
110,584 
EudraCT No.: 
2017-001735-39 
Study Sponsor: 
Chimerix, Inc. 
2505 Meridian Parkway, Suite 100 
Durham, North Carolina 27713 
USA 
Tel: +1 919-806-1074 
Chief Medical Officer: 
W. Garrett Nichols, MD, MS 
Tel: +1 919-806-1074 
Fax: +1 919-806-1146 
Email: gnichols@chimerix.com 
Chimerix Medical Monitor: 
Enrikas Vainorius, MD 
Senior Medical Director 
Tel: +1 919-287-6029 
Cell: +1 919-257-7091 
Fax: +1 919-313-6797 
Email: evainorius@chimerix.com 
 
By accepting delivery of this document, the recipient agrees to hold all information contained herein in the strictest confidence and 
not to use this information for any purpose other than evaluating, pursuing, or engaging in a mutually agreed-upon business 
relationship with Chimerix, Inc. (the “company”).  Any further distribution or reproduction of this document, or disclosure of any 
information contained herein, to a third party without the company’s express written permission is prohibited.  No rights or licenses 
to trademarks, inventions, copyrights, patents, or any other intellectual property rights are implied or granted hereby.  The delivery 
of this document does not impose any obligation upon the company to negotiate or consummate any transaction with the recipient, 
prevent the company from pursuing similar discussions with other parties, or obligate the company to continue discussions with 
the recipient.  The information contained herein shall at all times remain the property of the company and shall be returned to the 
company promptly upon request. 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
SPONSOR’S SIGNATURE PAGE 
An Open-label, Randomized, Multi-center, Parallel Group, Two-arm Study to 
Assess the Safety, Overall Tolerability, and Antiviral Activity of Brincidofovir 
versus Standard of Care for Treatment of Adenovirus Infections in High-risk 
Pediatric Allogeneic Hematopoietic Cell Transplant Recipients 
PROTOCOL No. CMX001-999 
Protocol Version/Date: Original, dated 26 September 2017 
 
 
This protocol has been approved by Chimerix, Inc.  The following signature documents this 
approval. 
 
 
W. Garrett Nichols, MD, MS  
 
 
 
 
 
 
 
 
 
Printed Name of Chimerix Medical Officer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Chimerix Medical Officer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 


Protocol No. CMX001-999 
Final: 26SEP2017 
4 
Confidential Property of Chimerix, Inc. 
INVESTIGATOR’S AGREEMENT 
An Open-label, Randomized, Multi-center, Parallel Group, Two-arm Study to 
Assess the Safety, Overall Tolerability, and Antiviral Activity of Brincidofovir 
versus Standard of Care for Treatment of Adenovirus Infections in High-risk 
Pediatric Allogeneic Hematopoietic Cell Transplant Recipients 
PROTOCOL No. CMX001-999 
Protocol Version/Date: Original, dated 26 September 2017 
 
 
I have received and carefully read the Investigator’s Brochure for Brincidofovir (CMX001, 
BCV).  I have carefully read this CMX001-999 study protocol and agree to conduct the study in 
accordance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP) guidelines, and all applicable local laws and regulations pertaining to the conduct of 
clinical trials. 
I will ensure that all subinvestigators and all other staff members involved with the conduct of 
the study read and understand all aspects of this protocol. 
I have received and read all study-related information provided to me. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
All rights of publication of the results reside with Chimerix, Inc., unless made in a separate 
agreement. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
CONTACTS IN CASE OF EMERGENCY 
Relevant sponsor medical contacts are provided in Table 1.  Emergency, 24-hour, and CRO 
contacts, as applicable, are provided in the study reference manual (SRM).  Any updates to the 
sponsor medical contacts will also be provided in the SRM. 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Study Sponsor 
Chimerix, Inc. 
2505 Meridian Parkway, Suite 100 
Durham, North Carolina 27713, USA 
Tel: +1 919-806-1074 
Fax: +1 919-806-1146 
Chimerix Chief Medical Officer 
W. Garrett Nichols, MD, MS 
Chief Medical Officer 
Chimerix, Inc. 
Tel: +1 919‐287‐6006 
Cell: +1 919‐257-1226 
Fax: +1 919-806-1146 
Email: gnichols@chimerix.com 
Chimerix Medical Monitor 
Enrikas Vainorius, MD 
Senior Medical Director 
Chimerix, Inc. 
Tel: +1 919‐287‐6029 
Cell: +1 919‐257‐7091 
Fax: +1 919-806-1146 
Email: evainorius@chimerix.com 
Chimerix Back-up Medical Monitor 
Marion Morrison, MD 
Executive Medical Director 
Chimerix. Inc. 
Tel: +1 919-313-2977 
Cell: +1 919-886-0830 
Fax: +1 919-313-6797 
Email: mmorrison@chimerix.com 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
1. 
SYNOPSIS 
Name of Sponsor/Company: Chimerix, Inc. (“Chimerix”) 
Name of Investigational Product: Brincidofovir (BCV); hexadecyloxypropyl-cidofovir; CMX001 
Name of Active Ingredient: Phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-
(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester 
Title of Study: An Open-label, Randomized, Multi-center, Parallel Group, Two-arm Study to Assess 
the Safety, Overall Tolerability, and Antiviral Activity of Brincidofovir versus Standard of Care for 
Treatment of Adenovirus Infections in High-risk Pediatric Allogeneic Hematopoietic Cell Transplant 
Recipients 
Short Title: The AdAPT Trial; Adenovirus after Allogeneic Pediatric Transplantation 
Study Center(s): This study will be conducted at multiple centers across Europe, North America, and 
possibly other regions. 
Phase of Development: Two (2) 
Objectives: 
This study is designed to assess the safety, overall tolerability, and antiviral activity of “short course” 
BCV therapy, as compared with current standard of care (SoC), for the treatment of adenovirus 
(AdV) infections in high-risk (i.e., T cell-depleted) pediatric allogeneic hematopoietic cell transplant 
(HCT) recipients.  A virologic response-driven approach to the duration of treatment will be 
evaluated, in which subjects randomized to BCV therapy are treated until AdV viremia is confirmed 
as undetectable or until a maximum of 16 weeks of therapy, whichever occurs first. 
Primary Objective: 
The primary objective of the study is to compare the safety, overall tolerability, and virologic 
response of BCV vs. SoC for the treatment of AdV infection in high-risk pediatric allogeneic HCT 
recipients. 
Secondary Objectives: 
• 
To assess the incidence of and time to all-cause, non-relapse, and AdV-associated mortality 
in pediatric subjects treated with BCV vs. SoC 
• 
To assess the correlation between virologic response and clinical outcome 
• 
To describe the incidence of and time to virologic relapse in subjects who have previously 
achieved undetectable AdV viremia 
• 
To assess resolution or progression in clinical symptoms associated with AdV disease 
(i.e., resolution of all disease to no disease among subjects with probable or definitive AdV 
disease at baseline and progression from no disease to any probable or definitive AdV disease 
among asymptomatic subjects at baseline) 
• 
To assess the correlation between AdV hexon “serotype,” virologic response, and clinical 
outcome 
• 
To evaluate the emergence of viral resistance among subjects treated with BCV vs. SoC 
• 
To characterize plasma BCV pharmacokinetic (PK) profiles and evaluate the impact of 
covariates of interest on PK 
• 
To characterize the potential impact of plasma BCV exposure on clinical safety, virologic, 
and mortality endpoints, and to evaluate the modifying influence of various covariates of 
interest on these relationships and endpoints 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
• 
To assess virologic response in other non-plasma biologic compartments (urine, stool, 
respiratory secretions), as well as the association between detectable AdV viral load in these 
compartments at AdV viremia clearance with subsequent AdV viremia relapse 
Exploratory Objectives 
• 
To assess the correlation between baseline HCT co-morbidity index and clinical outcome 
• 
To assess immunologic predictors of virologic response (all subjects) and relapse (among 
subjects with confirmed AdV clearance from plasma) 
• 
To evaluate exploratory biomarkers for BCV-related gastrointestinal (GI) toxicity 
(e.g., citrulline, suppression of tumorigenicity-2 [ST2], T cell immunoglobulin mucin-3 
[TIM3], and C-reactive protein [CRP]) 
• 
To assess healthcare resource utilization 
Methodology: This is a randomized, open-label, multi-center study of the safety, overall tolerability, 
and antiviral activity of BCV, as compared with SoC, in pediatric recipients of high-risk 
(i.e., T cell-depleted) allogeneic HCT.  Pediatric patients with AdV detected in plasma within the 
previous 21 days and for the first time since their qualifying transplant may be screened for 
participation in the study.  Subjects who meet all applicable entry criteria will be randomized in a 
2:1 ratio to receive either BCV or SoC.  The day of randomization is defined as Day 1.  During 
randomization, subjects will be stratified based on the following variables: last (non-baseline) 
screening AdV viremia (≥ 10,000 copies/mL vs. < 10,000 copies/mL), time from transplant to 
randomization (≥ 28 days vs. < 28 days), and T cell-depletion methodology (receipt of alemtuzumab 
or ex vivo depletion vs. receipt of anti-thymocyte globulin [ATG]).  Subjects randomized to receive 
BCV will be treated until AdV deoxyribonucleic acid (DNA) is confirmed to be undetectable in 
plasma, up to a maximum of 16 weeks post-randomization.  Subjects randomized to the SoC arm will 
be managed according to local or institutional practice guidelines for the treatment of AdV infection.  
All subjects, regardless of treatment assignment, will be followed in the study for a total of 36 weeks 
post-randomization.  Subjects will be assessed on a weekly basis through Week 16, with additional 
assessments performed at Weeks 24 and 36 post-randomization.  The data collected through Week 16 
will comprise the primary data set for the study; hence, the primary database will be locked and 
analyzed following capture of data for all subjects through Week 16.  In addition, all subjects (both 
BCV and SoC recipients) will be encouraged to enroll in the BCV Registry (Study CMX001-333) to 
assess the longer-term impact of exposure to BCV. 
Number of Subjects (Planned): 
The study will target the enrollment of a total of approximately 141 subjects, with 94 subjects 
randomized to the BCV arm and 47 subjects randomized to the SoC arm. 
Diagnosis and Main Criteria for Study Eligibility: 
Prospective subjects must be: 
• 
aged at least 2 months and less than 18-years-old on Day 1 AND 
• 
have received a T cell-depleted allogeneic (i.e., non-autologous) HCT within the previous 
100 days, where “T cell-depleted” describes EITHER: 
- 
ex vivo T cell depletion via positive selection (e.g., CD34+ cell) or negative selection 
(e.g., T cell receptor α/β or CD3+ cell removal by column filtration), OR 
- 
serotherapy with ATG (as cumulative dose of ≥ 3 mg/kg rabbit-derived ATG or 
≥ 50 mg/kg of equine-derived ATG) administered within 10 days prior to transplant or at 
any time post-transplant and prior to Day 1 OR 
- 
serotherapy with alemtuzumab administered within 30 days prior to transplant or at any 
time post-transplant and prior to Day 1. 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
Subjects must have had a first AdV detection in plasma since the qualifying transplant within 21 days 
prior to Day 1 and have a confirmed plasma AdV viremia of ≥ 1000 copies/mL and rising, defined as 
two consecutive AdV DNA polymerase chain reaction (PCR) test results ≥ 1000 copies/mL from the 
designated central virology laboratory, with the second result being greater than the first.  The 
second sample must be drawn at least 48 hours after the first sample and no more than 7 days prior to 
Day 1.  Prospective subjects may have multiple samples sent as screening samples, but will need to 
have two consecutive samples drawn at least 48 hours apart with AdV viremia ≥ 1000 copies/mL and 
rising as reported by the central virology laboratory to be eligible for randomization. 
Key exclusion criteria include: 
• 
Any CTCAE (United States [US] National Institutes of Health [NIH]/National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events) Grade 4 diarrhea 
(i.e., life-threatening consequences with urgent intervention indicated) within 7 days prior to 
Day 1 
• 
Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of ≥ 4 stools per day over baseline), unless 
attributed to AdV, within 7 days prior to Day 1 
• 
NIH Stage 4 acute graft versus host disease (GVHD) of the skin (i.e., generalized 
erythroderma with bullous formation) within 7 days prior to Day 1 
• 
NIH Stage 2 or higher acute GVHD of the liver (i.e., bilirubin > 3 mg/dL [SI: > 51 μmol/L]) 
within 7 days prior to Day 1 
• 
NIH Stage 2 or higher acute GVHD of the gut (i.e., diarrhea > 556 mL/m2/day, or severe 
abdominal pain with or without ileus) within 7 days prior to Day 1 
• 
Poor clinical prognosis (including active malignancy or use of vasopressors within 7 days 
prior to Day 1) 
• 
Requirement for mechanical ventilation within 7 days prior to Day 1, or sustained oxygen 
delivery for > 24 hours within 7 days prior to Day 1, or any oxygen requirement within 
48 hours prior to Day 1 
• 
Concurrent human immunodeficiency virus (HIV) infection, or active hepatitis B virus or 
hepatitis C virus infection 
• 
Specified out of range laboratory results (including alanine aminotransferase [ALT] greater 
than five times the upper limit of the normal reference range [> 5x ULN], aspartate 
aminotransferase [AST] > 5x ULN, total bilirubin > 3 mg/dL (SI: > 51 μmol/L), or 
prothrombin time – international normalized ratio [PT-INR] > 2x ULN) within 7 days prior to 
Day 1 
• 
Estimated creatinine clearance < 30 mL/min or use of renal replacement therapy within 
7 days prior to Day 1 
• 
Previous receipt of BCV at any time or receipt of intravenous (IV) cidofovir (CDV) within 
48 hours prior to Day 1 
• 
Received any cell-based anti-AdV therapy within 6 weeks prior to Day 1 or previously 
received an anti-AdV vaccine at any time 
As applicable, female subjects of childbearing potential (i.e., not pre-menarche) must not be pregnant 
or breastfeeding, and must agree to use two acceptable forms of contraception (one of which must be 
a barrier method) during heterosexual intercourse while enrolled in the study and for at least 90 days 
after the last dose of BCV.  [Note: For the purposes of this study, acceptable forms of contraception 
include barrier methods of contraception (e.g., male or female condom, diaphragm), an intra-uterine 
device, or hormonal contraception (e.g., oral pill, implant, injection, ring or transdermal patch).]  
Male subjects capable of fathering a child must agree to use a barrier method of contraception during 
heterosexual intercourse while enrolled in the study and for at least 90 days after the last dose of 


Protocol No. CMX001-999 
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Confidential Property of Chimerix, Inc. 
BCV. 
In accordance with applicable national or local law, and current institutional practice, written 
informed consent (or assent) to participate in the study will be obtained from each subject and his or 
her legal guardian(s).  Subjects must be available to participate in all required study activities for the 
entire duration of the study (i.e., through completion of the Week 36 assessment). 
Investigational Product, Dosage and Mode of Administration:  
Subjects randomized to the BCV arm will receive BCV as follows: 
• 
2 mg/kg (up to a maximum of 100 mg) twice weekly (BIW) for subjects not receiving 
concurrent cyclosporine 
• 
1.4 mg/kg (up to a maximum of 70 mg) BIW for subjects receiving concurrent cyclosporine 
(i.e., subjects taking cyclosporine on Day 1 or who initiate cyclosporine at any time while 
taking BCV) 
Subjects who discontinue cyclosporine while taking BCV should increase the BCV dose to 2 mg/kg 
(up to a maximum of 100 mg), starting with the next scheduled BCV dose following discontinuation 
of cyclosporine. 
Each dose of BCV will be administered orally as an oral suspension of 10 mg/mL strength.  The dose 
of BCV to be administered will be calculated using the lowest body weight recorded for the subject in 
the 30 days prior to Day 1.  Whenever possible, the BCV doses should be given with food (with or 
within 30 minutes after finishing a meal) to potentially improve tolerability.  Subjects who are unable 
to take medicines orally may be dosed through a nasogastric tube, gastrostomy tube, or other feeding 
tube that allows the dose to be delivered directly into the subject’s stomach or duodenum.  
Intrajejunal delivery is not advised as PK and tolerability data are not available for this route of 
administration.  The BCV doses should be administered at alternating 3- and 4-day intervals unless 
dosing is modified for tolerability reasons, as described below. 
Duration of Treatment/Study: 
For subjects randomized to the BCV arm, BCV will be administered for a maximum of 16 weeks, 
based on virologic response to treatment and tolerance to the drug.  In the absence of toxicity 
requiring dose interruption, BCV will be administered BIW until plasma AdV viremia is confirmed 
undetectable (two consecutive plasma viral load results of “undetectable” as reported by the 
designated central virology laboratory), or until Week 16 post-randomization, whichever occurs first.  
After a subject’s first AdV plasma viral load result is reported as “undetectable” by the designated 
central virology laboratory, a confirmatory blood sample must be drawn no sooner than 7 days (6 full 
calendar days and no later than 14 days (13 full calendar days) after the first sample was drawn.  Once 
AdV viremia is confirmed as undetectable, BCV will be discontinued. 
Until a subject has achieved sufficient immune reconstitution, reactivation of latent virus from the gut 
may result in a subsequent episode of AdV viremia.  Subjects who stop BCV therapy after achieving 
confirmed undetectable AdV viremia may re-initiate treatment with BCV if AdV viremia is 
subsequently confirmed at ≥ 1000 copies/mL by the designated central virology laboratory, unless 
precluded by the BCV toxicity management guidelines.  For the purposes of re-initiating BCV 
therapy, “confirmed AdV viremia ≥ 1000 copies/mL” is defined as two consecutive results 
≥ 1000 copies/mL from the designated central laboratory, with the second sample drawn at least 
48 hours after the first sample.  BCV dosing will be resumed at the same dose and dose frequency the 
subject was receiving when BCV therapy was stopped (i.e., if BCV dosing had been consolidated to 
once weekly [QW] administration for toxicity management purposes, the subject would resume at the 
QW dose). 
Subjects who permanently discontinue BCV for toxicity reasons are not eligible to re-initiate BCV 
therapy. 


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Confidential Property of Chimerix, Inc. 
Treatment with BCV may not be extended past Week 16 under this protocol.  Therefore, investigators 
wishing to extend or re-initiate treatment with BCV for a subject after Week 16 will need to request 
access to the drug through the local named patient program (NPP) or other expanded access program, 
where available. 
The duration of any therapy administered as part of SoC will be determined by local institutional 
practice.  Subjects randomized to the SoC arm will be managed according to local institutional 
practice and guidelines and any relevant product labelling.  To allow for a meaningful and 
interpretable comparison of safety and efficacy between treatment arms, subjects randomized to the 
SoC arm will NOT be eligible to receive BCV therapy prior to Week 16 post-randomization.  After 
completion of the Week 16 assessment, subjects randomized to the SoC arm may be able to access 
BCV through the local NPP or other expanded access program, as described above. 
All subjects will be followed for a period of 36 weeks post-randomization, regardless of treatment 
assignment, including SoC subjects who begin BCV treatment after Week 16 post-randomization. 
Reference Therapy, Dosage and Mode of Administration: 
BCV will be compared with local institutional SoC.  Subjects randomized to the SoC arm will be 
managed according to local or institutional practices and any relevant product labelling.  The 
decisions regarding SoC, including administration of therapy, dose and regimen of therapy, 
modification of immunosuppression, and monitoring will be the responsibility of the clinical team 
according to institutional guidelines, local practices, and applicable treatment guidelines for the 
management of AdV infection. 
Criteria for Evaluation: 
Subjects will be assessed at weekly intervals through the 16-week treatment period, with additional 
assessments performed at 24 and 36 weeks post-randomization as follows: 
• 
Assessments scheduled for Weeks 1, 2, 3, 4, 6, 8, 12, and 16 must be completed in the 
hospital or clinic (i.e., subjects who are being treated on an outpatient basis must return to the 
hospital/clinic). 
• 
For all other assessments (i.e., Weeks 5, 7, 9, 10, 11, 13, 14, 15, 24, and 36): 
- 
If a subject has detectable AdV in plasma, the subject will be required to return to the 
hospital or clinic to complete these assessments until such time as the subject achieves 
confirmed undetectable AdV viremia. 
- 
Thereafter, every effort should be made to have a subject return to the hospital or clinic 
for these assessments.  However, if return visits to the hospital or clinic are not practical 
(e.g., because the subject has returned to his or her home region), these visits may be 
performed through a home healthcare service provider or at a third-party facility that has 
been pre-approved by the sponsor (for the collection of samples including blood draws 
for safety and/or virologic analysis).  Telephone contact between the investigator and the 
subject or the subject’s caregiver (to assess adverse events [AEs], AdV symptoms, etc.) 
will need to occur in parallel. 
- 
If an approved home healthcare services provider or an approved third-party facility 
capable of performing the required procedures is not available, then all assessments must 
be performed at the hospital or clinic. 
Efficacy: Blood (plasma), urine, stool, and respiratory secretions, and other samples/specimens for 
virologic evaluations will be collected at screening, on Day 1 (before randomization), and at periodic 
intervals throughout the treatment and post-treatment periods of the study as follows: 
• 
Blood will be collected during screening, on Day 1 (before randomization), and at each 
subsequent assessment for real-time analysis of AdV viremia in plasma at the designated 
central virology laboratory.  These samples will also be analyzed in real time for 


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cytomegalovirus viremia.  The Day 1 (baseline) samples will also be analyzed for BK virus 
(BKV) viremia. 
• 
Urine, stool (where available), and respiratory secretions (nasopharyngeal swab and 
bronchoalveolar lavage, if appropriate, based on symptoms) will be collected from all 
subjects on Day 1 (before randomization) and at Weeks 4, 6, 8, 12, and 16.  Samples will also 
be collected from subjects: (1) at the same time that AdV viremia is confirmed as 
undetectable (i.e., at the time the confirmatory plasma sample is drawn), or (2) if BCV is 
re-initiated after the recurrence of AdV viremia ≥ 1000 copies/mL (with the samples 
collected prior to re-initiation of BCV), as applicable.  Samples may also be collected at any 
time on the basis of signs or symptoms suggestive of AdV disease.  Based on the clinical 
status of the subject, in consultation with the Chimerix Medical Monitor (or designee), 
investigators may request real time analysis of non-plasma specimens for AdV viral load. 
• 
While subjects are inpatient and, where practicable, once subjects are outpatient, stool 
samples will be collected on Day 1 (before randomization) and each subsequent assessment 
during treatment and follow-up and stored for possible virologic analyses (e.g., additional 
AdV or other double-stranded DNA virus viral load analyses, analyses for other viruses, viral 
genotypic and/or phenotypic assessments). 
• 
Collected samples (blood/plasma, urine, respiratory secretions, and stool) and/or remaining 
extracted DNA will be stored for possible future virologic/immunologic analyses 
(e.g., additional AdV or other dsDNA viral load analyses, viral typing, retrospective analyses 
for other viruses, longitudinal viral genotypic and/or phenotypic assessments, markers of 
AdV- and other virus specific immunity). 
Stored blood (plasma) samples or extracted DNA will be used for AdV typing by PCR amplification 
and sequencing of the variable region of the hexon gene.  Determination of baseline genotype will be 
carried out by PCR amplification and sequencing of the AdV DNA polymerase gene.  Emergence of 
antiviral-resistant AdV due to virologic failure will be determined by genotyping the AdV polymerase 
gene from subjects where: (1) confirmed recurrence of AdV viremia ≥ 1000 copies/mL is noted 
subsequent to viral clearance; (2) confirmed increase in plasma AdV DNA by ≥ 1 log10 after 
experiencing a ≥ 1 log10 decrease from baseline, and (3) non-responders and/or subjects with 
detectable plasma AdV DNA at the last on-treatment measurement.  Stored samples may also be used 
for AdV viremia/viral load assessments; additional resistance analyses based on newly available 
assays, including phenotyping for resistance and deep sequencing; and for retrospective analyses of 
other dsDNA virus viremia/viral loads.  No stored samples will be used for human genomic 
analyses. 
Changes in AdV-related disease signs and symptoms will be evaluated throughout the study. 
Safety: Safety will be assessed through physical examination findings, vital signs measurements, and 
the collection of blood and urine samples for routine safety assessments (analyzed by the designated 
central safety laboratory), including hepatic and renal assessments, determined at periodic intervals 
through 36 weeks post-randomization.  AEs will be recorded from the time of administration of the 
first dose of BCV or, for subjects randomized to SoC, from the date of randomization, until 
completion of the Week 16 assessment or premature discontinuation from the study.  In addition, any 
study procedure-related AE that occurs prior to administration of the first dose of BCV (or 
randomization to SoC) will be recorded as an AE.  After the Week 16 assessment, until completion of 
the Week 36 assessment, only serious adverse events (SAEs) will be recorded.  Subjects will also 
complete electronic diaries (e-diaries) collecting diarrhea symptoms on a daily basis (and date/time 
for each BCV dose and whether taken with food) through Week 16.  Concomitant medication use will 
be recorded through Week 16. 
Specific monitoring and BCV stopping criteria will be followed for targeted GI and hepatic 
abnormalities, as described below. 


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Pharmacokinetics: For subjects randomized to BCV, blood samples (5 samples collected pre-dose 
and up to 48 hours post-dose) will be collected on Day 1 and Week 2 (where blood volume loss limits 
allow) for analysis of plasma BCV concentrations by the designated bioanalytical laboratory.  
Samples collected from subjects who are receiving concurrent cyclosporine will also have 
cyclosporine concentrations analyzed.  The Week 2 PK samples will only be collected if the subject 
remains on BCV therapy. 
Safety Monitoring and Safety Reviews: 
Prior clinical experience has shown that the main toxicities associated with BCV dosing are GI 
events, in particular diarrhea, and increase in serum aminotransferase concentrations.  Investigators 
will be specifically trained on the management of BCV toxicity; subjects randomized to BCV therapy 
will be monitored for GI and hepatic abnormalities and managed as follows: 
Treatment-emergent Grade 1 GI-related AEs: 
Dosing with BCV may continue, while closely monitoring the subject for worsening of the AE(s). 
Symptomatic care may be provided as needed (e.g., anti-emetics, anti-diarrheals).  Hydration status 
should be closely monitored, and liquid and electrolyte intake should be encouraged, if appropriate, to 
avoid dehydration and the downstream consequences of dehydration on renal function. 
In the absence of extra-intestinal involvement, starting or increasing steroids and/or other 
immunosuppressants for the treatment of GVHD should be delayed if medically feasible for CTCAE 
Grade 1 diarrhea.  If steroid treatment of GVHD cannot be delayed (and BCV is continued) in 
subjects with Grade 1 symptoms, the subject’s response to GVHD therapy should be closely 
monitored. 
If diarrhea persists for > 14 days at CTCAE Grade 1, the complete subject profile should be reviewed, 
other etiologies for diarrhea considered, and if deemed appropriate, interruption of BCV should be 
considered in order to determine whether diarrhea resolves. 
Treatment-emergent Grade 2 or Higher Diarrhea in Subjects with ≤ Grade 1 Diarrhea at 
Baseline: 
For subjects enrolled with CTCAE Grade 1 diarrhea or no diarrhea at baseline, BCV must be 
interrupted for treatment-emergent CTCAE Grade 2 or higher diarrhea.  This includes new-onset 
Grade 2 or higher diarrhea or progression from Grade 1 to Grade 2 or higher diarrhea, regardless of 
the cause of the diarrhea. 
In general, changing multiple therapies at the same time (e.g., interrupting BCV and starting steroids 
for new-onset or worsening GI GVHD) is not recommended.  In order to assess response to BCV 
treatment interruption, start of (or increase in) steroid therapy for new-onset or worsening GI GVHD 
should be delayed, when possible. 
If diarrhea improves to ≤ CTCAE Grade 1 in intensity, subjects may resume dosing of BCV, but no 
sooner than 7 days (i.e., at least 6 full days off drug) following the last BCV dose administration.  
If resumed, BCV must be administered in a consolidated QW dose, i.e., 4 mg/kg (up to a maximum of 
200 mg) QW in the absence of concurrent cyclosporine or 2.8 mg/kg (up to a maximum of 140 mg) 
QW for subjects taking concurrent cyclosporine, to potentially improve tolerability, as weekly dosing 
allows more time for GI mucosal regeneration between doses.  Treatment with the consolidated QW 
BCV dose will be continued through Week 16 post-randomization or until confirmed undetectable 
AdV viremia in plasma, whichever occurs first. 
If diarrhea does not improve to ≤ CTCAE Grade 1 during interruption, BCV must not be resumed.  
Recurrence of CTCAE Grade 2 or higher diarrhea after restarting BCV requires permanent 
discontinuation of BCV. 


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Treatment-emergent Diarrhea AEs in Subjects with Grade 2 or 3 Diarrhea Attributed to AdV 
at Baseline: 
For subjects enrolled with CTCAE Grade 2 or 3 diarrhea at baseline that is attributed to AdV, BCV 
dosing must be interrupted if: 
• 
the diarrhea has not improved to ≤ CTCAE Grade 1 after 21 days of therapy, or 
• 
the subject experiences on-treatment worsening of one CTCAE grade or more at any time 
following initiation of BCV (i.e., Grade 2 worsens to ≥ Grade 3, or Grade 3 worsens to 
≥ Grade 4), regardless of the cause of the diarrhea 
If the diarrhea does not improve during interruption, BCV must not be resumed. 
If diarrhea improves to ≤ Grade 1 in intensity during interruption, subjects may resume dosing, but no 
sooner than 7 days (i.e., at least 6 full days off drug) following the last BCV dose administration.  If 
resumed, BCV must be administered in a consolidated QW dose as described above, i.e., 4 mg/kg (up 
to a maximum of 200 mg) QW in the absence of concurrent cyclosporine or 2.8 mg/kg (up to a 
maximum of 140 mg) QW for subjects taking concurrent cyclosporine. 
Treatment-emergent Non-diarrheal GI AEs: 
BCV dosing must be interrupted for Grade 3 or higher non-diarrheal GI events (e.g., abdominal pain, 
ileus, nausea, and vomiting).  If non-diarrheal GI AE(s) improve to ≤ Grade 2 in intensity, subjects 
who have interrupted BCV may resume dosing, but no sooner than 7 days (i.e., at least 6 full days off 
drug) following the last BCV dose administration.  If resumed, BCV must be administered in a 
consolidated QW dose as described above.  If non-diarrheal GI AE(s) do not improve during 
interruption, BCV must not be resumed.  In the event of recurrence of CTCAE Grade 3 or higher non-
diarrheal GI AEs after restarting BCV, BCV may be allowed to continue only after discussion and 
agreement with the Chimerix Medical Monitor (or designee). 
Increases in Serum Aminotransferases: 
Treatment with BCV must be interrupted for at least 7 days (i.e., 6 full days off drug) if any of the 
following confirmed abnormalities occur: 
1. ALT or AST > 8x ULN and ≥ 2x baseline value 
2. ALT or AST > 5x ULN and ≥ 2x baseline value for more than 2 weeks 
3. ALT or AST > 3x ULN and ≥ 2x baseline value and total bilirubin > 2x ULN or PT-INR 
> 1.5x ULN 
4. ALT or AST > 3x ULN and ≥ 2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
5. Total bilirubin > 3 mg/dL and ≥ 2x baseline value 
If an alternate reason for the laboratory abnormalities is identified and after the abnormalities 
decrease by ≥ 1 CTCAE grade below the grade that triggered BCV interruption, dosing with BCV 
may resume at the consolidated weekly dose described above.  Generally, subjects with persistent and 
significant ALT or AST elevations (> 5x ULN) should not resume administration of BCV unless 
there is clear evidence of a causal association with a viral disease being treated.  In these cases, 
continued treatment with BCV may be allowed after discussion and agreement with the Chimerix 
Medical Monitor (or designee).  Recurrence of the liver abnormalities after reintroduction of BCV 
requires permanent discontinuation of BCV. 
Data and Safety Monitoring Board (DSMB): 
A DSMB will be convened according to US Food and Drug Administration and European Medicines 
Agency guidelines on clinical trial data monitoring committees to monitor safety for this study.  The 
DSMB will review safety data on an ongoing and scheduled basis, as determined by the board and 
detailed in the DSMB charter. 


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The DSMB will define specific safety information to be provided for review at each meeting, but the 
review package will minimally include: 
• 
All SAEs 
• 
CTCAE Grade 3 or higher AEs 
• 
AEs resulting in permanent BCV or other anti-AdV drug discontinuation 
• 
AEs requiring BCV or other anti-AdV drug interruption 
• 
AEs requiring dose modification or consolidation of BCV or other anti-AdV drug  
• 
Incidence of and time to all-cause mortality and non-relapse mortality 
• 
Laboratory parameters predictive of liver abnormalities (e.g., ALT, AST, alkaline 
phosphatase, PT-INR, and total and direct bilirubin), renal abnormalities (creatinine 
clearance, estimated glomerular filtration rate [eGFR]), and hematologic cell counts 
predictive of graft function 
• 
Observed plasma BCV concentrations (as available) 
At least two safety reviews will be conducted by the DSMB.  The first safety review will be 
performed after the first 30 subjects enrolled have completed through Week 16.  The second safety 
review will be performed after the first 60 subjects enrolled have completed through Week 16. 
Study Drug Withdrawal Criteria: 
Subjects randomized to BCV who experience any of the following criteria after initiating treatment in 
this study will be required to discontinue BCV, but will continue to be followed in the study: 
• 
Subject request to discontinue for any reason 
• 
Treatment-emergent AE (TEAE) that necessitates the discontinuation of BCV as described 
above 
• 
If the investigator or the subject’s primary care provider believes that participation in the 
study is no longer in the best interests of the subject 
• 
Pregnancy in a female subject 
Female subjects who become pregnant will be immediately discontinued from BCV, but will 
continue to be followed in the study.  Pregnancies in female subjects randomized to the SoC 
arm must be reported according to local guidelines and relevant product labelling. 
• 
Discontinuation of the study at the request of Chimerix, a regulatory agency, or the governing 
ethics committee (EC) 
In addition, if any of the following criteria are met, BCV will be discontinued at the discretion of the 
investigator, in consultation with the Chimerix Medical Monitor (or designee): 
• 
Development of an exclusionary condition, including a decrease in eGFR to < 15 mL/min 
considered related to BCV, or unrelated to BCV but not being dialyzed 
• 
Treatment with, or requirement for treatment with, a prohibited or excluded medication 
• 
Subject is not compliant with the protocol (i.e., significant protocol deviation) 
Subjects randomized to the SoC arm in this study will be managed according to local or institutional 
practice guidelines and any relevant product labelling.  Investigators will need to consider the clinical 
status of the subjects and the local availability of treatment options. 
All subjects who are randomized will be followed through Week 36, including subjects who 
discontinue BCV for any reason and subjects who are randomized but not dosed in either arm.  
Subjects will be managed at the discretion of the responsible investigator according to local SoC, but 
will continue to be monitored in accordance with the Schedule of Study Assessments/Procedures. 


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Subjects who are randomized and who do not complete the study will not be replaced. 
Study Endpoints: 
Subjects will be assessed on a weekly basis through Week 16, with additional assessments performed 
at Weeks 24 and 36 post-randomization.  The data collected through Week 16 will comprise the 
primary data set for the study, with a database lock and analysis performed following completion of 
the last subject through Week 16 (or death or loss to follow-up, as applicable). 
Primary Efficacy Endpoint: 
The primary efficacy endpoint for this study is the time-averaged area under the concentration-time 
curve (AAUC) for AdV viremia (log10 copies/mL) from randomization through Week 16 post 
randomization. 
Key Secondary Efficacy Endpoint: 
The key secondary efficacy endpoint is the incidence of all-cause mortality through Week 16. 
Other Secondary Efficacy Endpoints: 
• 
Time to all-cause mortality through Week 16 
• 
Incidence of and time to all-cause mortality through Week 36 
• 
Incidence of and time to non-relapse mortality through Weeks 16 and 36 
• 
Incidence of and time to AdV-associated mortality through Weeks 16 and 36, where mortality 
is assessed by a blinded endpoint adjudication committee 
• 
Proportion of subjects with undetectable AdV viremia at Weeks 2, 4, 6, 12, and 16 
• 
Proportion of subjects with ≥ 2-log10 decline from baseline or undetectable AdV viremia at 
Weeks 2, 4, 6, 12, and 16 
• 
Proportion of subjects with ≥ 1-log10 decline from baseline or undetectable AdV viremia at 
Weeks 2, 4, 6, 12, and 16 
• 
AAUC at Weeks 2, 4, 6, and 12 
• 
Incidence of and time to first confirmed undetectable AdV viremia 
• 
Incidence of and time to virologic relapse (subsequent confirmed AdV viremia 
≥ 1000 copies/mL) among subjects with confirmed clearance of AdV from plasma (overall; 
by AdV in urine, stool, and respiratory secretions at the time of first undetectable AdV 
viremia; and by T cell-mediated immune function [e.g., CD4+ cells > or ≤ 50 cells/μL] at the 
time of first undetectable AdV viremia) 
• 
Maximum pediatric logistic organ dysfunction (PELOD) score through Week 16 
• 
Number of days spent in the hospital through Week 16 
• 
Number of days spent in the intensive care unit (ICU) through Week 16 
• 
Emergence of AdV mutations associated with genotypic resistance and phenotypic resistance 
(the latter when possible) to BCV or CDV 
• 
Incidence of and time to progression to probable or definitive AdV disease (among 
asymptomatic subjects at baseline) 
• 
Incidence of and time to resolution of AdV clinical disease (among subjects with probable or 
definitive AdV disease at baseline) 
• 
Primary model-based PK parameters, such as apparent clearance (CL/F), intercompartmental 
clearance (Q/F), volume of central compartment (Vc/F), volume of peripheral compartment 
(Vp/F), absorption rate constant (Ka), and lag time (Tlag), secondary PK parameters, such as 
maximum concentration (Cmax) and area under the concentration-time curve at steady state 


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(AUCss), and identification of covariates that influence these PK parameters 
• 
Relationship between plasma BCV exposure, other covariates of interest, and 
− 
safety endpoints, including GI AEs, diarrhea, ALT, total bilirubin, and other safety 
events of interest 
− 
virologic endpoints, including AAUC, AAUC minus baseline, viral load change from 
baseline, and other virologic endpoints of interest 
− 
all-cause and non-relapse mortality through Week 16 
Safety Endpoints: 
• 
Incidence of TEAEs, particularly those of ≥ CTCAE Grade 3 severity and SAEs 
• 
Incidence of treatment-related AEs, particularly those of ≥ CTCAE Grade 3 severity and 
SAEs 
• 
Incidence of AEs resulting in permanent BCV or other anti-AdV drug discontinuation 
• 
Incidence of AEs requiring BCV or other anti-AdV drug interruption 
• 
Incidence of AEs requiring dose modification or consolidation of BCV or other anti-AdV 
drug  
• 
Incidence of fatal AEs 
• 
Incidence of and time to CTCAE Grade 2 or higher diarrhea 
• 
Incidence of doubling, tripling, or quadrupling of baseline serum creatinine 
• 
Incidence of need for renal replacement therapy 
• 
Incidence of ≥ 1/2/3 CTCAE grade increases from baseline for safety laboratory parameters 
of interest (by visit, maximum on-treatment, last on-treatment, last on-study) 
• 
Distributions of change from baseline over time for central safety laboratory parameters of 
interest (by visit, maximum on-treatment, last on-treatment, last on-study) 
• 
Assessment of all deaths that occur through Week 16 and in follow up through Week 36 
Exploratory Endpoints: 
• 
Association of HCT co-morbidity index and clinical outcomes 
• 
Change from baseline in exploratory biomarker laboratory parameters (e.g., citrulline, ST2, 
TIM3, and CRP) 
• 
Association of exploratory biomarkers with treatment-emergent CTCAE Grade 2 diarrhea or 
GI GVHD 
• 
Number of and reasons for emergency room (A&E) visits; number of, duration, and reasons 
for hospital admissions; number of days spent in ICU, in isolation, or confined to bed; other 
infections; receipt of and duration of relevant concomitant medications and therapies; type 
and number of certain diagnostic or therapeutic procedures; and provision of home healthcare 
through Week 16 
• 
Association between immune reconstitution and viral response and clinical outcome 
(e.g., based on measurement and activity of AdV-specific cytotoxic T lymphocytes and other 
immune reconstitution parameters) 


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Statistical Methods: 
All subjects will be classified into Intent-to-Treat (ITT), modified Intent-to-Treat (mITT), Per 
Protocol (PP), Safety, and PK analysis sets.  The following definitions will be used: 
• 
ITT: The ITT analysis set will include all subjects who are randomized. 
• 
mITT: The mITT analysis set will include all subjects in the ITT analysis set with AdV 
viremia ≥ 1000 copies/mL measured by the designated central virology laboratory in the last 
sample on or prior to randomization.  Subjects randomized to BCV and not treated will be 
excluded from the mITT analysis set. 
• 
PP: The PP analysis set will include all subjects in the mITT analysis set who complete the 
study through Week 16 (or die prior to Week 16) and who do not have any major protocol 
deviations (defined as significant inclusion/exclusion criteria violation or noncompliance that 
would be expected to impact the analysis of efficacy). 
• 
Safety: The safety analysis set will include all subjects who are randomized to and receive at 
least one dose of BCV, and all subjects who are randomized to SoC. 
• 
PK: The PK analysis set will include all subjects who are randomized to and receive at least 
one dose of BCV, and have at least one blood sample collected for analysis of plasma BCV 
concentrations. 
• 
Safety Exposure-Response: The safety exposure-response analysis set will include subjects 
who are in both the safety analysis set and the PK analysis set. 
• 
Efficacy Exposure-Response: The efficacy exposure-response analysis set will include 
subjects who are in both the mITT analysis set and the PK analysis set. 
The ITT analysis set will be used to summarize all efficacy endpoints, including the primary 
endpoint/analysis.  The mITT and PP analysis sets will be determined prior to database lock for the 
primary analysis, and will be used for supportive primary efficacy analyses and possibly other 
selected endpoints.  All efficacy analyses will use the randomized treatment assignment.  The safety 
analysis set will be used for all safety analyses and the PK analysis set will be used for all PK 
analyses. 
The primary AAUC analysis will utilize all randomized subjects (ITT) in an analysis of covariance 
(ANCOVA) with all stratification factors included in the model: T cell-depletion method 
(alemtuzumab or ex vivo cell selection vs. ATG), time from HCT to randomization (< 28 days vs. 
≥ 28 days), and baseline AdV viremia (continuous log10 copies/mL).  In the ANCOVA, AdV viremia 
values that are undetectable will be imputed at 99 copies/mL (i.e., one less than the lower limit of 
detection of 100 copies/mL) and values that are detected but not quantifiable (BLQ) will be imputed 
at 189 copies/mL (i.e., one less than the lower limit of quantification of 190 copies/mL). 
The primary analysis will be supplemented by a number of planned sensitivity analyses to assess the 
impact of subjects who die prior to Week 16 and other potential influential elements on the primary 
inference. 
In addition, a supportive analysis of overall mortality (adjusting for advanced baseline disease, 
Matthes-Martin  2008) will examine the non-inferiority of BCV treatment to SoC.  No negative 
impact on mortality will be concluded if the upper bound of the one-sided 95% confidence interval 
(CI) for the absolute difference between BCV mortality and SoC mortality is < 10%.  In the event this 
supportive analysis concludes non-inferiority and the primary endpoint is met, superiority for overall 
mortality at Week 16 will be tested at alpha 0.05.  Non-relapse mortality will be assessed in a similar 
fashion. 
The primary and all-cause mortality endpoints will be analyzed by various subgroups, including, but 
not limited to, each of the stratification factors, sex, age, race, transplant characteristics, underlying 
disease (malignant, non-malignant), advanced disease status, and investigator’s intended SoC selected 


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Confidential Property of Chimerix, Inc. 
at the time of randomization.  Multivariate modelling will be considered and defined in the Statistical 
Analysis Plan (SAP). 
Continuous secondary efficacy analyses will use the same method used for the primary analysis. 
Dichotomous secondary efficacy analyses will be analyzed using a Cochran-Mantel-Haenszel test 
stratified by each of the stratification factors.  Number of failures and failure rates will be presented 
for each treatment arm.  Cochran-Mantel-Haenszel p-values, estimated common odds ratios, and 
corresponding approximate 95% CIs will be presented for each comparison.  The Breslow-Day test 
will be used to test the homogeneity of the odds ratios.  Missing data will be imputed as failure. 
Most time-to-event analyses will be performed using Kaplan-Meier methods/plots and Cox models.  
P-values and hazard ratios along with their 95% CIs will be presented for each treatment comparison.  
Missing data will be censored, generally at the earlier of the end of study for each subject or the time 
point for the specific analysis. 
Non-relapse mortality will be analyzed with relapse as a competing risk adjusted for baseline strata, 
with corresponding cumulative incidence plots, Fine-Gray models, and cause-specific and 
sub-distribution hazard ratios with corresponding 95% CIs. 
All safety analyses will be presented by randomized treatment arm using the safety analysis set.  
Inferential analyses will generally not be performed for safety endpoints. 
Sample size calculations were based on the primary endpoint, i.e., AAUC through Week 16.  
Assuming the observed standard deviation of ~ 1.03 log10 copies/mL in AAUC at Week 16 from a 
comparable subset of SoC subjects, the study has > 90% power with the currently planned sample 
size to demonstrate superiority of BCV vs. SoC, given that the true difference in means is > 0.6 log10 
copies/mL (i.e., an effect size of ~ 0.58).  In addition, the overall mortality at Week 16 non-inferiority 
comparison will have > 80% power in the event that the expected mortality for SoC is 20% to 30% 
and there is a true mortality advantage of 6% to 9% in favor of BCV (Feghoul 2015, Hiwarkar 2017, 
Mynarek 2014). 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR’S SIGNATURE PAGE .................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
CONTACTS IN CASE OF EMERGENCY ....................................................................................5 
1. 
SYNOPSIS ...................................................................................................................6 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............19 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................26 
4. 
INTRODUCTION ......................................................................................................29 
4.1. 
Background .................................................................................................................29 
4.2. 
Brincidofovir ...............................................................................................................30 
4.2.1. 
Summary of Toxicology Studies with BCV ...............................................................30 
4.2.2. 
Pharmacokinetics of BCV ..........................................................................................31 
4.2.2.1. 
Pharmacokinetics of BCV in Subjects with Hepatic or Renal Impairment ................32 
4.2.2.2. 
Pharmacokinetics of BCV across Age Groups ...........................................................32 
4.2.3. 
Clinical Experience with BCV ...................................................................................33 
4.2.3.1. 
Overview of Key BCV-related Toxicity: GI Events (Diarrhea) .................................33 
4.3. 
Overview of Study CMX001-999 Design and Rationale ...........................................36 
4.3.1. 
Study Rationale ...........................................................................................................36 
4.3.2. 
Rationale for Subject Population ................................................................................37 
4.3.3. 
Rationale for BCV Dosage Regimen and Treatment Duration ..................................38 
4.3.3.1. 
Rationale for BCV Dosage Regimen ..........................................................................38 
4.3.3.2. 
Rationale for Virologic Response-Driven BCV Treatment Duration ........................39 
4.3.4. 
Rationale for Safety Monitoring and Toxicity Management Guidance .....................40 
4.3.5. 
Rationale for Standard of Care Comparator ...............................................................40 
4.3.6. 
Rationale for Open Label Design ...............................................................................41 
4.3.7. 
Rationale for Primary Efficacy Endpoint and Secondary Endpoints .........................41 
4.3.7.1. 
Study CMX001-304 ....................................................................................................44 
4.3.7.2. 
Data from Literature ...................................................................................................44 
4.3.8. 
Rationale for Limiting Access to BCV for SoC Subjects to after Week 16 
Post-randomization .....................................................................................................46 


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4.3.9. 
PELOD Scoring ..........................................................................................................47 
4.3.10. 
Exploratory Biomarker Analyses ...............................................................................47 
4.4. 
Benefit:Risk Assessment ............................................................................................47 
4.5. 
Independent Safety Oversight .....................................................................................50 
4.5.1. 
Data and Safety Monitoring Board .............................................................................50 
4.5.2. 
Endpoint Adjudication Committee .............................................................................51 
5. 
STUDY OBJECTIVES AND OUTCOME MEASURES ..........................................52 
5.1. 
Primary Objective and Primary Efficacy Endpoint ....................................................52 
5.2. 
Secondary and Exploratory Objectives ......................................................................52 
5.2.1. 
Secondary Objectives: ................................................................................................52 
5.2.2. 
Exploratory Objectives ...............................................................................................52 
5.3. 
Secondary and Exploratory Endpoints .......................................................................53 
5.3.1. 
Key Secondary Efficacy Endpoint ..............................................................................53 
5.3.2. 
Other Secondary Efficacy Endpoints ..........................................................................53 
5.3.3. 
Safety Endpoints .........................................................................................................54 
5.3.4. 
Exploratory Endpoints ................................................................................................54 
6. 
INVESTIGATIONAL PLAN .....................................................................................56 
6.1. 
Overall Study Design ..................................................................................................56 
6.2. 
Schedule of Assessments/Procedures .........................................................................57 
6.3. 
Number of Subjects ....................................................................................................57 
6.4. 
Treatment Assignment ................................................................................................61 
6.5. 
End of Study and Study Completion ..........................................................................61 
6.6. 
Enrollment in Chimerix BCV Registry (Study CMX001-333) ..................................61 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................62 
7.1. 
Subject Inclusion Criteria ...........................................................................................62 
7.2. 
Subject Exclusion Criteria ..........................................................................................63 
7.3. 
Subject Withdrawal Criteria .......................................................................................64 
8. 
TREATMENT OF SUBJECTS ..................................................................................66 
8.1. 
Administration of Standard of Care ............................................................................66 
8.2. 
BCV Administration ...................................................................................................66 
8.2.1. 
Missed Doses of BCV ................................................................................................67 
8.2.2. 
Vomiting After Dosing ...............................................................................................67 
8.3. 
BCV Dosing Algorithm and Management .................................................................67 


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8.3.1. 
BCV Dosing Algorithm Based on Virologic Response .............................................68 
8.3.2. 
Safety Monitoring, Management, and Criteria for BCV Dose Adjustment ...............68 
8.3.2.1. 
Treatment-emergent Grade 1 GI-related AEs .............................................................69 
8.3.2.2. 
Treatment-emergent Grade 2 or Higher AEs of Diarrhea in Subjects with 
≤ Grade 1 Diarrhea at Baseline ...................................................................................70 
8.3.2.3. 
Treatment-emergent Diarrhea AEs in Subjects with Grade 2 or 3 Diarrhea 
Attributed to AdV at Baseline ....................................................................................70 
8.3.2.4. 
Grade 2 or Higher Non-diarrheal GI AEs ...................................................................72 
8.3.2.5. 
Elevations in Serum Aminotransferases .....................................................................73 
8.3.2.6. 
Decrease in Estimated Glomerular Filtration Rate to < 15 mL/min ...........................74 
8.4. 
Re-initiation of BCV Dosing for AdV Viremia .........................................................74 
8.5. 
Access to BCV after Week 16 ....................................................................................74 
8.6. 
Concomitant Medications ...........................................................................................74 
8.6.1. 
Prohibited Medications ...............................................................................................75 
8.6.1.1. 
Prohibited Medications for Subjects Randomized to Receive BCV ..........................75 
8.6.1.2. 
Prohibited Medications for Subjects Randomized to Receive SoC ............................76 
8.6.1.3. 
Co-enrollment in Other Studies ..................................................................................76 
8.7. 
Treatment Compliance ................................................................................................76 
8.7.1. 
Subject Electronic Diary .............................................................................................76 
8.8. 
Randomization and Blinding ......................................................................................77 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................78 
9.1. 
Description of Study Drug ..........................................................................................78 
9.2. 
Study Drug Packaging and Labelling .........................................................................78 
9.3. 
Study Drug Storage .....................................................................................................79 
9.4. 
Study Drug Accountability .........................................................................................79 
9.5. 
Study Drug Handling and Disposal ............................................................................79 
10. 
ASSESSMENT OF EFFICACY ................................................................................80 
10.1. 
Virologic Evaluations and Sample Collection ............................................................80 
10.1.1. 
Quantitative Assessment of AdV and Other dsDNA Viremia ...................................81 
10.1.2. 
Virologic Assessment at Local Laboratories ..............................................................81 
10.1.3. 
Adenovirus Hexon Sequencing (Typing) and Resistance Analysis ...........................81 
10.2. 
Assessment of Clinical Efficacy .................................................................................82 
10.3. 
Healthcare Resource Utilization .................................................................................83 


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10.4. 
Pharmacokinetic Assessments ....................................................................................83 
10.4.1. 
Blood PK Sample Collection and Analysis ................................................................83 
10.4.1.1. 
Day 1 and Week 2 PK Sampling ................................................................................83 
10.4.2. 
PK Sample Analysis ...................................................................................................84 
11. 
ASSESSMENT OF SAFETY .....................................................................................85 
11.1. 
Demographic/Medical History ...................................................................................85 
11.2. 
Height and Weight ......................................................................................................85 
11.3. 
Physical Examination .................................................................................................86 
11.4. 
HCT Comorbidities Assessment .................................................................................86 
11.5. 
PELOD Score .............................................................................................................86 
11.6. 
Daily Diarrhea Symptoms Assessment ......................................................................86 
11.7. 
Concomitant Medications ...........................................................................................86 
11.8. 
Laboratory Assessments .............................................................................................86 
11.8.1. 
Hematology and Serum Biochemistry ........................................................................86 
11.8.2. 
Urinalysis ....................................................................................................................87 
11.8.3. 
Pregnancy Screen ........................................................................................................87 
11.8.4. 
Biomarker Analysis ....................................................................................................88 
11.9. 
Adverse and Serious Adverse Events .........................................................................88 
11.9.1. 
Definition of Adverse Event .......................................................................................88 
11.9.2. 
Definition of Serious Adverse Event ..........................................................................89 
11.9.3. 
Recording Adverse Events .........................................................................................89 
11.9.4. 
Relationship to BCV or Other Anti-AdV Medication ................................................90 
11.9.5. 
Occurrence of Pregnancy and Reporting ....................................................................90 
11.9.6. 
Reporting Serious Adverse Events .............................................................................91 
12. 
STATISTICS ..............................................................................................................92 
12.1. 
Determination of Sample Size ....................................................................................92 
12.2. 
Analysis Sets ...............................................................................................................92 
12.3. 
Interim Analyses .........................................................................................................93 
12.4. 
Efficacy Analyses .......................................................................................................93 
12.4.1. 
Primary Efficacy Endpoint .........................................................................................93 
12.4.2. 
Secondary Efficacy Endpoints ....................................................................................95 
12.5. 
Virology Analyses ......................................................................................................95 
12.6. 
Safety Analyses ..........................................................................................................95 


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12.6.1. 
Adverse Events ...........................................................................................................95 
12.6.2. 
Laboratory Results ......................................................................................................96 
12.7. 
Pharmacokinetic and Exposure-Response Analyses ..................................................96 
12.8. 
Other Analyses ............................................................................................................97 
12.8.1. 
Subject Enrollment and Analysis Sets ........................................................................97 
12.8.2. 
Demographics and Baseline Characteristics ...............................................................97 
12.8.3. 
Prior and Concomitant Medications ...........................................................................97 
12.8.4. 
Study Drug Exposure/Compliance .............................................................................97 
12.8.5. 
Subject Disposition .....................................................................................................98 
12.9. 
Subgroup Analyses .....................................................................................................98 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................99 
13.1. 
Quality Controls and Study Monitoring .....................................................................99 
13.2. 
Quality Assurance Audits and Regulatory Inspections ..............................................99 
14. 
ETHICS ....................................................................................................................100 
14.1. 
Ethics Review ...........................................................................................................100 
14.2. 
Ethical Conduct of the Study ....................................................................................100 
14.3. 
Written Informed Consent/Assent ............................................................................100 
15. 
DATA HANDLING AND RECORD-KEEPING ....................................................102 
15.1. 
Data Collection .........................................................................................................102 
15.2. 
Inspection of Records ...............................................................................................102 
15.3. 
Retention of Records ................................................................................................102 
15.4. 
Confidentiality ..........................................................................................................102 
16. 
PUBLICATION POLICY ........................................................................................104 
17. 
LIST OF REFERENCES ..........................................................................................105 
APPENDIX 1. ACUTE GRAFT VERSUS HOST DISEASE NIH STAGING SCALE .........110 
APPENDIX 2. BCV DOSING TABLES ..................................................................................111 
APPENDIX 3. FLOW CHART FOR BRINCIDOFOVIR DOSING ALGORITHM ..............114 
APPENDIX 4. FLOW CHART FOR BRINCIDOFOVIR TOXICITY 
MANAGEMENT .....................................................................................................115 
APPENDIX 5. DEFINITIONS FOR PROBABLE OR DEFINITIVE ADENOVIRUS 
INFECTION OR DISEASE .....................................................................................116 
APPENDIX 6. HCT COMORBIDITY INDEX SCALE ..........................................................119 
APPENDIX 7. PELOD SCORE ...............................................................................................120 


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APPENDIX 8. BRISTOL STOOL FORM SCALE .................................................................122 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................5 
Table 2: 
List of Abbreviations ..................................................................................................26 
Table 3: 
Summary of Dose-normalized Plasma BCV PK by Age Group ................................32 
Table 4: 
Study CMX001-304: Early Virologic Response and Mortality Outcome ..................44 
Table 5: 
Schedule of Study Assessments/Procedures ...............................................................58 
Table 6: 
BCV Dosage Regimens for Study CMX001-999 .......................................................66 
Table 7: 
CTCAE Grading Scale for Diarrhea ...........................................................................68 
Table 8: 
BCV Interruption and Discontinuation Thresholds for Treatment-emergent 
Diarrhea ......................................................................................................................71 
Table 9: 
Recommended Management/Evaluation of Treatment-emergent GI Adverse 
Events during BCV Therapy ......................................................................................72 
Table 10: Investigational Product ...............................................................................................78 
Table 11: Study CMX001-999: Clinical Laboratory Evaluations ..............................................87 
Table 12: NIH Staging of Acute GVHD by Extent of Organ Involvement ..............................110 
Table 13: Percent Body Surfaces ..............................................................................................110 
Table 14 
BCV Suspension Volume by Dosing Weight for Subjects Receiving 
Concurrent Cyclosporine ..........................................................................................112 
Table 15 
BCV Suspension Volume by Dosing Weight for Subjects NOT Receiving 
Concurrent Cyclosporine ..........................................................................................113 
Table 16: Definitions and Criteria for Probable or Definitive Adenovirus Disease .................116 
Table 17: Definitions of HCT Comorbidities ...........................................................................119 
Table 18: PELOD Scoring System ...........................................................................................120 
 
LIST OF FIGURES 
Figure 1: 
Relationship between Weekly Plasma BCV AUC and Achievement of 
Undetectable Plasma AdV Viral Load .......................................................................39 
Figure 2: 
Study CMX001-304: AAUC through Week 16, Mortality at Week 16 .....................42 
Figure 3: 
Manchester Cohort: AAUCMB through Week 16, Mortality at Week 16 .................43 
Figure 4: 
AdVance Study: AAUC through Week 16, Mortality at Week 16 
(Preliminary Data from UK, Spain, and France) ........................................................43 


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Figure 5: 
Relationship between AdV Viremia and Mortality (Viremia Modelled as 
Time-varying Covariate) ............................................................................................45 
Figure 6: 
Relationship between Baseline Viral Load and Mortality (Viral Load as 
Time of Initial Viremia > 1000 copies/mL) ...............................................................46 
Figure 7: 
Virologic Responses after BCV or CDV Treatment in Pediatric HCT 
Recipients ...................................................................................................................48 
Figure 8: 
Lymphocyte Count at Resolution of Viremia Following Treatment with 
BCV (n = 15) or CDV (n = 8) ....................................................................................49 
Figure 9: 
Study Design Schema for CMX001-999 ....................................................................56 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations are used in this study protocol. 
Table 2: 
List of Abbreviations  
Abbreviation 
Explanation 
AAUC 
Time-averaged area under the concentration-time curve 
AAUCMB 
Time-averaged area under the concentration-time curve minus baseline 
ADL(s) 
Activity(ies) of daily living 
AdV 
Adenovirus 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area under the concentration-time curve 
AUCinf 
Area under the concentration-time curve from time zero (0) extrapolated to infinity 
AUClast 
Area under the concentration-time curve from time zero (0) to time of last measurable 
concentration 
AUCss 
Area under the concentration-time curve at steady state 
BCV 
Brincidofovir (CMX001) 
BIW 
Twice weekly 
BKV 
BK virus 
BLQ 
Below limit of quantitation 
CD3/4/8/34 
Cluster of differentiation 3/4/8/34 
CDV 
Cidofovir 
CDV-PP 
CDV-diphosphate 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CMV 
Cytomegalovirus 
CMX001 
Brincidofovir 
CRP 
C-reactive protein 
CTCAE 
(NIH/NCI) Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
%CV 
Percent coefficient of variation 


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Abbreviation 
Explanation 
CYP 
Cytochrome P450  
DNA 
Deoxyribonucleic acid 
dsDNA 
Double-stranded DNA 
DSMB 
Data and safety monitoring board 
EAC 
Endpoint adjudication committee 
EC 
Ethics committee 
ECIL 
European Conference on Infections in Leukaemia 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FDA 
(United States) Food and Drug Administration 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GVHD 
Graft versus host disease 
HBV 
Hepatitis B virus 
HCT 
Hematopoietic cell transplant 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
ITT 
Intent-to-treat 
IV 
Intravenous 
IV/WRS 
Interactive voice/web response system 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantification 
Max 
Maximum 
Min 
Minimum 
mITT 
Modified intent-to-treat 
MMF 
Mycophenolate mofetil 


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Abbreviation 
Explanation 
N, n 
Number of observations or events 
NCI 
(US) National Cancer Institute 
NIH 
(US) National Institutes of Health 
NPP 
Named patient program 
OAT1 
Organic anion transporter 1 
OATP1B1/3 
Organic anion transporting polypeptide 1B1 or 1B3 
PCR 
Polymerase chain reaction 
PELOD 
Pediatric logistic organ dysfunction 
P-gp 
P-glycoprotein 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PP 
Per protocol 
PT-INR 
Prothrombin time-international normalized ratio 
Q1 
First quartile 
Q3 
Third quartile 
QW 
Once weekly 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SoC 
Standard of care 
SRM 
Study reference manual 
ST2 
Suppression of tumorigenicity-2 
TEAE 
Treatment emergent adverse event 
TIM3 
T cell immunoglobulin mucin-3 
UK 
United Kingdom 
ULN 
Upper limit of normal reference range 
UND 
Undetectable 
US(A) 
United States (of America) 


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4. 
INTRODUCTION  
4.1. 
Background 
In immunocompetent individuals, adenovirus (AdV) infections and resulting illnesses are 
generally mild, typically self-limited and resolve without sequelae (Ison 2002a, Ison 2006, 
Lenaerts 2008).  However, patients who have undergone allogeneic hematopoietic cell transplant 
(HCT) are at especially high risk for developing AdV disease and, in this susceptible population, 
the development of AdV infection associated with viremia is much more prevalent and rapidly 
fatal without treatment (Florescu 2012, Ison 2006, Lion 2014, Sandkovsky 2014).  Children are 
at higher risk of infection and manifestations can be severe among pediatric patients (Lion 2014).  
Common disease manifestations of AdV infection in immunocompromised patients are serious 
and include hemorrhagic cystitis, pneumonia and bronchiolitis obliterans, liver failure, severe 
gastrointestinal (GI) disease (Ison 2006, Legrand 2001) and renal damage, such as nephritis and 
obstructive nephropathy (Mori 2003). 
The incidence of AdV infection and risk of serious disease is generally higher among children 
(Chakrabarti 2000, Howard 1999, Ison 2002b, Mynarek 2014) as well as recipients of 
T cell-depleted grafts (Chakrabarti 2002, Lee 2011, Mynarek 2014) and patients with acute graft 
versus host disease (GVHD) (Flomenberg 1994, Lion 2014, Runde 2001); risk is also high 
among recipients of unrelated or human leukocyte antigen-mismatched transplants due to 
profound and persistent immunodeficiency (Baldwin 2000, Bruno 2003, Howard 1999, 
Lion 2014).  Earlier detection of AdV viremia after HCT and higher viral loads have also been 
correlated with increased risk of fatal outcome (Mynarek 2014).  Severe and persistent 
lymphopenia is also associated with increased incidence of AdV infection, as well as progression 
to disseminated and often fatal AdV disease (Chakrabarti2002, 2007, Lion 2014).  The mortality 
rate for patients undergoing HCT approaches 26% for all symptomatic patients, and can reach 
50% to 80% in pediatric patients with disseminated AdV disease (Lion 2014). 
No product has received regulatory approval for the treatment or prevention of AdV infection or 
disease in the transplant setting.  Intravenous (IV) cidofovir (CDV) has been shown to have 
antiviral activity against AdV in vitro and in pediatric and adult patients with AdV infection and 
disease (de Pagter 2009, Doan 2007, Feghoul 2015, Legrand 2001, Nagafuji 2004, Refaat 2008, 
Williams 2009, Yusuf 2006).  However, IV CDV is associated with dose-limiting nephrotoxicity 
which can result in renal failure or death with a single administration (De Clercq 2003, 
Safrin 1997, Vistide Package Insert [Gilead Sciences 2010]).  This is of particular concern for 
HCT recipients who are at increased risk of acute renal injury during the first 100 days 
post-transplant, with doubling of serum creatinine reported in 15% to 73% of HCT recipients, 
and renal failure requiring dialysis in up to 8.5% of HCT recipients (Hingorani 2005, 
Rajpal 2013).  CDV is often given at reduced doses in an apparent effort to reduce the risk of 
toxicity, with the unintended consequence of selecting for viral resistance. 
There remains a major unmet medical need for a safe and efficacious treatment for AdV 
infection in the post-transplant patient population in whom disseminated AdV disease can be 
rapidly fatal. 


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4.2. 
Brincidofovir 
Brincidofovir (BCV, CMX001) is a compound of the antiviral class of drugs and is chemically 
designated as phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-
(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester.  BCV is designed to 
mimic a natural lipid, lysophosphatidylcholine, to utilize natural lipid uptake pathways to 
achieve optimal intracellular concentrations of BCV.  Inside the cell, BCV is cleaved to release 
CDV, which is then converted to the active antiviral, cidofovir diphosphate (CDV-PP) by 
intracellular anabolic kinases.  CDV-PP exerts its antiviral effects against herpesviruses, AdV, 
and orthopoxviruses by acting as an alternate substrate inhibitor for viral deoxyribonucleic acid 
(DNA) synthesis.  Overall, lipid conjugation of CDV results in more efficient intracellular 
delivery of BCV, which results in lower circulating plasma concentrations of CDV 
(Cundy 1999).  The lower peak plasma concentrations of CDV and the fact that BCV (unlike 
CDV) is not a substrate for the human organic anion transporter 1 (OAT1) greatly reduces the 
risk of CDV-like nephrotoxicity following administration of BCV (Tippin 2016). 
Because of its broad-spectrum antiviral activity, Chimerix, is developing BCV for the prevention 
and treatment of clinically significant infection and disease caused by double-stranded DNA 
(dsDNA) viruses with high unmet medical need, including AdV infections in adult and pediatric 
HCT recipients and as a possible medical countermeasure against smallpox (variola virus). 
4.2.1. 
Summary of Toxicology Studies with BCV 
The nonclinical safety profile of orally-administered BCV has been defined in rodents and 
non-human primates.  Importantly, analysis of systemic exposures in animals administered BCV 
via oral gavage indicate that human exposure exceeds exposures achieved in preclinical safety 
models.  BCV was negative for mutagenicity in the Ames test, negative for clastogenicity in the 
mouse micronucleus test and was weakly positive for increased structural aberrations in the 
absence of metabolic activation in the chromosome aberrations assay.  In repeat dose animal 
studies, transient aminotransferase elevations without a histopathological correlate occurred in 
rodents and monkeys.  These elevations were minor (2- to 5-fold), lacked dose-responsiveness 
and reversed upon cessation of treatment.  Additionally, GI and reproductive toxicity was 
observed in repeat dose studies up to 26 and 39 weeks’ duration in rats and monkeys, 
respectively.  The dose-limiting GI findings, diagnosed as gastropathy and enteropathy or 
enteritis, were observed following daily oral administration of BCV in rodents and monkeys.  
However, incidence and severity were significantly reduced when BCV was administered twice 
weekly (BIW) and recovery was demonstrated after cessation of dosing.  The BCV-related 
effects on the male reproductive system in rats and monkeys was characterized by an effect on 
the mitotic spermatogonia resulting in maturation depletion.  Based on this mechanism of 
testicular toxicity, the extent of cell types affected throughout the seminiferous tubules and the 
resumption of spermatogenesis upon cessation of dosing is dependent on the duration of 
exposure and the length of the spermatogenic cycle.  While recovery was not demonstrated in 
rats during a 12-week off-dose period after 13 weeks of BIW dosing, in monkeys, 
spermatogenesis resumed during a 26-week off-dose period after 39 weeks of BIW dosing. 
Additional BCV-related reproductive findings included embryo toxicity and fetal morphological 
changes in rabbits and decreased fertility, embryonal viability and growth and development of 


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pups, as well as delayed sexual maturation in rats.  Based on these data, BCV should be 
considered a potential teratogen and may affect female fertility. 
Mammary gland adenocarcinomas and squamous cell carcinomas were observed in rats 
approximately 9 weeks after the cessation of 13 weeks of BIW BCV dosing and additional 
tumors, including carcinomas, adenocarcinomas and hemangiocarcinomas in a variety of tissues 
were observed after 26 weeks of BIW dosing.  While tumors occurred in rats with extremely 
high frequency after as few as 26 doses of BCV and with peak BCV plasma concentrations 
(Cmax) as low as 0.4 ng/mL, neither masses nor neoplastic or preneoplastic lesions were detected 
in monkeys following administration of BCV at doses which achieved peak plasma 
concentrations > 80-fold higher than concentrations recorded in rat.  Furthermore, no 
BCV-related malignancies have been reported in any of the > 2000 patients who have received 
BCV treatment since the clinical program began in 2006.  Like the monkey, plasma exposure in 
humans also significantly exceeded exposures which resulted in tumors in rat.  Based on these 
data, BCV is considered a potential human carcinogen.  
Additional details on toxicology studies may be found in the BCV Investigator’s Brochure. 
4.2.2. 
Pharmacokinetics of BCV 
In virally-infected subjects, plasma BCV exposure increased dose proportionally after single oral 
dose administration over the range of 100 to 200 mg in adult subjects and greater than dose 
proportional over the range of 2 to 4 mg/kg in pediatric subjects.  In multiple-dose studies in 
healthy subjects and HCT recipients with adequate renal function, neither BCV nor CDV 
concentrations accumulate in plasma following once weekly (QW) or BIW oral dosing.  
In contrast, CDV-PP concentrations accumulate intracellularly; intracellular peripheral blood 
mononuclear cell CDV-PP area under the concentration time curve from time zero (0) to time of 
last measurable concentration (AUClast) measured 2 weeks after initiation of BCV treatment was 
associated with 3- and 6-fold accumulation for the 200 mg QW and 100 mg BIW oral regimens 
compared with AUClast on Day 1.  Exposure to CDV-PP in peripheral blood mononuclear cells 
appears to trend with plasma BCV exposure. 
Following oral administration, median time of maximum plasma concentration is approximately 
4 hours for BCV and 12 hours for CDV and geometric mean elimination half-life is 
approximately 8 to 12 hours for BCV and 50 hours for CDV in plasma.  Administration of BCV 
as an oral suspension resulted in slightly higher (17%) plasma BCV exposure (as measured by 
AUC) compared with administration as a tablet.  Administration of BCV tablets (200 mg dose) 
with a low-fat meal or a moderate-fat meal (compared to the fasted state) reduced area under the 
plasma concentration time curve extrapolated to infinity (AUCinf) by 29% and 31%, respectively, 
and Cmax by 32% and 49%, respectively. 
BCV is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 
and increased plasma BCV concentrations are observed when cyclosporine, a potent inhibitor of 
these transporters, is co-administered; see Section 4.3.3 for BCV dose adjustment for subjects 
receiving concurrent cyclosporine. 
After oral administration, BCV is eliminated through metabolism via multiple pathways; CDV 
represented 5% of total plasma radioactivity.  Major metabolites, CMX103 (3-hydroxypropyl 
ester of CDV) and CMX064 (4-[3-propoxy]butanoic acid ester of CDV), have little to no 


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measurable activity against dsDNA viruses.  CDV (minor metabolite) was active against dsDNA 
viruses in vitro; however, it was 25- to 380-fold less potent than BCV.  Thus, the major 
circulating BCV metabolites and CDV are not expected to substantially contribute to antiviral 
activity observed following administration of BCV. 
4.2.2.1. 
Pharmacokinetics of BCV in Subjects with Hepatic or Renal Impairment 
Among subjects with moderate or severe hepatic impairment, there was no observed clinically 
meaningful effect on plasma BCV pharmacokinetics (PK); therefore, no dose adjustment based 
on hepatic function is recommended. 
Following oral BCV administration, plasma CDV concentrations were significantly increased in 
subjects with renal impairment, but plasma CDV Cmax values remained well below values 
observed with IV CDV.  Detailed information on plasma BCV and CDV PK in subjects with 
renal impairment is provided in the BCV Investigator’s Brochure.  Because BCV and CDV share 
the same active moiety, surveillance and assessment for known adverse effects of CDV 
(i.e., nephrotoxicity) have been part of the BCV clinical development plan.  However, due to the 
lipid conjugation of CDV which results in the improved delivery of activated drug intracellularly 
there is a significantly lower peak plasma concentration of CDV following administration of 
BCV.  That, and the inability of BCV to be effectively transported by OAT1 have significantly 
reduced CDV-like nephrotoxicity.  Due to the shared active moiety with CDV, careful 
monitoring of renal function and hydration status (when subjects are experiencing diarrhea) is 
warranted during treatment with BCV.  In cases where the glomerular filtration rate (GFR) 
decreases to < 15 mL/min, the benefit:risk proposition of continuing treatment with BCV must 
be re-evaluated in each subject, because even with dialysis there remains a risk of increased 
CDV exposure.  Given the lack of alternative therapy for treatment of AdV in the setting of end 
stage renal disease, continuation of BCV in a subject receiving dialysis remains a reasonable 
option.  Detailed information on reports of renal events is provided in the BCV Investigator’s 
Brochure. 
4.2.2.2. 
Pharmacokinetics of BCV across Age Groups 
Following oral administration of 2 mg/kg BIW, plasma BCV Cmax was consistent across the age 
groups (Table 3).  Plasma BCV AUC was lowest in children < 2 years of age and highest in 
adolescents; on average (based on comparison of geometric means), plasma BCV AUC values 
observed in each pediatric age group were within 25% of adult values. 
Table 3: 
Summary of Dose-normalized Plasma BCV PK by Age Group 
Age Group 
N 
Dose-normalized Weekly AUC 
(ng.h/mL) 
N 
Dose-normalized Cmax 
(ng/mL) 
< 2 years 
38 
3772 (3103, 4585) [65] 
37 
187 (156, 264) [98] 
2 to < 6 years 
57 
3953 (3188, 4901) [96] 
49 
172 (136, 216) [88] 
6 to < 12 years 
47 
4140 (3437, 4987) [70] 
41 
157 (152, 226) [92] 
12 to < 18 years 
33 
5313 (4177, 6759) [77] 
32 
157 (116, 199) [110] 
Adult 
104 
4771 (4214, 5401) [71] 
96 
161 (126, 176) [86] 
Note: Data presented as geometric mean (95% CI) [%CV] of post hoc PK parameters for subjects with AdV 
infection enrolled in Studies CMX001-202, CMX001-304, and CMX001-350. 


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Dose-normalized Weekly AUC: normalized to 200 mg/week for adults; normalized to 4 mg/kg/week for pediatric 
subjects weighing < 50 kg and to 200 mg/week for pediatric subjects weighing ≥ 50 kg. 
Dose-normalized Cmax: normalized to 100 mg for adults; normalized to 2 mg/kg for pediatric subjects weighing 
< 50 kg and to 100 mg for pediatric subjects weighing ≥ 50 kg subjects. 
Abbreviations: AUC = area under the plasma concentration-time curve; CI = confidence interval; %CV = percent 
coefficient of variation. 
Additional details on clinical pharmacology studies may be found in the BCV Investigator’s 
Brochure. 
4.2.3. 
Clinical Experience with BCV 
As of 21 June 2017, 1554 patients and healthy subjects have been enrolled in the BCV clinical 
development program; of these, 1239 have received one or more oral doses of BCV and 30 have 
received a single IV dose of BCV in 21 completed or closed clinical studies.  Additionally, an 
estimated 1361 patients have been treated with BCV under expanded access or compassionate 
use regulations, including a completed expanded access study for the treatment of serious or 
life-threatening infections with dsDNA viruses (CMX001-350, N = 210), one ongoing expanded 
access protocol for the treatment of serious AdV infection or disease (CMX001-351, N = 123), 
as well as under Emergency Investigational New Drug Application regulations in the United 
States (US) and under foreign equivalent regulations outside of the USA, including the current 
Named Patient Program (NPP, N = 1028).  Approximately one-half of those through the NPP are 
pediatric patients and approximately 40% of the patients have been treated in Europe. 
Fifteen of the 21 clinical studies were Phase 1/clinical pharmacology studies, which enrolled 
healthy subjects, subjects with hepatic or renal impairment, or kidney transplant and HCT 
recipients with BK virus (BKV) viruria.  Two were Phase 2 clinical studies, one of which 
evaluated the safety and efficacy of BCV for the prevention of cytomegalovirus (CMV) infection 
in adult HCT recipients (CMX001-201), while the other evaluated BCV for the pre-emption of 
AdV disease in pediatric and adult HCT recipients (CMX001-202), and two were Phase 3 
studies.  One Phase 3 study (CMX001-301) evaluated the safety and efficacy of BCV for the 
prevention of CMV infection in CMV-seropositive adult HCT recipients, while the other, an 
open-label, single arm study (CMX001-304), assessed BCV in subjects with AdV infection or 
disease.  Two other Phase 3 studies of BCV for the prevention of CMV infection in adult kidney 
transplant recipients (CMX001-303 and CMX001-307) were initiated, but terminated early in 
March 2016 following completion of a 60-day post-last dose of study drug follow-up period.  
These studies were terminated after review of the top-line results from CMX001-301 showed no 
statistically significant difference in the incidence of clinically significant CMV infection 
through Week 24 between the BCV and placebo arms (Marty 2016). 
4.2.3.1. 
Overview of Key BCV-related Toxicity: GI Events (Diarrhea) 
In preclinical and clinical studies, GI events (primarily diarrhea, but also nausea, vomiting, and 
abdominal pain) have been observed in conjunction with the use of BCV, particularly in adults at 
doses of 200 mg BIW or higher for more than 2 to 4 weeks.  In the CMX001-201 study, diarrhea, 
frequently associated with other GI symptoms, and sometimes ascribed to a presumptive 
diagnosis of GI GVHD, was reported at a higher incidence in subjects receiving BCV at doses 
> 200 mg/week.  These diarrheal events were considered dose limiting in the HCT study 
population at the 200 mg BIW dose.  While events of diarrhea in the 100 mg BIW cohort were 


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also more frequent and severe than in placebo subjects, these events only infrequently led to 
permanent discontinuation of study drug.  Approximately one-third of subjects in the 100 mg 
BIW cohort (17 of 50) temporarily interrupted study drug dosing due to a diarrheal event, but the 
vast majority were able to resume study drug dosing.  These findings led to the development of 
toxicity management guidelines which focused on the differentiation of potentially drug-related 
diarrhea from GI GVHD, and to provide safety surveillance and toxicity management strategies 
to enable early identification of and intervention (including study drug interruption, if 
appropriate) for potential drug-related toxicities, as well as resumption of study drug dosing once 
adverse events (AEs) have subsided.  Dose interruption thresholds were also established for 
treatment-emergent liver laboratory abnormalities. 
In Study CMX001-202, which evaluated BCV as treatment for asymptomatic AdV viremia, 
acute GVHD and diarrhea were the most frequently reported serious adverse events (SAEs).  
None of the cases of acute GVHD were considered by the investigators to be treatment-related, 
and treatment-emergent diarrhea (reported at a higher incidence rate for subjects randomized to 
BCV BIW [57%] than to placebo [28%]) was generally considered mild-to-moderate in severity.  
Grade 3 or higher diarrhea was reported by 14% (2 of 14) subjects in the BCV BIW treatment 
group, compared with 6% (1 of 18) subjects in the pooled placebo group; no subjects were 
permanently discontinued from therapy due to diarrhea in the BCV BIW subject group.  At the 
time, this was interpreted as being due, at least in part, to successful implementation of the 
toxicity management guidelines developed following the CMX001-201 study, as well as 
administration of BCV with a low-fat meal which had been anecdotally reported as mitigating 
the GI-related events. 
In Study CMX001-301, a randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, Phase 3 study of the safety, tolerability, and efficacy of BCV for the prevention of 
CMV in adult CMV-seropositive allogeneic HCT recipients, GI events were the most commonly 
reported AEs (61% in BCV arm vs. 36% in placebo arm) and the most common reason given for 
the interruption and/or permanent discontinuation of study drug.  Overall, more than three times 
as many subjects in the BCV arm permanently discontinued treatment early due to AEs, as 
compared with the placebo arm (26% vs. 7% placebo, p < 0.001); the most frequent AEs leading 
to permanent discontinuation of study drug in the BCV treatment arm were acute GVHD (9% vs. 
2% placebo) and GI events (overall, 10% vs. 0% placebo), led by diarrhea (7% vs. 0% placebo). 
The primary endpoint in Study CMX001-301, the incidence of clinically significant CMV 
infection through Week 24, was not met, with no difference in the incidence of clinically 
significant infection between the BCV and placebo treatment arms through Week 24 (51% BCV 
vs. 52% placebo, p = 0.805) (Marty 2016).  Higher overall and non-relapse related mortality was 
observed among BCV-treated subjects, although the difference was not statistically significant.  
These differences between arms in both CMV infections and mortality appeared to be driven by 
higher rates of reported acute GVHD (57% in BCV-treated subjects, compared with 32% in 
placebo recipients), illustrating the importance of proper management of diarrhea when the 
differential diagnosis includes acute GI GVHD, given the overlapping timing and nature of 
BCV-related diarrhea and the development of GVHD post-transplant.  This was more evident 
than in the CMX001-201 study, likely due to the earlier initiation of study drug after HCT in 
Study CMX001-301 (median Day 15), compared with initiation of study drug after engraftment 
(typically around Day 28 post-HCT) in the CMX001-201 study.  Initiation of study drug before 
the gut had fully recovered from pre-HCT chemotherapy and conditioning regimens is thought to 


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have led to the earlier development of gut-related AEs, including those labelled as acute 
GI GVHD. 
Acute GVHD events in BCV-treated subjects were more likely to be severe, assessed as serious, 
and to prove fatal in Study CMX001-301.  Closer scrutiny of the acute GVHD data after 
adjudication by an independent committee suggests that the excess acute GI GVHD in the 
BCV treatment arm was likely drug-related diarrhea mimicking the signs and symptoms of acute 
GI GVHD; in many cases, diagnosis of GVHD was based on biopsy results, and a post hoc 
independent pathology review concluded that GI biopsy was not able to discern between 
GI GVHD and BCV-related diarrhea.  Treatment of diarrhea with corticosteroids while BCV 
therapy continued (with the rationale that subjects were at even greater risk for CMV 
reactivation) resulted in continued diarrhea, which was interpreted as refractory GVHD.  
The subsequent increased steroid use in BCV recipients (median 8-fold higher cumulative use 
compared with placebo recipients through Week 24, median 5-fold higher cumulative use 
compared with placebo recipients through Week 14) and/or the addition of second-line therapies, 
including T cell-depleting antibodies and other biologics, further increased the net state of 
immunosuppression, which had a negative impact on outcomes.  Subjects with diarrhea who 
were managed more conservatively with treatment interruptions had better outcomes, including 
improved overall mortality, when compared with subjects managed less conservatively 
(i.e., continued study drug dosing in the setting of persistent or worsening diarrhea attributed to 
GI GVHD). 
In Study CMX001-304, subjects were treated with 12 weeks of BCV for AdV, and GI events, in 
particular diarrhea, were still the most commonly reported AEs, although reports of acute GVHD 
were lower than in the CMX001-301 study.  Diarrhea is a common manifestation of AdV disease 
in patients with AdV infection post HCT; further, pediatricians are less likely to aggressively 
treat presumptive GVHD in the presence of AdV viremia, as reduction of steroids and other 
immunosuppressants is typically employed.  As a result, AdV is almost always treated in favor 
of GVHD, suspected or otherwise. 
Serious events of diarrhea were reported by 21 subjects (10% of dosed subjects) in the 
CMX001-304 study.  GI events were the most frequently reported AEs that led to BCV 
discontinuation (16% adults, 5% pediatric subjects); more specifically, diarrhea prompted BCV 
discontinuation in 9% adults and 5% of pediatric subjects, followed by abdominal pain (6% 
adults vs. < 1% pediatric subjects).  Overall, more adult subjects (34%) than pediatric subjects 
(19%) discontinued treatment with BCV due to any AE. 
Based on learnings to-date, it is recommended that BCV be interrupted for treatment-emergent 
diarrhea of ≥ CTCAE (National Institutes of Health/National Cancer Institute Common 
Terminology Criteria for Adverse Events) Grade 2, with a treatment interruption of at least 
7 days (i.e., at least 6 full days off drug) and until symptoms improve to ≤ Grade 1.  In doing so, 
interruption of BCV treatment serves as both a diagnostic test and, if the diarrhea is related to 
BCV, the time off drug also allows the gut epithelium an opportunity to regenerate.  If the 
diarrhea improves, BCV may be safely reintroduced thereafter.  A dose consolidation approach 
(administering the same total weekly dose at weekly dosing intervals to allow more time between 
doses for GI mucosal regeneration) is also recommended at re-introduction of BCV.  If there is 
no improvement following interruption of BCV, the likely etiology of diarrhea is not BCV; 


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nevertheless, BCV should not be reintroduced until the diarrhea improves, regardless of the 
underlying etiology. 
In conclusion, oral administration of BCV is associated with known GI toxicity, which cannot be 
reliably differentiated from GI GVHD histopathologically or based on GI symptoms.  Though 
clinical evaluation of other organ systems also affected by GVHD, namely the skin, may assist in 
determining the most appropriate patient management strategy, treatment-emergent diarrhea of 
Grade 2 or higher severity, regardless of etiology, should prompt BCV treatment interruption for 
at least 7 days (i.e., 6 full days off drug).  Initiation of steroid therapy for GVHD should be 
delayed, if clinically appropriate, in order to assess whether symptoms improve as a result of 
BCV withdrawal.  Resumption of BCV as a consolidated QW dose is possible if symptoms 
improve. 
Further details of this and other BCV-related toxicities are provided in the BCV Investigator’s 
Brochure. 
4.3. 
Overview of Study CMX001-999 Design and Rationale 
This study is a randomized, open-label, parallel group, two-arm, multi-center assessment of BCV 
compared with SoC in high-risk (i.e., T cell-depleted) pediatric allogeneic HCT recipients with 
AdV viremia.  A virologic response-driven approach to the duration of treatment will be 
evaluated, in which subjects randomized to BCV therapy are treated until AdV viremia is 
confirmed as undetectable or until a maximum of 16 weeks of therapy, whichever occurs first.  
All subjects will be followed in the study for a total of 36 weeks post-randomization, regardless 
of treatment assignment.  Subjects will be assessed on a weekly basis through Week 16, with 
additional assessments performed at Weeks 24 and 36 post-randomization.  The data collected 
through Week 16 will comprise the primary data set for the study; hence, the primary database 
will be locked and analyzed following capture of data for all subjects through Week 16. 
4.3.1. 
Study Rationale 
Allogeneic HCT recipients are at risk of AdV infection and disease progression.  Published 
guidelines recommend screening of high-risk HCT recipients and the application of antiviral 
therapy pre-emptively before AdV disease occurs.  However, there is currently no approved 
antiviral therapy for AdV. 
BCV is an investigational antiviral which has demonstrated activity against AdV in vitro and in 
clinical investigations.  In previous studies of oral BCV for AdV infection, initiation of therapy 
early in the course of infection (when plasma viral load was less than 104 or 105 copies/mL) was 
associated with rapid clearance of viremia. 
As described previously, diarrhea is the most common AE associated with oral BCV 
administration with typical onset in pediatric subjects from 4 to 6 weeks after initiating treatment 
with BCV.  In the context of HCT, BCV-related diarrhea can mimic symptoms of GI GVHD, 
which can confuse accurate diagnosis and management of patients (Detweiler 2016).  GI toxicity 
management that was conservative (i.e., specifically withholding further BCV dosing until 
symptoms resolved) appeared to be an effective and straightforward toxicity management 
approach, and was associated with better subject outcomes in Study CMX001-301 (Marty 2016).  
As described in Section 4.2.3.1, these clinical findings have led to further refinement of the 


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subject safety monitoring and management guidance for oral BCV to promote a more 
conservative management approach with clear and mandated stopping criteria.  The assessment 
of the effectiveness of these revised guidelines as a critical component in optimally managing 
subjects is a primary objective of this study. 
Therefore, this study is designed to assess the safety and overall tolerability of oral 
administration of BCV using defined safety monitoring and management criteria (Section 8.3) 
and to assess the impact of BCV in reducing AdV viremia in HCT recipients relative to the 
current SoC.  By studying the proposed treatment paradigm and toxicity management in a 
subject population likely to benefit from treatment, a more refined approach to overall treatment 
strategies can be established. 
4.3.2. 
Rationale for Subject Population 
Pediatric patients who have received a T cell-depleted allogeneic (i.e., not autologous) HCT 
within the last 100 days and have confirmed AdV DNA detectable in the blood will be 
considered for participation in this study.  For the purposes of this study, “T cell-depleted” 
describes: 
1. Ex vivo T cell depletion via positive (e.g., CD34+ cell) selection or negative selection 
(e.g., T cell receptor α/β or CD3+ cell removal by column filtration); 
2. Serotherapy with anti-thymocyte globulin (ATG, as cumulative dose of ≥ 3 mg/kg 
rabbit-derived ATG or ≥ 50 mg/kg of equine-derived ATG) administered within 10 days 
prior to transplant or at any time post-transplant and prior to Day 1, or 
3. Serotherapy with alemtuzumab administered within 30 days prior to transplant or at any 
time post-transplant and prior to Day 1. 
These subjects are among the highest risk for AdV infection and progression to disease and are 
also among those with the highest unmet medical need. 
Among patients who have undergone HCT, there are well-defined risk factors for AdV infection 
and progression; these include younger age, allogeneic transplant, cord blood transplants, and 
T cell depletion (Chakrabarti 2002, Kampmann 2005).  These subjects are at high risk for 
developing AdV disease due to profound and persistent immunodeficiency (Tromblyn 2009) and 
in this susceptible population, the development of AdV infection associated with viremia is much 
more prevalent, severe, often disseminated, and rapidly fatal without treatment (Florescu 2012, 
Ison 2006, Lion 2014, Sandkovsky 2014). 
Published European Conference on Infections in Leukaemia (ECIL) Treatment Guidelines 
(Matthes-Martin 2012) recommend routine monitoring of pediatric patients, especially pediatric 
patients with at least one defined risk factor for AdV viremia.  Identified cases of AdV viremia 
are recommended to decrease immunosuppression where possible (e.g., in patients without 
ongoing GVHD), together with the initiation of “off-label” treatment with IV CDV.  This 
population is at especially high risk, with adenoviral clearance intrinsically linked under normal 
circumstances to T cell recovery, which typically does not occur for many months post 
allogeneic HCT.  IV CDV is reportedly less effective in patients who have not reconstituted 
effective T cell function (Hiwarkar 2017). 


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Pediatric subjects have responded to BCV therapy.  Study CMX001-304 enrolled 201 subjects 
(130 pediatric, 71 adult) with disseminated AdV disease or with asymptomatic viremia or 
localized AdV infection who were at risk for progression to disseminated AdV disease.  
Subjects were treated with BCV for 12 weeks.  In this study, pediatric subjects had improved 
clinical outcomes compared with adult subjects (all-cause mortality at Week 36 was 39% in 
pediatric subjects vs. 63% in adults).  Key differences between these two groups at baseline 
suggest that the adults who enrolled in this trial had poorer prognoses than the children 
(e.g., indication for transplantation, frequency of T cell depletion).  Additionally, the time from 
transplant to BCV initiation was longer for adults (median 94 days) than pediatric subjects 
(median 53 days), which may reflect earlier diagnosis in the setting of screening protocols that 
are common at pediatric transplant centers.  Pediatric subjects tolerated BCV better than adults 
and had longer median duration of BCV therapy (78 days vs. 38 days in adults). 
Because pediatric recipients of T cell-depleted allogeneic HCT are at very high risk for AdV 
infection and progression to serious disease, they are among the most in need of new treatment 
options, and have demonstrated reasonable tolerability and responses with BCV-based therapy.  
Accordingly, this study will focus enrollment on this population most likely to benefit from 
treatment with BCV. 
Subjects to be excluded are those with baseline comorbidities AdV who are unlikely to survive 
to Week 4, such as subjects with renal failure or a need for renal replacement therapy, those with 
pre-existing coagulopathy, sepsis requiring vasopressors, or the need for ventilator support. 
4.3.3. 
Rationale for BCV Dosage Regimen and Treatment Duration 
Subjects will receive a BCV dosage regimen based on their lowest body weight measurement 
within 30 days prior to Day 1 (to best represent dry weight) and concurrent cyclosporine use.  
Subjects not receiving concurrent cyclosporine will receive BCV at a dose of 2 mg/kg (up to a 
maximum of 100 mg) BIW.  Subjects receiving concurrent cyclosporine will receive 1.4 mg/kg 
(up to a maximum of 70 mg) BIW; the BCV dose is adjusted to account for increased exposures 
observed with cyclosporine co-administration.  See Section 8.2 for additional dosing details. 
4.3.3.1. 
Rationale for BCV Dosage Regimen 
BCV 2 mg/kg (up to 100 mg) BIW has been selected as the dosage regimen for this study.  In the 
Phase 2 AdV pre-emption study (CMX001-202), there were trends for improved antiviral effect 
and survival (through 4 weeks post-end of treatment) with BCV 2 mg/kg (up to 100 mg) BIW 
compared with BCV 4 mg/kg (up to 200 mg) QW and placebo (Grimley 2017).  In the 
subsequent open-label, single arm AdV treatment study (CMX001-304), BCV 2 mg/kg (up to 
100 mg) BIW was associated with rapid virologic response; in the subset of pediatric HCT 
recipients remaining on-study at Week 4 and Week 6 (69 and 66 of 100 enrolled, respectively), 
59% achieved undetectable plasma AdV viral load by Week 4 and 68% achieved undetectable 
plasma AdV viral load by Week 6 (Section 4.3.7).  Rapid virologic response was associated with 
improved survival in subjects with disseminated AdV disease, and there were trends for an 
association between rapid virologic response and improved survival in subjects with 
asymptomatic or localized AdV disease (Section 4.3.7.1 and Section 4.3.7.2).  Similar rapid 
virologic responses were observed with BCV 2 mg/kg BIW in the compassionate use setting 
(Hiwarkar 2017). 


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Efficacy and safety exposure-response analyses suggest that high plasma BCV exposures are not 
required for antiviral activity for AdV (Figure 1) and that lower oral doses may be associated 
with lower BCV-associated AEs (see the BCV Investigator’s Brochure for details).  Actions 
taken to minimize PK variability and avoid high plasma BCV exposures in this study include 
BCV dose reduction for subjects receiving concurrent cyclosporine to account for drug 
interaction (Section 8.6).  Overall exposure will be decreased by applying treatment only until 
AdV DNA is cleared from the plasma, as explained below. 
Figure 1: 
Relationship between Weekly Plasma BCV AUC and Achievement of 
Undetectable Plasma AdV Viral Load 
 
Abbreviations: BCV AUC = brincidofovir weekly area under plasma concentration-time curve; UND4 = 
undetectable plasma AdV viral load at Week 4 (0 = no, 1 = yes). 
4.3.3.2. 
Rationale for Virologic Response-Driven BCV Treatment Duration 
Because of the observed toxicities associated with BCV therapy (primarily GI/diarrhea and 
elevations in liver enzymes), there is the recognized need to balance potential side effects against 
potential therapeutic benefit of BCV therapy.  Because of the rapid virologic response to BCV, a 
shorter course of BCV may be adequate for the treatment of AdV, while minimizing the risk of 
GI AEs.  Therefore, subjects randomized to BCV in this study will be managed according to a 
virologic response-driven approach, in which BCV therapy is administered until AdV plasma 
viremia is confirmed to be undetectable, up to a maximum of 16 weeks, contingent on their not 
meeting pre-defined tolerability thresholds requiring interruption or discontinuation of treatment 
(Section 8.3). 
A virologic response-driven approach for BCV is supported by the rapid antiviral response 
observed in clinical trials.  In Study CMX001-304, subjects treated with BCV overall 
demonstrated rapid declines in AdV plasma viremia, typically after 1 to 4 weeks of therapy with 
a median time to undetectable AdV viremia of 12 to 22 days among pediatric subjects; clearance 
of AdV respiratory secretions and urine as well as plasma was seen in the majority of subjects 
after 4 weeks of BCV.  Pediatric subjects with lower AdV viral loads at baseline 
(< 10,000 copies/mL) cleared within a median 8 days of BCV initiation.  Among pediatric 


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subjects with AdV DNA < 5 log10 (< 100,000 copies/mL), 72% cleared within 4 weeks 
(Prasad 2017).  Furthermore, subjects with an early virologic response had better outcomes (data 
presented in Section 4.3.7).  Similar rapid virologic responses were observed with BCV among 
patients treated in the expanded access setting (Florescu 2012, Hiwarkar 2017). 
A virologic response-driven approach is well established for the treatment of infectious diseases 
during the post-transplant period.  It is the current standard practice for the pre-emptive treatment 
of CMV, a virus that targets the same at-risk populations.  For CMV disease, the choice of 
medication, i.e., (val)ganciclovir or foscarnet, as well as the duration of treatment is determined 
based on the patient’s overall status and need for treatment and the known toxicities of each of 
the medications (Boeckh 2009).  In general, antiviral therapy is continued until clearance of 
CMV from the blood, followed by continued regular monitoring for CMV DNA by polymerase 
chain reaction (PCR).  Should CMV viremia recur, pre-emptive therapy is restarted. 
Because subjects participating in this study are likely to have persistent immune compromise, 
putting them at risk for recurrence of AdV viremia, subjects will be allowed to re-initiate BCV if 
AdV viremia recurs.  Details for initiating, stopping and restarting BCV dosing are in Section 8. 
4.3.4. 
Rationale for Safety Monitoring and Toxicity Management Guidance 
Pro-active identification and management of AEs potentially associated with BCV treatment 
(e.g., diarrhea and other GI events, as well as increases in serum liver enzymes) is critical to the 
optimal dosing of BCV.  To that end, the protocol specifies close surveillance, diagnosis and 
characterization of AEs, as well as definitive thresholds for interruption, or if necessary, 
discontinuation of BCV treatment.  Thresholds for interruption have been set to promote early 
recognition and action for specified events that reach a certain severity grade (using the CTCAE 
grading scales).  In cases of BCV-related toxicity, interruption at these times is generally 
associated with improvement or resolution of symptoms while the subject is off BCV therapy, 
allowing for possible resumption of BCV.  This approach allows differentiation between 
BCV-related toxicities and other toxicities or processes (such as GVHD).  Specific safety 
monitoring and toxicity management guidelines are detailed further in Section 8.3.2. 
Critical to the success of implementing and assessing a robust safety monitoring plan is accurate 
and timely collection of relevant information.  In this study, GI symptoms will be recorded daily 
on electronic diaries (e-diaries) provided to the subjects.  The e-diaries will promote subject 
awareness and vigilance, as well as alert study staff in order that they may intervene promptly, as 
clinically appropriate.  E-diaries will prove particularly useful for monitoring subjects when they 
are outpatients.   
Finally, a Data and Safety Monitoring Board (DSMB) will be chartered for this study to 
independently oversee the safety information obtained during the conduct of this study, and will 
be chartered to recommend any changes to the management of subjects to improve their 
outcomes over the course of the study (Section 4.5). 
4.3.5. 
Rationale for Standard of Care Comparator 
In this study, BCV will be compared with local institutional standard of care (SoC).  A standard 
placebo-controlled design is not considered to be an ethical or practical option because AdV 
infection or disease can be rapidly fatal in this population.  Similarly, an active control study 
design, in which patients would be randomized to BCV or IV CDV, is problematic because CDV 


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is not approved for this indication, is not standardly administered to all patients with AdV 
infection, and is not licensed for any indication in some countries.  Furthermore, when IV CDV 
is used to treat AdV in HCT recipients, the dose, regimen and duration of treatment are not 
standardized, with regimens varying between 5 mg/kg QW to 1 mg/kg three times weekly, which 
may be modified according to patient response.  The use of pre- and post- dose IV hydration and 
the use of probenecid are also variably applied.  Finally, a significant percentage of patients with 
AdV infection have renal insufficiency, which is a noted contraindication for IV CDV 
(Mori 2003, Vistide Package Insert [Gilead Sciences 2010]).  Therefore, physician-selected SoC 
represents the optimal comparator for this study, providing an opportunity to observe the efficacy 
and safety/tolerability of oral BCV vs. usual care for this condition, for which there are no 
approved therapies. 
4.3.6. 
Rationale for Open Label Design 
Blinding a study in which subjects are randomized to either oral BCV or a SoC arm that could 
include IV CDV is prohibitively difficult.  Co-administration of probenecid is recommended to 
reduce renal toxicity (Vistide Package Insert [Gilead Sciences 2010]).  Probenecid would, 
therefore, need to be provided under double-blind, double-dummy conditions.  However, at the 
doses required, probenecid is associated with side effects, such as nausea, which would 
functionally unblind the treatment assignment.  Administration of IV CDV also typically 
requires pre- and post-dose IV hydration which would have to be administered to all subjects to 
maintain the blind.  This IV fluid load is associated with its own risks, particularly for small 
children, which raises ethical concerns for subjects randomized to oral BCV. 
For these reasons, this study will be conducted as an open-label investigation.  SoC will be 
according to local guidelines and institutional practice and may include administration of IV 
CDV, reduction in immunosuppression or other approaches not prohibited by this protocol.  
Given that the primary endpoint of the study is objective (clearance of AdV DNA from the 
plasma), biased assessment of the primary endpoint is unlikely. 
4.3.7. 
Rationale for Primary Efficacy Endpoint and Secondary Endpoints 
Powering a study for superiority on the basis of mortality was not considered ethical or feasible 
due to the large number of subjects that would need to be included.  Multiple non-mortality 
clinical outcomes were considered as potential primary endpoints (such as progression of AdV 
disease or infection) and were rejected for a variety of reasons, including: (1) lack of consensus 
definitions of AdV disease and progression; (2) multiple etiologies that can result in similar 
signs/symptoms, and (3) the reluctance to require invasive diagnostic procedures to document 
progressive AdV disease (e.g., liver biopsy to document AdV hepatitis).  For example, 
respiratory compromise can be the result of worsening AdV disease, the sequelae of the patient’s 
conditioning regimen, or another infectious etiology; and renal dysfunction can be the 
culmination of multiple nephrotoxic insults, including AdV disease, and is commonly observed 
after CDV administration as well other known nephrotoxic medications.  Gut injury is perhaps 
even more complicated with clinical, gross pathology and even histopathologic analysis unable 
to differentiate from progression of AdV disease, gut GVHD, and injury related to prolonged 
oral administration of BCV.  In contrast, a primary endpoint based on control of AdV viremia is 
considered to be both feasible and clinically relevant. 


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The primary efficacy endpoint selected for this study is the time-averaged area under the 
concentration-time curve (AAUC) for plasma AdV viremia (log10 copies/mL) through Week 16 
post-randomization.  This viral AAUC endpoint was selected based on evidence collected from 
prior BCV clinical trials and expanded access programs, as well as data from the literature 
evaluating SoC, showing that virologic response is predictive of clinical outcomes.  AdV viremia 
has been demonstrated in natural history studies to be a valid predictor of disease-related 
outcomes, with thresholds of peak viremia identified which predict significant changes in 
expected survival, thus supporting the use of AdV viremia as a surrogate that is reasonably likely 
to predict clinical benefit.  In addition, the positive impact on survival has been noted with 
reductions in AdV viral load following investigational interventions, including with adoptive 
T cells (Feucht 2015), IV CDV, and BCV (see Section 4.3.7.1 and Section 4.3.7.2). 
To illustrate the clinical relevance of this endpoint, Chimerix has analyzed the data from 
pediatric HCT subjects enrolled in Cohorts A and B in the CMX001-304 study with AdV viral 
load ≥ 1000 copies/mL at baseline who were within 100 days of transplant (n = 40).  In this 
group, 28% (11 of 40) subjects died by Week 16.  A boxplot looking at distribution of AAUC 
through Week 16 by vital status (i.e., alive or dead) at Week 16 shows that survivors had reduced 
AAUC when compared with non-survivors (t-test p = 0.11) (Figure 2). 
Figure 2: 
Study CMX001-304: AAUC through Week 16, Mortality at Week 16 
 
Similar analyses have been conducted for two retrospective patient cohorts: a historical dataset 
dating back more than 10 years from Royal Manchester Children’s Hospital in the United 
Kingdom (UK) (the “Manchester Cohort”) (Figure 3) and preliminary data from three countries 
(France, Spain, and UK) from the AdVance study (Figure 4), which is a natural history study 
sponsored by Chimerix that will explore the association of AdV viremia, response to SoC 
therapy, and clinical outcomes (including overall survival and non-relapse mortality) in a 
contemporary multicenter cohort.  The results from these two retrospective patient cohorts also 
support the correlation between the proposed endpoint (viral AAUC) and mortality under SoC 


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treatment with IV CDV (Manchester Cohort n = 24, p = 0.0032; AdVance n = 51, p = 0.007).  
(Note that a Manchester Cohort analysis looking at AAUC vs. mortality was not available in 
time to contribute; therefore, a previous analysis looking at time-averaged area under the curve 
minus baseline, or AAUCMB, is presented.) 
Figure 3: 
Manchester Cohort: AAUCMB through Week 16, Mortality at Week 16 
 
Figure 4: 
AdVance Study: AAUC through Week 16, Mortality at Week 16 
(Preliminary Data from UK, Spain, and France) 
 
A viral AAUC endpoint also provides the opportunity to correlate total viral burden with 
secondary endpoints of clinical outcomes, including all-cause and non-relapse mortality, as well 
as other clinical benefits, such as decreased progression to AdV pneumonia, and decreased 
number of days spent in the hospital or intensive care unit (ICU). 


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The study will also provide a holistic assessment of safety that includes the known side effects of 
oral BCV (GI toxicity) and IV CDV (renal injury).  Immunosuppressant therapies utilized in the 
study will be recorded to document that short course BCV therapy and updated safety 
management guidance has mitigated the overuse of steroids observed in the CMX001-301 study 
(Section 4.2.3.1).  Though it is anticipated that control of AdV replication will limit resulting 
organ damage and numerically improve survival in patients treated with oral BCV, a 
non-inferiority analysis of overall mortality at Week 16 between the BCV and SoC arms is 
included as a key secondary efficacy endpoint in order to rule out an untoward effect of BCV on 
outcomes. 
4.3.7.1. 
Study CMX001-304 
In a landmark analysis of data from Study CMX001-304, lower mortality outcomes were 
observed among subjects with early virologic response across both Cohort A (localized or 
asymptomatic AdV infection) and Cohort B (disseminated disease).  Specifically, improved 
survival was observed among pediatric subjects with an undetectable viremia result at Week 4 
(mortality 24% Cohort A and 29% Cohort B vs. 44% and 47%, respectively among 
non-responders who did not achieve undetectable AdV viremia at Week 4) (see Table 4).  
Pediatric subjects with disseminated disease (Cohort B) who achieved undetectable AdV viremia 
by Week 6 also had an improved overall survival (25% mortality vs. 54% mortality in pediatric 
subjects who did not achieve undetectable AdV viremia at Week 6).  Similar observations were 
made in adult subjects, although overall survival rates were lower. 
Table 4: 
Study CMX001-304: Early Virologic Response and Mortality Outcome 
Responder 
Definition 
Pediatrics 
Adults 
Proportion 
Respondera 
Mortality 
among 
Responders 
Mortality 
among Non-
responders 
Proportion 
Respondera 
Mortality 
among 
Responders 
Mortality 
among Non-
responders 
Cohort A (localized or asymptomatic AdV infection) 
Undetectable at 
Week 4 
17/26 (65%) 
4/17 (24%) 
4/9 (44%) 
7/13 (54%) 
3/7 (43%) 
5/6 (83%) 
Undetectable at 
Week 6 
17/25 (68%) 
5/17 (29%) 
2/8 (25%) 
8/13 (62%) 
4/8 (50%) 
4/5 (80%) 
Cohort B (disseminated AdV disease) 
Undetectable at 
Week 4 
24/43 (56%) 
7/24 (29%) 
9/19 (47%) 
9/26 (35%) 
5/9 (56%)b 
15/17 (88%) 
Undetectable at 
Week 6 
28/41 (68%) 
7/28 (25%)b 
7/13 (54%) 
10/24 (42%) 
5/10 (50%)b 
13/14 (93%) 
a Denominator reflects subjects with baseline AdV viremia still on study at Week 4 or Week 6. 
b p < 0.05 vs. non-responders, Cox model for time to death. 
Note: Cohort A total n (pediatric n, adult n):  Enrolled 65 (42, 23), Week 4: 39 (26, 13), Week 6: 38 (25, 13). 
Note: Cohort B total n (pediatric n, adult n):  Enrolled 93 (58, 35), Week 4: 69 (43, 26), Week 6: 65 (41, 24). 
4.3.7.2. 
Data from Literature 
Reports in the literature suggest that viral dynamics are correlated to risk of mortality for AdV; 
AdV infection has been established as an independent risk factor for death (Hiwarkar 2013, 


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Lion 2010, Mynarek 2014, Symeonidis 2007).  Overall survival was associated with lowest peak 
AdV viremia levels; patients with peak AdV viremia < 1000 copies/mL had an overall survival 
similar to AdV viremia-negative patients (Mynarek 2014).  In this same study, patients with peak 
AdV viremia levels > 10,000 copies/mL had poorer survival (hazard ratio=3.81; p=0.003).  
Hiwarkar and colleagues demonstrated in a retrospective cohort of 291 high-risk children 
(years 2005 to 2010) that AdV viremia was a major independent predictor of mortality (p < 0.05) 
(Hiwarkar 2013).  In this cohort, AdV reactivation caused prolonged hospitalization (p < 0.05) 
and accounted for 15% of all mortality.  Recently, Hiwarkar and colleagues have shown that 
death from disseminated adenoviral disease may be associated with failure to respond to therapy, 
as measured by cumulative viral load despite treatment with IV CDV (Hiwarkar 2017). 
Ongoing work at the Royal Manchester Children’s Hospital in the UK to explore the impact of 
AdV viremia upon outcomes has shown the clear impact of increasing AdV viremia (in spite of 
the application of pre-emptive IV CDV therapy) on increasing mortality (Figure 5). 
Figure 5: 
Relationship between AdV Viremia and Mortality (Viremia Modelled as 
Time-varying Covariate) 
 
Source: Professor Robert Wynn, Royal Manchester Children’s Hospital, unpublished data. 
Each point (“+”) on the plot represents an individual viral load measurement, plotted against its 
Martingale residual (i.e., “excess mortality”), which is defined as observed mortality minus 
expected mortality.  Observed mortality is “0” for censored observations (i.e., alive at next 
measurement or censored prior to next measurement) and “1” for events (i.e., dead prior to next 
measurement or censored).  Expected mortality is the integrated hazard obtained from a Cox 


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model with viral load included as a time-varying covariate.  A non-parametric smoothing line is 
used to show the relationship. 
Figure 6 represents a similar analysis using viremia at the time of initial diagnosis of significant 
AdV.  While the trend is less clear, even with this small sample size, there is still evidence to 
suggest that higher viremia is associated with higher mortality. 
Figure 6: 
Relationship between Baseline Viral Load and Mortality (Viral Load as Time 
of Initial Viremia > 1000 copies/mL) 
 
Source: Professor Robert Wynn, Royal Manchester Children’s Hospital, unpublished data. 
4.3.8. 
Rationale for Limiting Access to BCV for SoC Subjects to after Week 16 Post-
randomization 
While a BCV crossover option for subjects who fail to respond to SoC therapy would be 
expected to have support from physicians who have used BCV for IV CDV failures via the NPP, 
subjects who are randomized to the SoC arm in this study must remain in their assigned 
treatment arm without the option for BCV treatment through a minimum of Week 16 
post-randomization to allow for a meaningful and interpretable comparison of safety and efficacy 
between the treatment arms.  The aim of this study is to show a positive risk-benefit for BCV 
when compared with SoC-based preemptive therapy for AdV viremia in pediatric HCT 
recipients.  This will only be possible if SoC-treated subjects are not allowed to switch to BCV in 
the event of failure during the 16-week virologic response-driven treatment period.  Crossover in 
a substantial proportion of SoC-treated patients has the potential to negatively impact 
interpretation of the planned efficacy comparisons for BCV vs. SoC by decreasing the sample 
size available in the SoC arm after the switch for several of the secondary efficacy endpoints, 
including time to clearance of AdV viremia and sustained virologic response.  Similarly, early 


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switching could also potentially complicate interpretation of the safety and tolerability 
assessments of BCV vs. SoC.  Attribution of events such as SAEs and all-cause and non-relapse 
mortality in this complicated post-HCT patient population could also be more difficult.  There 
would also be the potential for significant differences in the duration of BCV vs. antiviral 
exposure in the SoC arm and follow-up times. 
4.3.9. 
PELOD Scoring 
Because the pathogenesis of AdV infection is related to lysis of cells in key organs, such as the 
lungs, liver and gut (and viral load in plasma is thought to reflect the extent of cellular lysis, 
supported by correlations between peak viral load and mortality; Heim 2011), capturing 
decreased viral burden (as viral AAUC) is highly likely to correlate with decreased organ 
damage.  Maximum pediatric logistic organ dysfunction (PELOD) score has been added as a 
validated surrogate outcome measure for severely-ill pediatric ICU patients (Leteurtre 2003).  It 
quantifies the degree of dysfunction across several organ systems (neurologic, cardiovascular, 
renal, respiratory, hematologic, and hepatic) and has been shown to correlate with mortality in 
pediatric HCT recipients (Balit 2016), thus offering an opportunity to quantify the effect of BCV 
vs. SoC in limiting the occurrence of organ dysfunction by AdV infection. 
4.3.10. 
Exploratory Biomarker Analyses 
Because early detection of BCV-related GI AEs could allow early intervention, several 
exploratory biomarkers are proposed for potential use in these patients, including citrulline as a 
marker of GI toxicity (van der Velden 2010), suppression of tumorigenicity-2 (ST2) and T cell 
immunoglobulin mucin-3 (TIM3) as markers of GVHD (McDonald 2015), and C-reactive 
protein (CRP) concentrations as a non-specific marker of inflammation (Clyne 1999).  Because 
of the unknown effect of BCV on these markers, they are considered exploratory.  Analysis of 
these biomarkers may support their use in future clinical studies of BCV. 
4.4. 
Benefit:Risk Assessment 
There is no approved therapy for the treatment of AdV infection.  The current SoC may include 
reducing immunosuppression or off-label use of IV CDV; ribavirin is not recommended by ECIL 
and is rarely used.  The efficacy of IV CDV for the treatment of AdV viremia in HCT recipients 
has not been formally established, with some reports in the literature describing high success 
rates in controlling viremia and others describing very poor response rates (Ganapathi 2016, 
Lion 2014).  The ECIL Treatment Guidelines note that while pre-emptive treatment of AdV with 
CDV has been reported in several studies, the “evidence concerning the effectiveness on 
mortality is inconsistent,” with AdV-related mortality rates varying from 23% to 50% despite 
pre-emptive treatment, and an AdV-related mortality of 18% has been reported for patients not 
receiving pre-emptive therapy (Matthes-Martin 2012). 
Hiwarkar and colleagues have recently reported their experience with oral BCV, obtained via the 
NPP (Hiwarkar 2017).  They compared virologic response amongst BCV recipients (generally 
applied in the setting of IV CDV contraindications or failure of IV CDV therapy) vs. those that 
were treated with IV CDV, as shown in Figure 7. 


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Figure 7: 
Virologic Responses after BCV or CDV Treatment in Pediatric HCT 
Recipients 
 
 
Abbreviations: ADV = adenovirus. 
Source: Hiwarkar 2017. 
Rapid virologic response in pediatric HCT recipients (defined by the authors as ≥ 2 log10 
copies/mL decline in AdV viremia at two weeks) was more common with oral BCV (13/18, 
72%) when compared with IV CDV (2/23, 9%).  Patients were treated until viremia cleared; the 
median time to clearance of viremia with BCV was 4 weeks (range: 2 to 9 weeks) compared with 
9 weeks (range: 3 to 15 weeks) with IV CDV (p < 0.005).  The rapid antiviral response reported 
in these cohorts is consistent with the responses observed in interventional clinical trials with 
BCV (see Section 4.3.7 and the BCV Investigator’s Brochure for more details).  Furthermore, the 
lymphocyte count at the time of resolution of viremia was lower in patients receiving BCV than 
for those who received CDV.  It is also noteworthy that many of the BCV patients had 
previously failed CDV. 
Figure 8 shows the lymphocyte count at the resolution of viremia with BCV (n = 15) and CDV 
(n = 8).  The median lymphocyte count at the resolution of viremia after BCV was 320 cells/μL 
and after CDV was 910 cells/μL.  Thus, the resolution of viremia occurred in the BCV group 


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despite significant lymphopenia, while resolution of viremia occurred in the CDV group when 
lymphocyte count was > 300/μL (p < 0.05).  The academic consortium also concluded that BCV 
was generally well tolerated: only 1 of 18 patients temporarily interrupted oral BCV for GI AEs, 
while renal toxicity was observed in 9 of 23 patients treated with IV CDV.  The lower GI 
toxicity may in part be attributable to the shorter courses of BCV therapy used in these cohorts. 
Figure 8: 
Lymphocyte Count at Resolution of Viremia Following Treatment with BCV 
(n = 15) or CDV (n = 8) 
 
Abbreviations: BCV = brincidofovir; CDV = cidofovir. 
Source: Hiwarkar 2017. 
The primary risk associated with IV CDV is nephrotoxicity, which can result in renal failure or 
death (De Clercq 2003, Safrin 1997, Vistide Package Insert [Gilead Sciences 2010]).  This is of 
particular concern for HCT recipients who are at increased risk of acute renal injury during the 
first 100 days post-transplant, with doubling of serum creatinine values reported in 15% to 73% 
of HCT recipients, and renal failure requiring dialysis in up to 8.5% of HCT recipients 
(Hingorani 2005, Rajpal 2013). 
Cohort studies have shown that kidney injury is associated with poorer prognosis and mortality 
in pediatric HCT patients (Bhadri 2009, Ljungman 2003, Vora 2015).  One retrospective cohort 
of pediatric patients who received IV CDV for the treatment of AdV demonstrated significant 
association of acute kidney injury (defined as ≥ 0.3 mg/dL [SI: ≥ 27 μmol/L] increase in serum 
creatinine) and mortality.  All 6 subjects who met this threshold died, whereas, all 17 subjects 
who did not meet this threshold survived (Vora 2015). 
The primary clinical risks associated with BCV therapy are GI in nature, particularly diarrhea, 
and elevations in serum aminotransferases.  The emergence of diarrhea in the early post-HCT 
period is problematic due to mimicry of the symptoms of GI GVHD (Detweiler 2016, 
Marty 2016), which led to a significantly higher use of immunosuppressants on the BCV arm 
that resulted in poor outcomes in Study CMX001-301.  Based on clinical trial experience to-date, 
the monitoring and management stopping rules for BCV therapy have been refined to include 


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clear and mandated thresholds at which BCV should be temporarily withheld and when BCV 
should be permanently discontinued, regardless of the suspected etiology of the diarrhea (see 
Section 8.3.2).  Further, a response-driven approach to shorten BCV treatment duration, 
supported by the early and rapid antiviral response observed with BCV treatment, will be 
assessed to minimize exposure and the risk of BCV toxicity by treating until AdV viremia is 
cleared (see Section 8.3). 
Safe and effective therapy for treatment of AdV is currently not available.  The BCV 
response-driven treatment strategy, combined with clear and definitive toxicity management 
guidelines, informed by clinical trial and cohort data available to-date, are intended to maximize 
potential benefit to subjects, while decreasing the risk.  As a result, the benefit:risk profile is 
considered sufficiently favorable for the continued assessment of oral BCV in pediatric 
recipients of T cell-depleted allogeneic HCT with AdV viremia.  A DSMB will be chartered to 
evaluate the PK, safety, tolerability, and mortality data by treatment arm on an ongoing basis 
throughout the conduct of the trial (Section 4.5). 
All sites will be encouraged to enroll their subjects in the “Chimerix Registry for BCV” (Study 
CMX001-333: A Prospective Observational Study for the Long-term Follow-up of Subjects 
Previously Enrolled in Selected Clinical Studies of BCV) to assess the long-term impact of 
exposure to BCV.  Both BCV and SoC recipients will be invited to participate, with the latter 
serving as a control group for the BCV treated group. 
More detailed information about the known and expected benefits and risks of BCV, including 
the Reference Safety Information, is provided in the BCV Investigator’s Brochure. 
4.5. 
Independent Safety Oversight 
4.5.1. 
Data and Safety Monitoring Board 
A DSMB will be convened according to US Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) guidelines on clinical trial data monitoring committees to monitor 
safety for this study.  The DSMB will review safety data on an ongoing and scheduled basis, as 
determined by the board and detailed in the DSMB charter.  The DSMB Chair will be allowed to 
convene ad hoc meetings, as necessary, and meetings may be convened more frequently if 
unexpected safety issues arise. 
The DSMB will define specific safety information to be provided for review at each meeting, but 
the DSMB review package will minimally include: 
• All SAEs 
• CTCAE Grade 3 or higher AEs 
• AEs resulting in permanent BCV or other anti-AdV drug discontinuation 
• AEs requiring BCV or other anti-AdV drug interruption 
• AEs requiring dose modification or consolidation of BCV or other anti-AdV drug  
• Incidence of and time to all-cause mortality and non-relapse mortality 


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• Laboratory parameters predictive of liver abnormalities (e.g., ALT, aspartate 
aminotransferase [AST], alkaline phosphatase, prothrombin time-international 
normalized ratio [PT-INR], and total and direct bilirubin), renal abnormalities 
(creatinine clearance, eGFR), and hematologic cell counts predictive of graft function 
• Observed plasma BCV concentrations (as available) 
At least two safety reviews will be conducted by the DSMB.  The first safety review will be 
performed after the first 30 subjects enrolled into the study have completed through Week 16 (or 
have died or are lost to follow-up).  The second safety review will be performed after the first 
60 subjects enrolled have completed through Week 16 (or have died or are lost to follow-up). 
The DSMB Chair will receive copies of all expedited safety reports issued for BCV at the same 
time these reports are submitted to investigators, and may decide to convene ad hoc DSMB 
meetings based on these expedited reports.  If the DSMB recommends changes to the study 
design, including changes to the protocol dosing regimens because of safety issues, regulatory 
authorities will be consulted, as appropriate, prior to implementation. 
4.5.2. 
Endpoint Adjudication Committee 
A blinded endpoint adjudication committee (EAC) will be convened to provide an independent 
assessment of whether the deaths in the study are attributable to AdV.  The EAC will adjudicate 
all deaths following procedures defined in the EAC charter.  The EAC will comprise at least two 
members who are experts in the field of AdV infection and/or HCT and not otherwise involved 
in the study. 


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5. 
STUDY OBJECTIVES AND OUTCOME MEASURES 
5.1. 
Primary Objective and Primary Efficacy Endpoint 
The primary objective of this study is to compare the safety, overall tolerability, and virologic 
response of BCV vs. SoC for the treatment of AdV infection in high-risk pediatric allogeneic 
HCT recipients.  A virologic response-driven approach to the duration of treatment will be 
evaluated, in which subjects randomized to BCV therapy are treated until AdV viremia is 
confirmed as undetectable or until a maximum of 16 weeks of therapy, whichever occurs first.  
The primary efficacy endpoint is the AAUC for AdV viremia (log10 copies/mL) from 
randomization through Week 16 post-randomization. 
5.2. 
Secondary and Exploratory Objectives 
5.2.1. 
Secondary Objectives: 
• To assess the incidence of and time to all-cause, non-relapse, and AdV-associated 
mortality in pediatric subjects treated with BCV vs. SoC 
• To assess the correlation between virologic response and clinical outcome 
• To describe the incidence of and time to virologic relapse in subjects who have 
previously achieved undetectable AdV viremia 
• To assess resolution or progression in clinical symptoms associated with AdV disease 
(i.e., resolution of all disease to no disease among subjects with probable or definitive 
AdV disease at baseline and progression from no disease to any probable or definitive 
AdV disease among asymptomatic subjects at baseline) 
• To assess the correlation between AdV hexon “serotype,” virologic response, and clinical 
outcome 
• To evaluate the emergence of viral resistance among subjects treated with BCV vs. SoC 
• To characterize plasma BCV PK profiles and evaluate the impact of covariates of interest 
on PK 
• To characterize the potential impact of plasma BCV exposure on clinical safety, 
virologic, and mortality endpoints, and to evaluate the modifying influence of various 
covariates of interest on these relationships and endpoints 
• To assess virologic response in other non-plasma biologic compartments (urine, stool, 
respiratory secretions), as well as the association between detectable AdV viral load in 
these compartments at AdV viremia clearance with subsequent AdV viremia relapse 
5.2.2. 
Exploratory Objectives 
• To assess the correlation between baseline HCT co-morbidity index and clinical 
outcome 
• To assess immunologic predictors of virologic response (all subjects) and relapse 
(among subjects with confirmed AdV clearance from plasma) 


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• To evaluate exploratory biomarkers for BCV-related GI toxicity (e.g., citrulline, ST2, 
TIM3, and C-reactive protein) 
• To assess healthcare resource utilization 
5.3. 
Secondary and Exploratory Endpoints 
5.3.1. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the incidence of all-cause mortality through Week 16. 
5.3.2. 
Other Secondary Efficacy Endpoints 
• Time to all-cause mortality through Week 16 
• Incidence of and time to all-cause mortality through Week 36 
• Incidence of and time to non-relapse mortality through Weeks 16 and 36 
• Incidence of and time to AdV-associated mortality through Weeks 16 and 36, where 
mortality is assessed by a blinded EAC 
• Proportion of subjects with undetectable AdV viremia at Weeks 2, 4, 6, 12, and 16 
• Proportion of subjects with ≥ 2-log10 decline from baseline or undetectable AdV 
viremia at Weeks 2, 4, 6, 12, and 16 
• Proportion of subjects with ≥ 1-log10 decline from baseline or undetectable AdV 
viremia at Weeks 2, 4, 6, 12, and 16 
• AAUC at Weeks 2, 4, 6, and 12 
• Incidence of and time to first confirmed undetectable AdV viremia 
• Incidence of and time to virologic relapse (subsequent confirmed AdV viremia 
≥ 1000 copies/mL) among subjects with confirmed clearance of AdV from plasma 
(overall; by AdV in urine, stool, and respiratory secretions at the time of first 
undetectable AdV viremia; and by T cell-mediated immune function [e.g., CD4+ cells 
> or ≤ 50 cells/μL] at the time of first undetectable AdV viremia) 
• Maximum PELOD score through Week 16 
• Number of days spent in the hospital through Week 16 
• Number of days spent in the ICU through Week 16 
• Emergence of AdV mutations associated with genotypic resistance and phenotypic 
resistance (the latter when possible) to BCV or CDV 
• Incidence of and time to progression to probable or definitive AdV disease (among 
asymptomatic subjects at baseline) 
• Incidence of and time to resolution of AdV clinical disease (among subjects with 
probable or definitive AdV disease at baseline) 


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• Primary model-based PK parameters, such as apparent clearance (CL/F), 
intercompartmental clearance (Q/F), volume of central compartment (Vc/F), volume 
of peripheral compartment (Vp/F), absorption rate constant (Ka), and lag time (Tlag), 
secondary PK parameters, such as Cmax and area under the plasma concentration time 
curve at steady state (AUCss), and identification of covariates that influence these PK 
parameters 
• Relationship between plasma BCV exposure, other covariates of interest, and 
− safety endpoints, including GI AEs, diarrhea, ALT, total bilirubin, and other 
safety events of interest 
− virologic endpoints including AAUC, AAUCMB, viral load change from 
baseline, and other virologic endpoints of interest, 
− all-cause and non-relapse mortality through Week 16 
5.3.3. 
Safety Endpoints 
• Incidence of treatment-emergent AEs (TEAEs), particularly those of ≥ CTCAE 
Grade 3 severity and SAEs 
• Incidence of treatment-related AEs, particularly those of ≥ CTCAE Grade 3 severity 
and SAEs 
• Incidence of AEs resulting in permanent BCV or other anti-AdV drug discontinuation 
• Incidence of AEs requiring BCV or other anti-AdV drug interruption 
• Incidence of AEs requiring dose modification or consolidation of BCV or other 
anti-AdV drug  
• Incidence of fatal AEs 
• Incidence of and time to CTCAE Grade 2 or higher diarrhea 
• Incidence of doubling, tripling, or quadrupling of baseline serum creatinine 
• Incidence of need for renal replacement therapy 
• Incidence of ≥ 1/2/3 CTCAE grade increases from baseline for safety laboratory 
parameters of interest (by visit, maximum on-treatment, last on-treatment, last 
on-study) 
• Distributions of change from baseline over time for central safety laboratory 
parameters of interest (by visit, maximum on-treatment, last on-treatment, last 
on-study) 
• Assessment of all deaths that occur through Week 16 and in follow up through 
Week 36 
5.3.4. 
Exploratory Endpoints 
• Association of HCT co-morbidity index and clinical outcomes 


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• Change from baseline in exploratory biomarker laboratory parameters (e.g., citrulline, 
ST2, TIM3, and CRP) 
• Association of exploratory biomarkers with treatment-emergent CTCAE Grade 2 
diarrhea or GI GVHD 
• Number of and reasons for emergency room (A&E) visits; number of, duration, and 
reasons for hospital admissions; number of days spent in ICU, in isolation, or 
confined to bed; other infections; receipt of and duration of relevant concomitant 
medications and therapies; type and number of certain diagnostic or therapeutic 
procedures; and provision of home healthcare through Week 16 
• Association between immune reconstitution and viral response and clinical outcome 
(e.g., based on measurement and activity of AdV-specific cytotoxic T lymphocytes 
[CTLs] and other immune reconstitution parameters) 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a randomized, open-label, multi-center study of the safety, overall tolerability, and 
antiviral activity of BCV, as compared with SoC, in pediatric recipients of a high-risk 
(i.e., T cell-depleted) allogeneic (i.e., non-autologous) HCT.  Pediatric patients with AdV 
detected in plasma within the previous 21 days and for the first time since their qualifying 
transplant may be screened for participation in the study.  Approximately 141 subjects who meet 
all applicable entry criteria will be randomized in a 2:1 ratio to receive either BCV or SoC.  The 
day of randomization is defined as Day 1.  Subjects randomized to receive BCV will be treated 
until AdV DNA is confirmed to be undetectable in plasma, up to a maximum of 16 weeks 
post-randomization.  During randomization, subjects will be stratified based on the following 
variables: last (non-baseline) screening AdV viremia (≥ 10,000 copies/mL vs. 
< 10,000 copies/mL), time from transplant to randomization (≥ 28 days vs. < 28 days), and 
T cell-depletion methodology (receipt of alemtuzumab or ex vivo depletion vs. receipt of ATG).  
Subjects randomized to the SoC arm will be managed according to local or institutional practice 
guidelines for the treatment of AdV infection.  All subjects, regardless of treatment assignment, 
will be followed in the study for a total of 36 weeks post-randomization.  Subjects will be 
assessed on a weekly basis through Week 16, with additional assessments performed at 
Weeks 24 and 36 post-randomization.  The data collected through Week 16 will comprise the 
primary data set for the study; hence, the primary database will be locked and analyzed following 
capture of data for all subjects through Week 16. 
A schema of the overall study design is provided in Figure 9. 
Figure 9: 
Study Design Schema for CMX001-999 
 
Abbreviations: AUC = area under curve; BCV = brincidofovir; BIW = twice weekly. 


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6.2. 
Schedule of Assessments/Procedures 
Subjects will be assessed at weekly intervals through the 16-week treatment period, with 
additional assessments performed at 24 and 36 weeks post-randomization as follows: 
• Assessments scheduled for Weeks 1, 2, 3, 4, 6, 8, 12, and 16 must be completed in the 
hospital or clinic (i.e., subjects who are being treated on an outpatient basis must 
return to the hospital/clinic). 
• For all other assessments (i.e., Weeks 5, 7, 9, 10, 11, 13, 14, 15, 24, and 36): 
− If a subject has detectable AdV in plasma, the subject will be required to return to 
the hospital or clinic to complete these assessments until such time as the subject 
achieves confirmed undetectable AdV viremia. 
− Thereafter, every effort should be made to have a subject return to the hospital or 
clinic for these assessments.  However, if return visits to the hospital or clinic are 
not practical (e.g., because the subject has returned to his or her home region), 
these visits may be performed through a home healthcare service provider or at a 
third-party facility that has been pre-approved by the sponsor (for the collection of 
samples including blood draws for safety and/or virologic analysis).  Telephone 
contact between the investigator and the subject or the subject’s caregiver (to 
assess AEs, AdV symptoms, etc.) will need to occur in parallel. 
− If an approved home healthcare services provider or an approved third-party 
facility capable of performing the required procedures is not available, then all 
assessments must be performed at the hospital or clinic. 
Subjects who interrupt or discontinue BCV (for any reason) will remain on the same schedule of 
assessments/procedures through completion of the final study assessment at Week 36.  Subjects 
randomized to the SoC arm will follow the same schedule of assessments/procedures through 
Week 36 as subjects randomized to BCV with the exception of BCV dosing and PK sample 
collections. 
Unless otherwise specified, all study-required laboratory assessments will be performed at the 
designated central laboratories. 
The time schedule described for weekly assessments should be followed as closely as possible.  
Allowable time windows are ± 2 days for the weekly assessments through Week 16, ± 7 days for 
the Week 24 assessment, and + 14 days for the Week 36 follow-up assessment. 
A schedule of study assessments/procedures is provided in Table 5. 
6.3. 
Number of Subjects 
Approximately 141 pediatric subjects will be randomized between the two treatment arms in a 
2:1 ratio to receive either BCV or SoC. 
 


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Table 5: 
Schedule of Study Assessments/Procedures 
Assessment/Procedure 
Screeninga 
Baselineb 
Treatment Periodc 
Follow-upc 
Study Week 
-3 to -1 
0 
1 
2 
3 
4 
5* 
6 
7* 
8 
9* 
10* 
11* 
12 
13* 
14* 
15* 
16 
24* 
36* 
Planned Study Day 
-21 to -1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
169 
253 
Written informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/review entry criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/review medical 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HCT comorbidityf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PELOD scoreg 
 
X 
<------------------------------------------------------------ X -------------------------------------------------------> 
 
 
Urine pregnancy testh 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HIV, HBV, HCV testsi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BCVj 
 
 
<------------------------------------------------------------ X -------------------------------------------------------> 
 
 
SoCk 
 
 
<------------------------------------------------------------ X -------------------------------------------------------> 
 
 
Height/length 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weightl 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma for real-time AdV 
and CMVm and storage for 
other virologic assessmentsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine, stool and respiratory 
secretion sample for AdV 
assessmento 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Stool collection for storage 
(possible future virologic 
analyses)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess clinical signs and 
symptoms for AdV disease 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Assessment/Procedure 
Screeninga 
Baselineb 
Treatment Periodc 
Follow-upc 
Study Week 
-3 to -1 
0 
1 
2 
3 
4 
5* 
6 
7* 
8 
9* 
10* 
11* 
12 
13* 
14* 
15* 
16 
24* 
36* 
Planned Study Day 
-21 to -1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
169 
253 
Clinical chemistry and 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lymphocyte (CD4+/CD8+) 
subsets and other potential 
immunologic predictors of 
virologic response 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Diarrhea symptoms 
assessment and review 
subject e-diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Perform drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical AE assessmentq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review and record all 
concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Record 
hospitalizations/procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK sample collectionr 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for exploratory 
biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Enrollment in BCV Registrys 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
a All screening procedures do not need to be completed on the same day, but all screening procedures must be completed and the results reviewed prior to 
randomization on Day 1. 
b All Baseline/Day 1 study procedures (other than post-dose PK samples) should be evaluated or obtained prior to randomization. 
c Visits marked with an asterisk (*) may be performed by a home healthcare provider or at a third party facility (where available) for subjects who are outpatients 
and who have achieved confirmed undetectable AdV viremia. 
d Written consent (or assent) must be obtained from the subject and the subject's legal guardian as required by national or local law and institutional practice. 
e A complete examination will be performed as part of the screening evaluation.  An abbreviated (symptom-driven) examination, targeted to new signs and 
symptoms, will be performed prior to randomization on Day 1 (baseline) and at Weeks 4, 8, 12, and 16. 
f HCT comorbidities present at baseline will be scored using the HCT comorbidity index assessment; see Appendix 6 for scoring table. 
g PELOD score will be captured at baseline and as a maximum (aggregate) score over the 16-week treatment period; see Appendix 7 for scoring table. 


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h For females of child-bearing potential only (or as required by local practice).  Testing will be performed locally as a urine dipstick (or as required by local 
practice).  A positive result must be confirmed with a local serum test.  BCV dosing must not initiate or continue in subjects with a positive pregnancy test. 
i Tests for HBV, HCV, and/or HIV will be performed at screening if there are no results within prior 6 months evident in patient record. 
j Subjects randomized to receive BCV will be treated until AdV DNA in plasma is confirmed to be undetectable (two consecutive plasma viral load results of 
“undetectable” as reported by the designated central virology laboratory), or up to a maximum of 16 weeks post-randomization, whichever occurs first.  After a 
subject’s first AdV plasma viral load result is reported as “undetectable” by the designated central virology laboratory, a confirmatory blood sample must be 
drawn no sooner than 7 days (6 full calendar days and no later than 14 days (13 full calendar days) after the first sample was drawn.  Once AdV viremia is 
confirmed as undetectable, BCV will be discontinued. 
k Subjects randomized to the SoC arm will be managed according to local or institutional practices and any relevant product labelling.  The decisions regarding 
SoC, including administration of therapy, dose and regimen of therapy, modification of immunosuppression, and monitoring will be the responsibility of the 
clinical team according to institutional guidelines, local practices, and applicable treatment guidelines for the management of AdV infection. 
l The lowest weight within 30 days prior to Day 1 will be used to calculate dosing weight for BCV suspension. 
m Blood will be collected during screening, on Day 1 (before randomization), and at each subsequent assessment during treatment and follow-up and sent to the 
designated central virology laboratory for real-time analysis of AdV and CMV viremia in plasma.  (Note: The plasma collected on Day 1 [baseline] will also be 
analyzed for BKV viremia.)  Subjects will be qualified for the study virologically after recording two consecutive AdV viremia results from the designated 
central virology laboratory of ≥ 1000 copies/mL and rising, with the second (confirmatory) result drawn at least 48 hours after the first sample and no more 
than 7 days prior to Day 1.  Subjects may have multiple samples sent as screening samples, but will need to have two consecutive samples drawn at least 
48 hours apart with AdV viremia ≥ 1000 copies/mL and rising as reported by the central virology laboratory to be eligible for randomization. 
n Material remaining after processing and viral quantification (i.e., plasma and/or extracted DNA) will be stored for possible future virologic/immunologic 
analyses (e.g., additional AdV or other dsDNA virus viral load analyses, analyses for other viruses, viral genotypic and/or phenotypic assessments, markers of 
AdV or other virus-specific immunity). 
o Additional samples will be collected at (1) the time that AdV viremia is confirmed as undetectable (i.e., when the confirmatory plasma sample is drawn); (2) if 
BCV is re-initiated after the recurrence of AdV viremia ≥ 1000 copies/mL (with the samples collected prior to re-initiation of BCV), or (3) at any time, on the 
basis of signs or symptoms suggestive of AdV disease.  Based on the clinical status of the subject, in consultation with the Chimerix Medical Monitor (or 
designee), investigators may request real time analysis of some or all non-plasma specimens for AdV viral load. 
p While subjects are inpatient and, where practicable, once subjects are outpatient, stool samples will be collected on Day 1 (before randomization) and each 
subsequent assessment during treatment and follow-up and stored for possible future virologic analyses (e.g., additional AdV or other dsDNA virus viral load 
analyses, analyses for other viruses, viral genotypic and/or phenotypic assessments). 
q AEs will be recorded from the time of administration of the first dose of BCV or, for subjects randomized to SoC, from the date of randomization, until the 
subject has completed the Week 16 assessment or premature discontinuation from the study.  In addition, any study procedure-related AE that occurs after 
study participants have signed the informed consent form and prior to administration of the first dose of BCV (or randomization to SoC) will be recorded as an 
AE for the purposes of this protocol.  After the Week 16 assessment, until completion of the Week 36 assessment, only SAEs will be reported to Chimerix 
Safety (or designee). 
r PK samples for analysis of plasma BCV concentrations will be drawn from subjects randomized to the BCV arm and only while they remain on therapy.  
Samples will be analyzed for both BCV and cyclosporine for subjects receiving concurrent cyclosporine.  No PK samples will be drawn from subjects 
randomized to the SoC arm. 
s Subjects will be encouraged to additionally participate in the Chimerix CMX001 Registry (Chimerix Study CMX001-333) to assess the longer-term impact of 
BCV administration on malignancy and survival.  While participation in the Registry is encouraged, subjects will not be required to participate in order to 
participate in the CMX001-999 study. 


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6.4. 
Treatment Assignment 
Subjects who meet all eligibility criteria will be randomized in a 2:1 ratio to BCV or SoC 
according to the randomization code through an automated interactive voice or web response 
system (IV/WRS). 
• Arm 1: BCV until plasma AdV viremia is confirmed undetectable, up to a maximum 
of 16 weeks.  BCV suspension will be dosed at 2 mg/kg, up to a maximum of 
100 mg, BIW, or, for subjects taking concurrent cyclosporine, at 1.4 mg/kg, up to a 
maximum of 70 mg.  Details of the dosing algorithm are in Section 8.3. 
• Arm 2: Local or institutional SoC. 
BCV and any SoC regimens will be administered open-label.  The first dose of BCV should be 
administered as soon as possible following randomization and must be administered no more 
than 24 hours after randomization. 
All subjects, regardless of treatment assignment, will be followed for a period of 36 weeks 
post-randomization. 
6.5. 
End of Study and Study Completion 
Study subjects will be considered to have completed the study after completion of the Week 36 
assessment. 
6.6. 
Enrollment in Chimerix BCV Registry (Study CMX001-333) 
All subjects (both BCV and SoC recipients) will be encouraged to additionally participate in the 
Chimerix BCV Registry (Chimerix Study CMX001-333) to assess the longer-term impact of 
BCV administration on malignancy and survival.  The BCV Registry assesses vital status and 
other outcomes over a 10-year period (at 6-month intervals for the first 3 years and annually 
thereafter).  While participation in the BCV Registry is encouraged, subjects will not be required 
to enroll in the Registry in order to participate in the current study.  As allowed by study center 
practice, subjects will be asked to consider enrollment in the BCV Registry following completion 
of the Week 16 assessment. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
All screening procedures do not need to be completed on the same day, but all screening 
procedures must be completed and the results reviewed and approved prior to randomizing a 
subject. 
Subjects who are within 100 days of the qualifying transplant may be eligible to participate in the 
study.  The screening window for this study is 21 days from first detection of AdV in plasma by 
the local virology laboratory.  Subjects will be qualified for the study virologically after 
recording two consecutive AdV viremia results from the designated central virology laboratory 
of ≥ 1000 copies/mL and rising, with the second (confirmatory) result drawn at least 48 hours 
after the first sample and no more than 7 days prior to Day 1.  (Day 1 in the study is defined as 
the day of randomization.)  In addition, the sample for serum biochemistry testing by the 
designated central safety laboratory must be drawn no more than 7 days prior to Day 1.  
Exclusionary laboratory results may be retested (including repeating AdV viremia until two 
consecutive qualifying results are obtained); exclusionary serum biochemistry results (ALT, 
AST, or total bilirubin) may be retested once.  Retest results must be available within the 
relevant screening window to be considered for eligibility, e.g., the second qualifying AdV 
viremia result must be collected within the maximum 21-day window. 
It is the investigator’s responsibility to use clinical judgment and consult appropriate treatment 
guidelines to confirm the suitability of enrolling each subject into a study assessing an orally 
administered investigational agent with consideration to the likelihood that subjects can complete 
all study assessments through Week 36. 
Subject eligibility must be assessed based on results from the designated central 
laboratories.  Any local laboratory results must be confirmed by the relevant central laboratory 
prior to randomization. 
Eligibility for each potential study subject must be reviewed and approved by the Chimerix 
Medical Monitor (or designee) prior to randomization.  See details for this procedure in the 
SRM. 
7.1. 
Subject Inclusion Criteria 
Subject must meet all of the following criteria, as applicable, to be eligible for participation in 
this study: 
1. Aged at least 2 months and less than 18-years-old on Day 1 
2. Have received a T cell-depleted allogeneic (i.e., non-autologous) HCT within the 
previous 100 days, where “T cell-depleted” describes EITHER: 
− ex vivo T cell depletion via positive selection (e.g., CD34+ cell) or negative 
selection (e.g., T cell receptor α/β or CD3+ cell removal by column filtration), OR 
− serotherapy with ATG (cumulative dose of ≥ 3 mg/kg rabbit-derived ATG or 
≥ 50 mg/kg of equine-derived ATG) administered within 10 days prior to 
transplant or at any time post-transplant and prior to Day 1 OR 
− serotherapy with alemtuzumab administered within 30 days prior to transplant or 
at any time post-transplant and prior to Day 1 


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3. First detectable AdV DNA plasma viremia since the qualifying transplant occurred 
within 21 days prior to Day 1 
4. AdV DNA plasma viremia ≥ 1000 copies/mL and rising, defined as two consecutive 
results ≥ 1000 copies/mL from the designated central virology laboratory, with the 
second result being greater than the first.  The second sample must be drawn at least 
48 hours after the first sample and no more than 7 days prior to Day 1 
5. If male of reproductive potential, willing to use an acceptable contraceptive method(s) 
throughout the duration of his participation in the study and until 90 days following last 
dose of BCV when engaging in sexual intercourse with a female partner of childbearing 
potential 
6. If female of child-bearing potential (i.e., post menarche and not surgically sterilized), 
willing to use two acceptable contraceptive methods, one of which must be a barrier 
method, throughout the duration of her participation in the study and until 90 days 
following last dose of BCV when engaging in sexual intercourse with a non-sterile male 
7. Able to provide written informed consent or assent, with legal guardian consent, as 
required by applicable local or national law and institutional practice, based on the age of 
the subject 
8. Available to participate in all required study activities for the entire duration of the study 
(i.e., inclusive of the Week 36 assessment) 
7.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria, as applicable, are not eligible to participate in 
this study.  Retesting of exclusionary laboratory results (through the designated central 
laboratory) is permitted. 
[Note: The CTCAE grading scales for diarrhea (Table 7) and the NIH staging scales for acute 
GVHD (Appendix 1) will be used to determine eligibility into this study.  Current stool output or 
volume, as appropriate, should be compared with each subject’s pre-transplant stool output or 
volume (= baseline).  Contact the Chimerix Medical Monitor (or designee) for eligibility 
questions where baseline stool output or volume is unknown or the subject’s clinical condition 
warrants consideration of an alternative baseline measure.] 
1. Any CTCAE Grade 4 diarrhea (i.e., life-threatening consequences with urgent 
intervention indicated) within 7 days prior to Day 1 
2. Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of ≥ 4 stools per day over baseline), 
unless attributed to AdV, within 7 days prior to Day 1 
3. NIH Stage 4 acute GVHD of the skin (i.e., generalized erythroderma with bullous 
formation) within 7 days prior to Day 1 
4. NIH Stage 2 or higher acute GVHD of the liver (i.e., bilirubin > 3 mg/dL 
[SI: > 51 μmol/L]) within 7 days prior to Day 1 
5. NIH Stage 2 or higher acute GVHD of the gut (i.e., diarrhea > 556 mL/m2/day, or severe 
abdominal pain with or without ileus) within 7 days prior to Day 1 


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6. Active malignancy (with the exception of non-melanoma skin cancer), including relapse 
or progression of the underlying disease for which qualifying transplant was performed 
7. Use of vasopressors within 7 days prior to Day 1 
8. PT-INR > 2x upper limit of normal reference range (ULN) in the absence of 
anticoagulation within 7 days prior to Day 1 
9. Requirement for mechanical ventilation within 7 days prior to Day 1, or sustained oxygen 
delivery for > 24 hours within 7 days prior to Day 1, or any oxygen requirement within 
48 hours prior to Day 1 
10. Estimated creatinine clearance < 30 mL/min or use of renal replacement therapy 
(e.g., hemodialysis, continuous renal replacement therapy, peritoneal dialysis) within 
7 days prior to Day 1 
11. ALT > 5x ULN, AST > 5x ULN, or total bilirubin > 3 mg/dL [SI: > 51 μmol/L] within 
7 days prior to Day 1 
12. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection within 
6 months prior to Day 1, as demonstrated by detectable HBV DNA or HCV ribonucleic 
acid (RNA) in blood, plasma, or serum.  [Note: A negative or undetectable HBV DNA or 
HCV RNA test is required at screening to confirm the absence of active infection unless 
testing was performed by the local laboratory within 6 months prior to screening.] 
13. Human immunodeficiency virus (HIV) infection as detected through any laboratory 
method (e.g., enzyme-linked immunosorbent assay, Western Blot, RNA PCR).  
[Note: Testing to confirm the absence of HIV infection is required at screening unless 
testing was performed by the local laboratory within 6 months prior to screening.] 
14. Females who are pregnant or breastfeeding or planning to become pregnant within 
90 days after their last anticipated dose of BCV 
15. Receiving or anticipated to receive medications prohibited in this protocol (see 
Section 8.6.1) 
16. Hypersensitivity (not including renal dysfunction or eye disorder) to CDV or to BCV or 
its formulation excipients 
17. Receipt of IV CDV within 48 hours prior to Day 1 
18. Previous receipt of BCV at any time 
19. Participation in another interventional clinical trial unless prior approval has been 
received from the Chimerix Medical Monitor (or designee) (see Section 8.6.1.3) 
20. Received any cell-based anti-AdV therapy within 6 weeks prior to Day 1 or previously 
received an anti-AdV vaccine at any time 
7.3. 
Subject Withdrawal Criteria 
Subjects randomized to receive BCV must be managed according to the toxicity management 
criteria described in Section 8.3.2.  Subjects randomized to the SoC arm will be managed 
according to local or institutional practice guidelines and any relevant product labelling. 


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Subjects randomized to BCV who experience any of the following criteria after initiating 
treatment in this study will be required to discontinue BCV, but will continue to be followed in 
the study: 
• Subject request to discontinue for any reason 
• TEAE that necessitates the discontinuation of BCV as described in Section 8.3.2 
• If the investigator or the subject’s primary care provider believes that participation in 
the study is no longer in the best interests of the subject 
• Pregnancy in a female subject 
Female subjects who become pregnant will be immediately discontinued from BCV, 
but will continue to be followed in the study.  See Section 11.9.5 for actions to take 
and reporting requirements for pregnancy.  Pregnancies in female subjects 
randomized to the SoC arm must be reported according to local guidelines and 
relevant product labelling. 
• Discontinuation of the study at the request of Chimerix, a regulatory agency, or the 
governing institutional review board, research ethics board, or independent ethics 
committee (collectively referred to as “ethics committee” [EC]) 
In addition, if any of the following criteria are met, BCV will be discontinued at the discretion of 
the investigator, in consultation with the Chimerix Medical Monitor (or designee): 
• Development of an exclusionary condition, including a decrease in eGFR to 
< 15 mL/min considered related to BCV, or unrelated to BCV but not being dialyzed; 
see Section 8.3.2.6 
• Treatment with, or requirement for treatment with, a prohibited or excluded 
medication; see Section 8.6.1.1 
• Subject is not compliant with the protocol (i.e., significant protocol deviation) 
All subjects who are randomized will be followed in the study through completion of the 
Week 36 assessment, including subjects who discontinue BCV for any reason and subjects who 
are randomized but not dosed in either arm.  The subjects will be managed at the discretion of 
the responsible investigator according to local SoC, but will continue to be monitored in 
accordance with the Schedule of Study Assessments/Procedures (see Section 6.2). 
Subjects who are randomized and who do not complete the study will not be replaced. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Administration of Standard of Care 
Subjects randomized to the SoC arm in this study will be managed according to local or 
institutional practice guidelines and any relevant product labelling.  The decisions regarding 
SoC, including administration of therapy, dose and regimen of therapy, modification of 
immunosuppression, and monitoring will be the responsibility of the clinical team according to 
institutional guidelines, local practices, and applicable treatment guidelines for the management 
of AdV infection.  Investigators will need to consider the clinical status of the subjects and the 
local availability of treatment options. 
8.2. 
BCV Administration 
Subjects randomized to the BCV treatment arm will receive BCV administered orally as 
10 mg/mL suspension. 
Subjects will receive a BCV dosage regimen based on their lowest body weight within 30 days 
prior to Day 1 (to best represent dry weight) and their concurrent cyclosporine use (Table 6). 
Table 6: 
BCV Dosage Regimens for Study CMX001-999 
 
Initial BCV Dose Regimen 
Consolidated BCV Dose Regimen 
Cyclosporine 
 
1.4 mg/kg (up to maximum 70 mg) BIW 
2.8 mg/kg (up to maximum 140 mg) QW 
No cyclosporine 
 
2 mg/kg (up to maximum 100 mg) BIW 
4 mg/kg (up to maximum 200 mg) QW 
Note: Dosing weight = lowest body weight (in kilograms) within 30 days prior to Day 1. 
Abbreviations: BIW = twice weekly; QW = once weekly 
As described in Section 8.6, co-administration of BCV and cyclosporine has been shown to 
increase plasma BCV exposure.  Therefore, subjects taking cyclosporine on Day 1 or who 
initiate cyclosporine at any time while taking BCV will receive a modified dose of BCV of 
1.4 mg/kg, up to a maximum of 70 mg, BIW.  Subjects who discontinue cyclosporine while 
taking BCV should increase the BCV dose to 2 mg/kg, up to a maximum of 100 mg, starting 
with the next scheduled BCV dose following the discontinuation of cyclosporine. 
Each BCV dose should be administered using an oral dosing syringe.  A 5-mL dosing syringe is 
recommended for BCV doses ≤ 50 mg, and a 10-mL dosing syringe is recommended for BCV 
doses > 50 mg.  [Note: The study drug kits DO NOT include oral dosing syringes.] 
Referring to Section 8.3.2, subjects who resume BCV therapy after a mandated interruption due 
to a TEAE will resume therapy at a consolidated QW dose of 4 mg/kg (up to a maximum of 
200 mg) QW for subjects not receiving concurrent cyclosporine, or 2.8 mg/kg (up to a maximum 
of 140 mg) QW for subjects receiving concurrent cyclosporine (Table 6). 
The dose (volume of BCV oral suspension to be administered) should be determined using the 
dosing tables provided in Appendix 2 (see Table 14 for BCV dosing of subjects receiving 
concurrent cyclosporine and Table 15 for BCV dosing of subjects not receiving concurrent 
cyclosporine). 


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See Section 9 for detailed description of appropriate storage and management of BCV. 
Whenever possible, the BCV doses should be given with food (with or within 30 minutes of 
finishing a meal) to potentially improve tolerability. 
Subjects who are unable to take medicines orally may be dosed through a nasogastric tube, 
gastrostomy tube, or other feeding tube that allows the dose to be delivered directly into the 
subject’s stomach or duodenum followed by a flush.  Intrajejunal delivery is not advised as PK 
and tolerability data are not available for this route of administration. 
Subjects should take BCV doses on the same day(s) each week.  BIW dosing will alternate at 
3- and 4-day intervals (e.g., each Monday and Thursday, or each Tuesday and Friday).  Subjects 
who have switched to QW dosing for toxicity management should take BCV on the same day 
each week (e.g., each Monday, or each Tuesday). 
8.2.1. 
Missed Doses of BCV 
When a dose of BCV is missed, subjects should take the missed dose as soon as possible, and no 
later than 2 days prior to the next scheduled dose (i.e., either the next day if the originally 
scheduled next dose is in 3 days, or within the next 2 days if the originally scheduled next dose is 
in 4 days). 
A subject who normally takes his/her BIW BCV doses on Mondays and Thursdays each week 
may take a missed Monday dose on Tuesday and a missed Thursday dose on Friday or Saturday. 
A subject taking his/her QW BCV doses every Monday should take their missed dose as soon as 
possible, but may take a missed dose as late as Thursday, which allows 4 days between the late 
dose and the next scheduled Monday dose. 
If the subject cannot take the late dose within these timeframes, it should be omitted and the 
subject should wait until the next scheduled dosing day to take his/her next dose.  The original 
dosing schedule should be resumed following any missed or omitted doses. 
It is important to capture the actual dates and times of all BCV doses and whether each dose was 
taken with food in the electronic case report form (eCRF), even if the actual dates and times 
deviate from scheduled.  E-dairies will be provided to the subjects to facilitate the collection of 
this information when outpatient. 
8.2.2. 
Vomiting After Dosing 
If a subject vomits within 30 minutes of receiving a dose of BCV, the subject may be re-dosed, 
as described in the pharmacy manual.  If the vomiting occurs more than 30 minutes after dosing, 
it should be assumed that there was significant absorption of BCV, in which case, the subject 
should not be re-dosed. 
8.3. 
BCV Dosing Algorithm and Management 
In this study, BCV will be dosed using a response-driven approach to the duration of treatment 
based on both viral response and the emergence of BCV-related toxicity.  BCV therapy will be 
continued until the virus is cleared from the plasma, unless toxicity stopping criteria are met.  
Investigators will be specifically trained on the management of BCV toxicity. 


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8.3.1. 
BCV Dosing Algorithm Based on Virologic Response 
The duration of BCV treatment will be determined using results from the designated 
central virology laboratory only. 
In the absence of toxicity requiring dose interruption, BCV will be administered BIW for up to 
16 weeks or until plasma AdV viremia is confirmed as undetectable (i.e., two consecutive 
plasma viral load results of “undetectable” as reported by the designated central virology 
laboratory).  The confirmatory sample must be drawn no sooner than 7 days (6 full calendar 
days) and no later than 14 days (13 full calendar days) after the last sample was drawn.  Once 
AdV viremia is confirmed as undetectable, BCV will be discontinued.  If AdV viremia is 
subsequently confirmed at ≥ 1000 copies/mL by the designated central virology laboratory, BCV 
dosing may be re-initiated, unless precluded by the BCV toxicity guidelines (see Section 8.4).  
See Appendix 3 for a flow chart of the BCV dosing algorithm. 
8.3.2. 
Safety Monitoring, Management, and Criteria for BCV Dose Adjustment 
Subjects with signs or symptoms suggestive of BCV-related toxicity must be managed according 
to the guidelines described in this section.  See Appendix 4 for a flow chart for BCV toxicity 
management. 
Investigators should pay particular attention to GI signs and symptoms when questioning 
subjects about adverse reactions at every study visit.  In particular, when a decrease in serum 
albumin of ≥ 0.4 g/dL (SI: ≥ 4 g/L) to < 3.0 g/dL (SI: < 30 g/L) (suggestive of protein losing 
enteropathy) is noted, investigators should intensify their questioning of subjects with respect to 
symptoms of diarrhea (recognizing that albumin loss does not discriminate between GI GVHD 
and BCV-associated diarrhea) and remind subjects to record daily diarrhea symptoms in the 
e-diary. 
All AEs should be graded in accordance with the protocol-defined scale (CTCAE scale); 
management of GI-related AEs and hepatobiliary laboratory abnormalities and BCV dosing 
guidelines are based on CTCAE severity/intensity grading, as described below.  The CTCAE 
severity grading for diarrhea, which is defined as “characterized by frequent and watery bowel 
movements,” is summarized in Table 7. 
Table 7: 
CTCAE Grading Scale for Diarrhea 
Grade 
Definition: 
Grade 1 
Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline 
Grade 2 
Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output compared to baseline 
Grade 3 
Increase of ≥ 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in 
ostomy output compared to baseline; limiting self-care ADLsa 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Results in death 
a Self-care ADLs (activities of daily living) refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
Note: Pre-transplant stool output (= baseline). 


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Educational and risk minimization materials will be used in this study to highlight the potential 
for BCV-related diarrhea in subjects who are randomized to receive BCV.  For example, a 
reference card summarizing the management of diarrhea may be left in the subject’s bedside 
notes to serve as a reminder to the physicians and nurses caring for the patient to inquire about 
diarrheal symptoms.  Also, the subject or the subject’s caregiver may be given a patient alert card 
describing the potential for BCV-related GI problems and the actions they should take if the 
subject experiences diarrhea while taking BCV.  Examples of the reference and patient alert 
cards are provided in the SRM. 
Please contact the Chimerix Medical Monitor (or designee) for questions related to toxicity 
management. 
8.3.2.1. 
Treatment-emergent Grade 1 GI-related AEs 
Dosing with BCV may continue, while closely monitoring the subject for worsening of the 
AE(s). 
Symptomatic care may be provided as needed (e.g., anti-emetics, anti-diarrheals).  Hydration 
status should be closely monitored, and liquid and electrolyte intake should be encouraged, if 
appropriate, to avoid dehydration and the downstream consequences of dehydration on renal 
function. 
Additionally: 
• Nutritional advice should be given to avoid foods and drinks that affect intestinal 
water transport (e.g., caffeine, alcohol, carminative spices, and concentrated sugar 
syrups) as well as lactose- and sucrose-containing drinks because intestinal 
inflammation may result in down-regulation of intestinal disaccharidases 
• Consideration should be given to adjusting medications associated with GI effects 
(e.g., macrolide antibiotics, magnesium sulfate salts and mycophenolate mofetil 
[MMF]) 
• Other causes of new GI symptoms should be investigated promptly and treated as 
appropriate (e.g., infections) 
For treatment-emergent Grade 1 GI AEs, aggressive treatment of GVHD should be initiated only 
if the diagnosis is confirmed at another organ site (e.g., skin or liver).  GI biopsy results, if 
endoscopy and biopsy are performed, may not differentiate GVHD from BCV-related toxicity 
because GI biopsies from subjects with BCV GI toxicity may show findings (such as crypt 
apoptotic bodies) that are also observed in biopsies from subjects with GVHD.  If the subject is 
experiencing GVHD symptoms in other organ systems (e.g., skin or liver), biopsy specimens 
from those sites may be more informative. 
In the absence of extra-intestinal involvement, starting or increasing steroids and/or other 
immunosuppressants for the treatment of GVHD should be delayed if medically feasible for 
Grade 1 diarrhea. 
If steroid treatment of GVHD cannot be delayed (and BCV is continued) in subjects with 
Grade 1 symptoms, the subject’s response to GVHD therapy should be closely monitored. 


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• If diarrhea persists for > 14 days at Grade 1, the complete subject profile should be 
reviewed, other etiologies for diarrhea considered, and if deemed appropriate, 
interruption of BCV should be considered in order to determine whether diarrhea 
resolves. 
If diarrhea worsens to Grade 2 or higher, please see Section 8.3.2.2 below. 
8.3.2.2. 
Treatment-emergent Grade 2 or Higher AEs of Diarrhea in Subjects with 
≤ Grade 1 Diarrhea at Baseline 
For subjects with CTCAE Grade 1 diarrhea or no diarrhea at baseline, BCV must be interrupted 
for treatment-emergent CTCAE Grade 2 or higher diarrhea.  This includes new-onset Grade 2 or 
higher diarrhea or progression from Grade 1 to Grade 2 or higher diarrhea, regardless of the 
cause of the diarrhea. 
In general, changing multiple therapies at the same time (e.g., interrupting BCV and starting 
steroids for new-onset or worsening GI GVHD) is not recommended.  In order to assess response 
to BCV treatment interruption, start of (or increase in) steroid therapy for new-onset or 
worsening GI GVHD should be delayed, when possible. 
• If diarrhea does not improve following ≥ 7 days interruption (at least 6 calendar days 
off BCV), a trial of steroid therapy for new-onset or worsening GI GVHD (while 
BCV is still being held) may be considered if deemed clinically appropriate. 
If diarrhea does not improve to ≤ CTCAE Grade 1 during interruption, BCV must not be 
resumed. 
If diarrhea improves to ≤ CTCAE Grade 1 in intensity, subjects may resume dosing of BCV, but 
no sooner than 7 days (i.e., at least 6 full days off drug) following the last BCV dose 
administration. 
• If resumed, BCV must be administered in a consolidated QW dose (total weekly dose 
administered once weekly, i.e., 4 mg/kg, up to a maximum of 200 mg, QW in the 
absence of concurrent cyclosporine, or 2.8 mg/kg, up to a maximum of 140 mg, QW 
for subjects taking concurrent cyclosporine) to potentially improve tolerability, as 
weekly dosing intervals allow more time for GI mucosal regeneration between doses. 
Treatment with the consolidated QW BCV dose will be continued through Week 16 
post-randomization or until confirmed undetectable AdV viremia in plasma, whichever occurs 
first. 
Recurrence of CTCAE Grade 2 or higher diarrhea after restarting BCV requires permanent 
discontinuation of BCV. 
8.3.2.3. 
Treatment-emergent Diarrhea AEs in Subjects with Grade 2 or 3 Diarrhea 
Attributed to AdV at Baseline 
For subjects with CTCAE Grade 2 or 3 diarrhea at baseline that is attributed to AdV, BCV 
dosing must be interrupted if: 
• the diarrhea has not improved to ≤ CTCAE Grade 1 after 21 days of therapy, or 


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• the subject experiences on-treatment worsening of one CTCAE grade or more at any 
time following initiation of BCV (i.e., Grade 2 worsens to ≥ Grade 3, or Grade 3 
worsens to ≥ Grade 4), regardless of the cause of the diarrhea 
If the diarrhea does not improve during interruption, BCV must not be resumed. 
If diarrhea improves to ≤ Grade 1 in intensity during interruption, subjects may resume dosing, 
but no sooner than 7 days (i.e., at least 6 full days off drug) following the last BCV dose 
administration. 
• If resumed, BCV must be administered in a consolidated QW dose (total weekly dose 
administered once weekly, i.e., 4 mg/kg, up to a maximum of 200 mg, QW in the 
absence of concurrent cyclosporine, or 2.8 mg/kg, up to a maximum of 140 mg, QW 
for subjects taking concurrent cyclosporine) to potentially improve tolerability, as 
weekly dosing intervals allow more time for GI mucosal regeneration between doses. 
Recurrence of CTCAE Grade 2 or higher diarrhea after restarting BCV requires permanent 
discontinuation of BCV. 
See Table 8 and Table 9 for tabular summaries of the interruption and discontinuation thresholds 
for managing BCV in the setting of treatment-emergent diarrhea and recommendations for the 
management/evaluation of treatment-emergent GI AEs during BCV therapy. 
Table 8: 
BCV Interruption and Discontinuation Thresholds for Treatment-emergent 
Diarrhea 
Action Taken with 
BCV 
≤ Grade 1 Diarrhea at 
Baseline 
AdV-related Grade 2 
Diarrhea at Baseline 
AdV-related Grade 3 
Diarrhea at Baseline 
Temporary 
interruption 
• 
Interrupt if diarrhea 
worsens to ≥ Grade 2 
• 
Consider interruption 
for Grade 1 diarrhea if 
persists for > 14 days, 
and starting treatment 
for acute GVHD 
• 
Interrupt if diarrhea not 
≤ Grade 1 within 21 days 
of first dose of BCV 
• 
Interrupt if diarrhea 
worsens to ≥ Grade 3 at 
any time 
• 
Interrupt if diarrhea 
not ≤ Grade 1 within 
21 days of first dose of 
BCV 
• 
Interrupt if diarrhea 
worsens to ≥ Grade 4 
at any time 
Resumption 
• 
May resume if diarrhea improves to ≤ Grade 1, and after a minimum 7-day 
interruption (i.e., at least 6 full days off BCV) 
• 
Must resume at 4 mg/kg (max 200 mg) QW or 2.8 mg/kg (max 140 mg) QW with 
concurrent cyclosporine administration 
Permanent 
discontinuation 
• 
Permanently discontinue BCV if, following resumption of dosing, diarrhea ≥ Grade 2 
returns 
Grade 1: Increase of < 4 stools per day over baseline; or mild increase in ostomy output compared to baseline 
Grade 2: Increase of 4 to 6 stools per day over baseline; or moderate increase in ostomy output compared to 
baseline 
Grade 3: Increase of ≥ 7 stools per day over baseline; incontinence; hospitalization indicated; or severe increase in 
ostomy output compared to baseline; limiting self-care activities of daily living (ADLs) 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Note: Action taken with BCV is regardless of the etiology of diarrhea. 
Note: Pre-transplant stool output (= baseline). 


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Table 9: 
Recommended Management/Evaluation of Treatment-emergent GI Adverse 
Events during BCV Therapy 
 
Grade 1 Events 
Grade 2 or Higher Events 
Action with BCV 
See Table 8 and Section 8.3.2 
Other 
interventions 
• 
Avoid food/drinks that affect water 
transport (e.g., caffeine, alcohol, 
carminative spices, concentrated sugar 
syrups) 
• 
Avoid lactose- and sucrose-containing 
products 
• 
Adjust other medications associated with 
GI effects (e.g., macrolides, magnesium, 
MMF) 
• 
Symptomatic treatment dosed as needed 
(e.g., anti-emetics, anti-diarrheals)  
• 
Avoid starting 
steroid/immunosuppressants for GVHD 
(while dosing BCV) unless Grade 1 
diarrhea persists for > 14 days 
• 
Same as for Grade 1 events 
• 
Interrupt other medications that may 
cause GI events (e.g., magnesium 
supplements, MMF) 
• 
Measure levels of immunosuppressants 
• 
Consider symptomatic treatment 
(e.g., anti-emetics, anti-diarrheals) dosed 
at regular intervals, if clinically 
appropriate 
• 
Fluid supplementation to maintain 
hydration 
Other diagnostic 
evaluations 
• 
Monitor hydration status, and supplement 
as needed 
• 
Evaluate for other infection 
• 
Evaluate for acute GVHD in other organ 
systems; consider non-GI biopsy 
• 
Same as for Grade 1 events 
NOTE: When considering new-onset or worsening GI GVHD as the cause of GI symptoms: 
• 
Co-administration of BCV and steroids for GI GVHD is not recommended 
• 
In order to assess response to BCV treatment interruption, start of (or increase in) steroid therapy for 
GI GVHD should be delayed, when possible 
If diarrhea does not improve following ≥ 7 days interruption (i.e., at least 6 full days off BCV), a trial of steroid 
therapy for new or worsening GI GVHD (while BCV is still being held) may be considered, if deemed clinically 
appropriate. 
8.3.2.4. 
Grade 2 or Higher Non-diarrheal GI AEs 
For CTCAE Grade 2 or higher non-diarrheal GI AEs (e.g., nausea, vomiting, abdominal pain) 
measures described in Section 8.3.2.1 for Grade 1 events should be considered, including 
anti-emetic medications for nausea and vomiting, if clinically appropriate.  In addition, 
investigators should remain vigilant to worsening of symptoms over time and interrupt BCV if 
non-diarrheal GI AEs reach Grade 3 in intensity.  
For one or more Grade 3 or higher non-diarrheal GI events, BCV dosing must be interrupted. 
If non-diarrheal GI AE(s) improve to ≤ Grade 2 in intensity, subjects who have interrupted BCV 
may resume dosing, but no sooner than 7 days (i.e., at least 6 full days off drug) following the 
last BCV dose administration. 
• If resumed, BCV must be administered in a consolidated QW dose (total weekly dose 
administered once weekly, i.e., 4 mg/kg QW up to a maximum of 200 mg QW in the 
absence of concurrent cyclosporine or 2.8 mg/kg up to a maximum of 140 mg QW for 


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subjects taking concurrent cyclosporine) to potentially improve tolerability, as weekly 
dosing intervals allow more time for GI mucosal regeneration between doses. 
If non-diarrheal GI AE(s) do not improve during interruption, BCV must not be resumed. 
In the event of recurrence of CTCAE Grade 3 or higher non-diarrheal GI AEs after restarting 
BCV, BCV may be allowed to continue only after discussion and agreement with the Chimerix 
Medical Monitor (or designee). 
8.3.2.5. 
Elevations in Serum Aminotransferases 
Treatment with BCV must be interrupted for at least 7 days (i.e., at least 6 full days off drug) if 
any of the following confirmed abnormalities occur: 
1. ALT or AST > 8x ULN and ≥ 2x baseline value 
2. ALT or AST > 5x ULN and ≥ 2x baseline value for more than 2 weeks 
3. ALT or AST > 3x ULN and ≥ 2x baseline value and total bilirubin > 2x ULN or 
PT-INR > 1.5x ULN 
4. ALT or AST > 3x ULN and ≥ 2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%) 
5. Total bilirubin > 3 mg/dL and ≥ 2x baseline value 
Abnormal laboratory values should be confirmed at the central laboratory as soon as feasible.  
Both initial and confirmatory values should be central laboratory values, however, if waiting for 
central laboratory confirmation is not deemed clinically appropriate, a sample can be drawn in 
parallel for local laboratory analysis, and if necessary, BCV may be interrupted pending further 
investigation of the laboratory abnormalities. 
If confirmed, increases in serum aminotransferases, as described above, should result in 
immediate interruption of BCV dosing.  The investigations to be undertaken should include, but 
are not limited to: imaging, testing for hepatotropic infections, evaluations for GVHD, review of 
other concomitant medication, and possibly liver biopsy, as appropriate.  Potential lactic acidosis 
should also be ruled out.  For subjects on azoles, interruption of dosing with azoles should be 
considered if criterion 2 above is the only one met (i.e., there is no bilirubin elevation). 
If an alternate reason for the laboratory abnormalities is identified and after the abnormalities 
decrease by ≥ 1 CTCAE grade below the grade that triggered BCV interruption listed above, 
dosing with BCV may resume, however, BCV should be administered as a consolidated weekly 
dose (i.e., 4 mg/kg, up to a maximum of 200 mg, QW in the absence of concurrent cyclosporine, 
or 2.8 mg/kg, up to a maximum of 140 mg, QW for subjects taking concurrent cyclosporine). 
Generally, subjects with persistent and significant ALT or AST elevations (> 5x ULN) should 
not resume administration of BCV unless there is clear evidence of a causal association with a 
viral disease being treated.  In these cases, continued treatment with BCV may be allowed after 
discussion and agreement with the Chimerix Medical Monitor (or designee). 
Recurrence of the liver abnormalities after reintroduction of BCV requires permanent 
discontinuation of BCV. 


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8.3.2.6. 
Decrease in Estimated Glomerular Filtration Rate to < 15 mL/min 
To be eligible for this study, subjects must have an estimated creatinine clearance of 
≥ 30 mL/min and must not have received renal replacement therapy (e.g., hemodialysis, 
continuous renal replacement therapy, or peritoneal dialysis) within 7 days prior to Day 1.  
In cases where the eGFR of a subject receiving BCV therapy decreases to < 15 mL/min, the 
benefit:risk proposition of continuing treatment with BCV must be re-evaluated for the subject, 
because even with dialysis there remains a risk of increased CDV exposure.  Given the lack of 
alternative therapy for treatment of AdV in the setting of end-stage renal disease, continuation of 
BCV in a subject receiving dialysis may be considered after consultation with the Chimerix 
Medical Monitor and/or designee. 
8.4. 
Re-initiation of BCV Dosing for AdV Viremia 
Subjects who stop BCV therapy due to confirmed undetectable AdV viremia may re-initiate 
treatment with BCV if AdV viremia is subsequently confirmed at ≥ 1000 copies/mL by the 
designated central virology laboratory.  For the purposes of re-initiating BCV therapy, 
“confirmed viremia ≥ 1000 copies/mL” is defined as two consecutive results ≥ 1000 copies/mL 
from the designated central laboratory, with the second sample drawn at least 48 hours after the 
first sample.  BCV dosing will be resumed at the same dose and dose frequency the subject was 
receiving when BCV therapy was stopped (e.g., if BCV dosing had been consolidated to QW 
administration for toxicity management purposes, the subject would resume at the QW dose).  
Subjects should be managed as per the toxicity monitoring and management criteria as outlined 
in Section 8.3.2. 
Subjects who permanently discontinue BCV for toxicity reasons are not eligible to re-initiate 
BCV dosing. 
8.5. 
Access to BCV after Week 16 
Subjects randomized to the BCV arm may receive up to 16 weeks of therapy with BCV (through 
Week 16 post-randomization).  Treatment with BCV may not be extended past Week 16 under 
this protocol.  Therefore, investigators wishing to extend or re-initiate treatment with BCV for a 
subject after Week 16 will need to request access to the drug through the local NPP (or other 
expanded access program), where available.  If applicable, approval for access to BCV through 
the NPP should be secured prior to the subject completing the Week 16 assessment to ensure 
continuity of care. 
Subjects randomized to the SoC arm are not allowed to receive BCV during the 16-week 
treatment period, whether under this protocol or through an expanded access mechanism.  After 
completion of the Week 16 assessment, investigators may request access to BCV through the 
local NPP (or other expanded access program), where available. 
8.6. 
Concomitant Medications 
All concomitant medication use (with the exception of IV fluids, vitamins, and nutritional or 
electrolyte supplements other than oral magnesium) will be captured through Week 16. 
BCV was a direct in vitro inhibitor of cytochrome (CYP)3A, 2B6 and 2C8 (IC50 5 to 17 μM); 
and CYP1A2, 2C9, 2C19, and 2D6 (IC50 22 to 28 μM) in human liver microsomes.  


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No significant induction of CYP enzymes 1A2, 2B6, and 3A by BCV was observed after 
incubation with freshly isolated and cultured human hepatocytes.  Inhibition of the drug 
transporters P-glycoprotein (P-gp, IC50 20 μM), breast cancer resistance protein (IC50 11 μM), 
and OATP1B1 (IC50 21 μM) by BCV was observed in vitro. 
BCV is not an inhibitor of either CYP3A or P-gp in vivo.  Co-administration of oral BCV 
200 mg with IV and oral midazolam, a sensitive CYP3A substrate, did not alter plasma 
midazolam PK.  Co-administration of oral BCV 200 mg with oral dabigatran etexilate 150 mg, a 
sensitive P-gp substrate, did not increase plasma total dabigatran exposure.  Therefore, BCV is 
not expected to alter concentrations of other compounds metabolized by CYP enzymes or other 
compounds transported by P-gp. 
BCV was not a substrate for P-gp or breast cancer resistance protein; however, BCV was a 
substrate for OATP1B1 and OATP1B3. 
Cyclosporine 
Co-administration of cyclosporine (a potent OATP inhibitor) increased plasma BCV exposure.  
Based on population PK analysis, plasma BCV exposure (AUCss) is increased by approximately 
43% when cyclosporine is co-administered.  The magnitude of PK interaction identified in a 
drug-drug interaction study (CMX001-120) conducted in healthy volunteers (average 4.74-fold 
increase in plasma BCV AUCinf) was greater than estimated in virally-infected patients enrolled 
in BCV clinical studies based on a Population PK analysis.  To adjust for the PK interaction 
observed in patients, subjects receiving concurrent cyclosporine in this study will receive a lower 
BCV dose (Table 6). 
Analyses conducted with data from subjects enrolled in five clinical studies showed that the 
co-administration of cyclosporine and unadjusted BCV increased the odds of elevations of total 
bilirubin ≥ Grade 2 and of moving to a higher hepatobiliary AE level (levels were “no AE,” 
“non-serious/< Grade 3,” and “serious/≥ Grade 3”).  BCV and cyclosporine had independent, not 
synergistic, effects on total bilirubin and hepatobiliary AEs in a safety exposure-response 
analysis. 
Due to the overlap of BCV and cyclosporine safety profiles, subjects receiving BCV and 
cyclosporine should be closely monitored for hepatobiliary AEs and laboratory abnormalities, as 
specified in Section 8.3.2.  Other immunosuppressant therapies (e.g., tacrolimus) should be 
considered, if clinically appropriate. 
8.6.1. 
Prohibited Medications 
8.6.1.1. 
Prohibited Medications for Subjects Randomized to Receive BCV 
The following medications are prohibited while subjects are receiving treatment with BCV. 
Cidofovir (Vistide) 
As CDV and BCV deliver the same active antiviral (CDV-PP), these two medications must not 
be administered concurrently.  Subjects who are receiving IV CDV at randomization and who 
are randomized to the BCV arm should wait at least 48 hours after administration of the last 
CDV dose (dose-to-dose) before initiating treatment with BCV. 


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Ketoconazole (non-topical formulations) and Sesamin-containing Products 
In vitro experiments have shown that BCV is a substrate of CYP4F2.  No clinical drug-drug 
interaction studies have been completed with CYP4F2 inhibitors to-date; however, given the 
in vitro data, co-administration of BCV with the potent CYP4F2 inhibitor ketoconazole 
(non-topical formulations) and sesamin-containing products is contraindicated. 
No interaction is expected with other azole antifungals, including voriconazole, fluconazole, or 
posaconazole, based on in vitro data demonstrating that these drugs do not inhibit CYP4F2 at 
relevant physiologic concentrations, providing therapeutic alternatives to treatment with 
ketoconazole. 
8.6.1.2. 
Prohibited Medications for Subjects Randomized to Receive SoC 
As described in Section 8.5, subjects randomized to SoC will not be allowed to receive treatment 
with BCV until after completion of the Week 16 assessment. 
8.6.1.3. 
Co-enrollment in Other Studies 
Co-enrollment of subjects in other interventional clinical studies involving the administration of 
an investigational drug(s) (i.e., a drug or drugs not approved by the appropriate regulatory 
authority for any indication) is not permitted while enrolled in the current study (including the 
post-treatment follow-up period). 
Co-enrollment into other interventional studies involving the administration of 
non-investigational drugs, which includes the administration of market-approved drugs being 
evaluated for non-approved indications, is permitted with the prior approval of the Chimerix 
Medical Monitor (or designee). 
Generally, co-enrollment in other studies involving conditioning regimens or graft manipulation 
in HCT recipients will be allowed as long as the study intervention and endpoint exclude impact 
on AdV infection.  In particular, for pediatric subjects, enrollment in multiple studies should take 
into consideration the blood volumes required for participation in the studies. 
8.7. 
Treatment Compliance 
While subjects are inpatients, BCV should be administered under the supervision of site 
personnel.  Once subjects are scheduled to be discharged from the hospital, the subjects and/or 
their caregivers must receive careful instructions on continued BCV dosing prior to discharge.  
Subjects and their caregivers should make every reasonable effort to adhere to the dosing 
instructions upon discharge and should alert site personnel as soon as practicable if a dose is 
missed or if dosing days need to be changed.  If preferred, investigators may require some or all 
outpatient doses to be administered under supervision.  Subjects and their caregivers will be 
required to bring the bottles of BCV (even if empty) back to the clinic at each assessment during 
the treatment period, so site personnel can complete drug accountability. 
8.7.1. 
Subject Electronic Diary 
All subjects will be provided with software and/or devices equipped with an e-diary for 
collection of study information.  Subjects or caregivers will record daily diarrhea symptoms and 
may record the dates and times of doses of BCV and whether each dose was taken with food (for 


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subjects randomized to the BCV treatment arm) in the e-diary through Week 16 (see 
Section 11.6).  While subjects are inpatients, the information may be entered in the e-diary by 
study staff. 
8.8. 
Randomization and Blinding 
All treatments will be administered under open-label conditions. 
Subjects who meet all applicable eligibility criteria will be randomized to one of two treatment 
arms (BCV or SoC) in a 2:1 ratio using an automated IV/WRS.  During randomization, subjects 
will be stratified based on the following variables: 
• last (non-baseline) screening AdV viremia (≥ 10,000 copies/mL vs. 
< 10,000 copies/mL) 
• time from transplant to randomization (≥ 28 days vs. < 28 days), and 
• T cell-depletion methodology (receipt of alemtuzumab or ex vivo depletion vs. 
receipt of ATG) 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
BCV will be administered orally as 10 mg/mL oral suspension (Table 10). 
Table 10: 
Investigational Product 
Product Name: 
Brincidofovir Oral Suspension 10 mg/mL 
Product Code: 
CMX001-P-SUS-HPI-001 
Dosage Form: 
Oral suspension 
Unit Dose: 
10 mg/mL 
Route of Administration: 
Per os (oral) 
Physical Description: 
An opaque-white to yellowish suspension in a round, 
amber bottle 
Manufacturer: 
Halo Pharma, Inc. 
30 North Jefferson Road 
Whippany, New Jersey 07981, USA 
Clinical Labelling and Shipment to Clinical Sites: 
PCI Pharma Services 
Biotec House, Central Park 
Western Avenue 
Bridgend CF31 3RT, UK 
Xerimis, Inc. 
102 Executive Drive, Suite 8 
Moorestown, New Jersey 08057, USA 
Standard of care, including CDV and other anti-AdV medications, will be administered 
according to local institutional practice. 
9.2. 
Study Drug Packaging and Labelling 
BCV 10 mg/mL oral suspension formulation is supplied as an amber polyethylene terephthalate 
bottle with a child-resistant closure with press-in bottle adaptor insert.  The suspension 
formulation is supplied in a kit containing one bottle with a 55 mL-fill volume. 
At the start of treatment, each subject randomized to BCV will be dispensed one kit according to 
the randomization number assigned to that subject by the IV/WRS.  Additional kits will be 
dispensed by the IV/WRS at future visits as additional study drug is needed. 
The kits of BCV 10 mg/mL oral suspension will be shipped to the study centers from a depot 
using a traceable courier service.  Each kit of BCV suspension will be labelled in accordance 
with applicable regulatory requirements and will include the following minimum information: 
• Chimerix protocol number (CMX001-999) 
• Sponsor name and address 
• Name of study drug and strength 
• Contents 


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• Lot number 
• Subject number line 
• Kit identification number 
• Storage conditions 
• Expiry date (if applicable) 
• Route of administration 
• Applicable caution statement according to in-country requirements 
Label information will be translated into approved in-country languages, as applicable. 
9.3. 
Study Drug Storage 
Once received at the study center, the study drug kits should be stored in a securely locked area, 
accessible only to authorized site personnel. 
The study drug kits should be stored at controlled room temperature, i.e., 15oC to 25oC (59oF to 
77oF), with excursions permitted to 30oC (86oF), and protected from freezing. 
9.4. 
Study Drug Accountability 
The investigator (or qualified designee) is responsible for ensuring adequate accountability of all 
used and unused study drug.  This includes acknowledgment of receipt of the shipment(s) of 
study drug kits (date, quantity, and condition), subject dispensing records and returned or 
destroyed study drug kits/study drug.  Dispensing records will document the dispensing of the 
kits to individual subjects (including kit number, date dispensed, and subject identifier number), 
the initials of the person(s) dispensing the study drugs, and the return and/or disposal of those 
kits (including any unused study drug returned by subjects).  Subjects will be required to bring 
their current bottle (even if empty) and e-diary to each study visit so site personnel can conduct 
drug accountability.  Subjects will be instructed not to dispose of the bottle once empty.  All 
study drug records must be maintained at the site and copies must be submitted to Chimerix at 
the end of the study. 
9.5. 
Study Drug Handling and Disposal 
After verification of the study drug records by the study monitor, all remaining study drug 
supplies should be destroyed according to directions provided in the pharmacy manual and/or 
any applicable site-specific standard operating procedures.  If necessary, unused study drug 
supplies may also be returned to the appropriate depot with prior approval from Chimerix (or its 
designee).  If unused study drug is destroyed on site, the investigator must maintain accurate 
records for all study drug destroyed.  Records must show the identification and quantity of each 
unit destroyed, the method of destruction, and person who disposed of the drug. 


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10. 
ASSESSMENT OF EFFICACY 
It is recognized that the volume of blood required for all protocol assessments may be 
constrained due to clinical or ethical considerations, e.g., taking into account subject age, weight, 
and overall clinical condition.  Consult the SRM for guidance on managing and prioritizing 
samples.  Consult the Chimerix Medical Monitor (or designee) with any questions or to discuss 
specific issues for a subject. 
10.1. 
Virologic Evaluations and Sample Collection 
Blood (plasma), urine, stool, and respiratory secretions, and other samples/specimens for 
virologic evaluations will be collected at screening, on Day 1 (before randomization), and at 
periodic intervals throughout the treatment and post-treatment periods of the study as follows: 
• Blood will be collected during screening, on Day 1 (before randomization), and at 
each subsequent assessment for real-time analysis of AdV viremia in plasma at the 
designated central virology laboratory.  These samples will also be analyzed in real 
time for CMV viremia.  The Day 1 (baseline) samples will also be analyzed for BKV 
viremia.  The testing for BKV viremia will not be performed in real-time and the 
results will not be reported to the sites. 
• Urine, stool (where available), and respiratory secretions (nasopharyngeal swab and 
bronchoalveolar lavage, if appropriate, based on symptoms) will be collected from all 
subjects on Day 1 (before randomization) and at Weeks 4, 6, 8, 12, and 16.  Samples 
will also be collected from subjects: (1) at the same time that AdV viremia is 
confirmed as undetectable (i.e., at the time the confirmatory plasma sample is drawn), 
or (2) if BCV is re-initiated after the recurrence of AdV viremia ≥ 1000 copies/mL 
(with the samples collected prior to re-initiation of BCV), as applicable.  Samples 
may also be collected at any time on the basis of signs or symptoms suggestive of 
AdV disease.  Based on the clinical status of the subject, in consultation with the 
Chimerix Medical Monitor (or designee), investigators may request real time analysis 
of some or all non-plasma specimens for AdV viral load. 
• While subjects are inpatient and, where practicable, once subjects are outpatient, stool 
samples will be collected on Day 1 (before randomization) and each subsequent 
assessment during treatment and follow-up and stored for possible virologic analyses 
(e.g., additional AdV or other dsDNA virus viral load analyses, analyses for other 
viruses, viral genotypic and/or phenotypic assessments). 
• Collected samples (blood/plasma, urine, respiratory secretions, and stool) and/or 
remaining extracted DNA will be stored for possible future virologic/immunologic 
analyses (e.g., additional AdV or other dsDNA viral load analyses, viral typing, 
retrospective analyses for other viruses, longitudinal viral genotypic and/or 
phenotypic assessments, markers of AdV- and other virus specific immunity).  See 
Section 10.1.3 for details of AdV-specific resistance testing. 
Detailed instructions for the collection, processing, storage, and shipping of samples for 
virologic analysis to the designated central virology laboratory are provided in the laboratory 
manual. 


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Samples and viral DNA extracted may be stored for a period of up to 10 years after study 
completion.  Stored samples will not be used for any other purposes than virologic/immunologic 
testing for AdV and/or other viruses of interest, and/or additional testing to measure 
concentrations of BCV and its metabolites.  No stored samples will be used for human genomic 
analyses.  Potential additional use of the samples for research purposes, not inclusive of human 
genomics, will be subject to review and approval by a central EC, as applicable. 
10.1.1. 
Quantitative Assessment of AdV and Other dsDNA Viremia 
Currently, there is no FDA-approved assay for quantitative determination of AdV viremia in 
plasma.  For this study, AdV viremia in plasma and other samples, as applicable, will be 
determined by the designated central virology laboratories using the 7500 Adenovirus 
Quantitative Real-time (PCR) Test (Viracor Eurofins Clinical Diagnostics).  The stated range of 
quantitation in human plasma is 190 to 1 x 1010 copies/mL.  The lower limit of detection (LLOD) 
is 127 copies/mL.  Thus, AdV titers from 127 to 189 copies/mL are defined as detectable, but 
below the lower limit of quantification (LLOQ). 
CMV viremia in plasma will be determined by the designated central laboratories using the 
FDA-approved and Conformité Européene-marked COBAS® AmpliPrep/COBAS® TaqMan® 
CMV Test (Roche Molecular Systems, Inc.).  The stated range of quantitation in human plasma 
is 137 to 9.1 x 106 IU/mL (or 150.7 to 1.0 x 107 copies/mL) and the LLOD is 91 IU/mL 
(or 100 copies/mL).  Thus, CMV DNA titers from 100 to 150 copies/mL are defined as 
detectable, but below the LLOQ (i.e., < 151 copies/mL after rounding). 
BKV viremia in plasma will be determined by the designated central laboratory using the 
2500 BK Virus Quantitative Real time PCR Test (Viracor Eurofins Clinical Diagnostics).  The 
stated range of quantitation in human plasma is 39 to 1 x 1010 copies/mL and the LLOD is 
26 copies/mL.  Thus, BKV titers from 26 to 39 copies/mL are defined as detectable, but below 
the LLOQ. 
10.1.2. 
Virologic Assessment at Local Laboratories 
If and when samples are collected for AdV DNA testing in a local virology laboratory, including 
any unscheduled AdV assessments performed per local SoC, samples should be collected and 
sent to the designated central virology laboratory for analysis in parallel.  Results from local 
laboratories may not be used to determine subject eligibility nor to make protocol-defined 
treatment decisions.  Results from local laboratories will not be used for data analysis. 
If local practice allows, samples should be sent to the designated central virology laboratory as 
priority over local laboratories to keep the blood draw volume for study participants as low as 
possible. 
10.1.3. 
Adenovirus Hexon Sequencing (Typing) and Resistance Analysis 
Currently, there is no approved assay for AdV typing, resistance phenotyping, or genotyping of 
AdV DNA polymerase.  AdV viral typing and resistance analyses will be performed by the 
Chimerix Virology Laboratory (Durham, North Carolina) using assays developed in-house.  
Historically, the Adenoviridae family has been subdivided into seven serotypes (A to G) based 
on antibody neutralization assays.  However, virus neutralization assays are suboptimal because 
of the lack of a full panel of hyper immune sera against every known serotype and the 


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requirement for the successful propagation of virus in cell culture.  Chimerix has adopted a 
method to determine AdV type using DNA sequencing of the hexon gene.  Because the hexon 
gene encodes the dominant epitopes recognized by neutralizing antibodies it is recognized as the 
preferred major identifier of AdV type and has the advantage of being amenable to standard 
amplification and sequencing methods (Aoki 2011). 
Stored blood (plasma) samples, or extracted DNA, will be used for AdV typing by PCR 
amplification and sequencing of the variable region of the hexon gene.  Determination of 
baseline genotype will be carried out by PCR amplification and sequencing of the AdV DNA 
polymerase gene.  The emergence of potential antiviral resistance in subjects who are virologic 
failures will be determined by genotyping the AdV polymerase gene from subjects where: 
(1) confirmed recurrence of AdV viremia ≥ 1000 copies/mL is noted subsequent to viral 
clearance; (2) confirmed increase in plasma AdV DNA by ≥ 1 log10 copies/mL after 
experiencing a ≥ 1 log10 copies/mL decrease from baseline, and (3) non-responders and/or 
subjects with detectable plasma AdV DNA at the last on-treatment measurement.  Stored 
samples may also be used for AdV viremia/viral load assessments; additional resistance analyses 
based on newly available assays, including phenotyping for resistance and deep sequencing; and 
for retrospective analyses of other dsDNA virus viremia/viral loads. 
10.2. 
Assessment of Clinical Efficacy 
Subjects will be monitored for clinical signs and symptoms of AdV disease at every visit 
throughout the study.  Investigators will be prompted to enter symptom information into the 
eCRF at each visit.  Definitions and criteria for assessing probable and definitive AdV disease 
are summarized below and in Appendix 5. 
AdV Infection: 
• AdV infection defined as positive AdV test, regardless of the biological specimen 
analyzed 
• Systemic AdV infection or viremia is defined as positive AdV PCR, virus isolation, 
or antigen detection in peripheral blood 
AdV Disease: 
• Probable AdV disease is defined as AdV infection plus symptoms and signs attributed 
to AdV without histological confirmation 
• Definitive AdV disease is defined as AdV infection plus symptoms and signs 
attributed to AdV with histological confirmation 
Disseminated AdV Disease defined as:  
• AdV disease (probable or definitive) in one or more organ systems with AdV viremia 
• AdV disease (probable or definitive) in two or more organ systems without AdV 
viremia 


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10.3. 
Healthcare Resource Utilization 
The clinical impact of treatment with BCV, as compared with SoC, on healthcare resource 
utilization will be assessed by number of and reasons for emergency room (A&E) visits; number 
of, duration, and reasons for hospital admissions (i.e., initial and subsequent hospitalizations); 
number of days spent in ICU; number of days spent in isolation; number of days confined to bed; 
other infections; receipt of and duration of relevant concomitant medications and therapies 
(e.g., transfusions, receipt of hematopoietic growth factors, anti-infective medications, and 
calcineurin inhibitors and other immunosuppressive medications of interest); type and number of 
certain diagnostic or therapeutic procedures (e.g., invasive GI procedures, such as endoscopies, 
biopsies, renal dialysis, mechanical ventilation, bladder irrigations); and provision of home 
healthcare (other than home healthcare services provided through this protocol to facilitate 
sample collection for subjects who are outpatients) through Week 16. 
10.4. 
Pharmacokinetic Assessments 
Blood samples for analysis of plasma concentrations of BCV will be drawn from all subjects 
randomized to BCV (i.e., PK samples will not be drawn from subjects randomized to the SoC 
arm). 
10.4.1. 
Blood PK Sample Collection and Analysis 
Blood samples for plasma BCV PK analysis will be collected from all subjects randomized to 
BCV on Day 1 and Week 2 (where blood volume loss limits allow).  The Week 2 PK samples 
will only be collected if the subject receives a BCV dose in Week 2, i.e., subjects who have 
permanently discontinued BCV by Week 2 or have their therapy interrupted due to toxicity 
during Week 2 will not have PK samples drawn.  In addition, the blood samples collected from 
BCV subjects who are receiving concurrent cyclosporine will be analyzed for both BCV and 
cyclosporine concentrations. 
10.4.1.1. Day 1 and Week 2 PK Sampling 
A blood sample will be collected within each of the following time windows (for a total of 5 PK 
samples) beginning on Day 1 and during Week 2. 
• First sample: Pre-dose (within 2 hours prior to BCV dose) 
• Second sample: From 1 to 2 hours after BCV dose 
• Third sample: From 3 to 5 hours after BCV dose 
• Fourth sample: From 8 to 12 hours after BCV dose 
• Fifth sample: From 24 to 48 hours after BCV dose 
If PK samples cannot be collected over the 24 to 48 hours following administration of the first 
BCV dose on Day 1, e.g., due to significant scheduling or resource issues, then the PK samples 
may be collected following administration of the second dose of BCV on Day 4. 
The following information will be captured in the eCRF: 
• Actual date and time of the last dose of BCV administered prior to collection of the 
pre-dose PK sample on Week 2 (and Day 4 if samples are not collected on Day 1) 


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• The actual date and time of the BCV dose administered on Day 1 and Week 2 after 
collection of the pre-dose PK sample 
• Actual date and time that each PK sample on Day 1 and Week 2 was collected 
Note: It is important to capture the actual dates and times for BCV dosing and each PK sampling, 
even if the actual dates and times deviate from scheduled times. 
Cyclosporine: The blood samples collected on Day 1 and Week 2 from BCV subjects who are 
receiving concurrent cyclosporine will be analyzed for both plasma BCV and whole blood 
cyclosporine concentrations.  The following additional information will need to be captured in 
the eCRF: 
• Actual date and time and the actual dose of the last dose of cyclosporine administered 
prior to collection of the pre-dose PK sample on Day 1 (or Day 4 if samples are not 
collected on Day 1) and Week 2 
• The actual date and time and the actual dose of each cyclosporine dose administered 
to the subject through Week 3 
10.4.2. 
PK Sample Analysis 
Concentrations of BCV in plasma and, where applicable, cyclosporine in whole blood will be 
determined using validated bioanalytical assays.  Concentrations of BCV metabolites may also 
be determined.  The PK samples will be shipped to a bioanalytical laboratory(ies) designated by 
Chimerix for analysis. 
Detailed instructions for the collection, processing, storage and shipping of the PK samples for 
BCV (and, where applicable, cyclosporine analysis) will be provided in a separate document. 


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11. 
ASSESSMENT OF SAFETY 
Safety monitoring procedures, including complete/targeted physical examination, vital sign 
measurements, the collection of blood and urine for clinical laboratory testing, and the recording 
of AEs, concomitant medication intake, and interventions with non-drug therapies or procedures, 
will be performed at screening, on Day 1 prior to randomization (to establish baseline), and at 
periodic intervals throughout the treatment and post-treatment periods of the study. 
11.1. 
Demographic/Medical History 
Subject demographic and baseline characteristics, including birth month and year (where allowed 
by local regulations), sex, race, ethnicity, medical history, and qualifying transplant information 
will be obtained from each subject as part of the screening evaluation. 
Medication history will include: 
• Pre-transplant induction/conditioning regimen 
• All systemic antivirals (including CDV) and immunosuppressants (including steroids) 
taken from the time of HCT to Day 1 
• All other medications taken within 30 days prior to Day 1 
The date of first positive laboratory AdV result post-HCT (by any laboratory, in any biological 
matrix) will be documented for each subject as the date of diagnosis for the current episode being 
treated (i.e., disregarding any episodes of AdV infection prior to HCT). 
Medical and medication history will be obtained from available medical records and by 
consulting with the subject.  If there is a question concerning items in the subject’s 
medical/medication history, then medical records may be requested from the subject’s primary 
care physician, if appropriate.  Any conditions in the subject’s medical history that are still 
ongoing on Day 1 should be noted. 
Qualifying transplant information will include transplant date, underlying condition(s) 
responsible for qualifying transplant, graft source (cord blood, bone marrow, peripheral blood 
stem cell), type of graft received (cord blood, matched related donor, matched unrelated donor, 
mismatched, or haploidentical), T cell depletion method (ex vivo T cell depletion via positive or 
negative selection or serotherapy [ATG or alemtuzumab]), and pre-transplant 
induction/conditioning regimen (myeloablative or reduced intensity) with the relevant 
drugs/interventions specified (e.g., ATG, alemtuzumab, total body irradiation, etc.). 
Methods of contraception, as applicable, should be documented in the source documentation.  
[Note: For the purposes of this study, acceptable forms of contraception include barrier methods 
of contraception (e.g., male or female condom, diaphragm), an intra-uterine device, or hormonal 
contraception (e.g., oral pill, implant, injection, ring, or transdermal patch).] 
11.2. 
Height and Weight 
Height (or length, as applicable) will be collected and recorded on Day 1.  Body weight will be 
collected and recorded at the screening evaluation and on Day 1 and at Week 2 to support 
analysis of PK data.  In addition, dosing weight (= lowest body weight measurement in the 
30 days prior to Day 1) will be recorded. 


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11.3. 
Physical Examination 
A complete examination will be performed as part of the screening evaluation and will include 
all body organ systems.  (Note: A full pelvic examination for females may be omitted unless 
medically indicated.)  An abbreviated (symptom-driven) examination, targeted to new signs and 
symptoms, will be performed prior to randomization on Day 1 (baseline) and at Weeks 4, 8, 12, 
and 16, to assess for any changes from previous status and review of those organ systems.  
Clinically significant abnormalities or findings that meet the definition of an AE (see 
Section 11.9.1) will be recorded on the AE eCRF module, and abnormalities present at screening 
or prior to randomization on Day 1 will be recorded as medical history.  Findings that meet the 
definition of SAE will be recorded and reported as directed in Section 11.9. 
11.4. 
HCT Comorbidities Assessment 
HCT comorbidities present at baseline will be scored using the HCT comorbidity index 
assessment (Sorror 2005) (see Appendix 6 for scoring table). 
11.5. 
PELOD Score 
Each subject’s PELOD score will be captured at baseline and as a maximum (aggregate) score 
over the 16-week treatment period; see Appendix 7 for scoring table.  For each organ system, the 
maximum (i.e., worst-case) score over the 16-week treatment period will be used to calculate an 
aggregate score for the subject. 
11.6. 
Daily Diarrhea Symptoms Assessment 
Subjects or their caregivers will use an e-diary to record daily diarrhea symptoms, capturing the 
number and consistency of stools based on the Bristol Stool Form Scale (see Appendix 8).  The 
e-diary will be reviewed with the subject and caregiver at each visit. 
11.7. 
Concomitant Medications 
All medications taken by subjects will be assessed and recorded in the eCRF at each study visit 
through Week 16, as described in Section 8.6. 
11.8. 
Laboratory Assessments 
The minimum test parameters to be evaluated are presented in Table 11. 
11.8.1. 
Hematology and Serum Biochemistry 
Blood for hematology, coagulation panel, and serum biochemistry testing will be collected as 
part of the screening evaluation, prior to randomization on Day 1 (baseline), and at each study 
visit. 
Lymphocyte subset (percent and total [absolute] CD4+ and CD8+ counts) will be performed 
prior to randomization on Day 1 (baseline) and at each study visit.  Other potential immunologic 
predictors of virologic response (e.g., AdV-specific CTLs) may be analyzed. 
Estimated GFR will be calculated and reported by the central safety laboratory based on serum 
creatinine results. 


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11.8.2. 
Urinalysis 
Samples for standard urinalysis will be collected as part of the screening evaluation, prior to 
randomization on Day 1 (baseline), and at Weeks 4, 8, 12, and 16. 
Table 11: 
Study CMX001-999: Clinical Laboratory Evaluations 
BIOCHEMISTRY PANEL 
Alanine aminotransferase (ALT [SGPT]) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST [SGOT]) 
Bilirubin (total and direct [conjugated]) 
Blood urea nitrogen (BUN) 
Calcium 
Creatine phosphokinase (CPK) 
Creatinine 
Electrolyte Panel (Na+, K+, Cl-, and HCO3 [or CO2]) 
Gamma-glutamyltransferase (GGT) 
Globulin, total 
Glucose 
Lactate dehydrogenase (LDH) 
Lipase 
Phosphate 
Protein (total) 
Uric acid 
 
URINALYSIS PANEL 
Albumin (microalbumin) 
Blood* 
Glucose 
Leukocytes (leukocyte esterase)* 
Protein 
*Reflex to microscopic analysis if blood or leukocytes are 
present 
HAEMATOLOGY PANEL 
Hematocrit 
Hemoglobin 
Mean cell hemoglobin (MCH) 
Mean cell hemoglobin concentration (MCHC) 
Mean cell volume (MCV) 
Platelet count (PLT) 
Red blood count (RBC) 
RBC morphology (reticulocytes, schistocytes, etc.) 
White blood count (WBC) with differential (percent 
and absolute) 
Lymphocyte subset (percent and total [absolute] 
CD4+ and CD8+) 
 
MISCELLANEOUS TESTS 
Prothrombin time-international normalized ratio 
(PT-INR) 
Pregnancy Test 
HBV DNA, HCV RNA, HIV RNAa 
Samples for exploratory biomarker analysis for 
BCV-related toxicity (e.g., citrulline, ST2, TIM3, and 
CRP) 
Immunologic predictors of virologic response 
(e.g., AdV-specific CTLs) 
a If documented results within 6 months prior to Day 1 are not available 
11.8.3. 
Pregnancy Screen 
Urine screens for pregnancy in female subjects of childbearing potential will be performed as 
part of the screening evaluation, prior to randomization on Day 1 (baseline), and at Weeks 4, 8, 
12, and 16 (or as required by standard site practice).  The central safety laboratory will provide 
urine pregnancy test kits for use at each site, although, if preferred, the site may use testing 
protocols specified by standard site practice. 


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11.8.4. 
Biomarker Analysis 
Blood will be collected for exploratory biomarker analysis (e.g., citrulline, ST2, TIM3, and CRP) 
prior to randomization on Day 1 (baseline) and at each study visit through Week 16.  Samples 
will be stored for future analyses. 
11.9. 
Adverse and Serious Adverse Events 
11.9.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease (new or exacerbated), 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
AEs will be recorded from the time of administration of the first dose of BCV or, for subjects 
randomized to SoC, from the date of randomization, until the subject has completed the Week 16 
assessment or premature discontinuation from the study.  In addition, any study procedure-
related AE that occurs after study participants have signed the informed consent form (ICF) and 
prior to administration of the first dose of BCV (or randomization to SoC) will be recorded as an 
AE for the purposes of this protocol.  After the Week 16 assessment, and until completion of the 
Week 36 assessment, only SAEs, regardless of treatment arm or relatedness, will be recorded 
and reported to Chimerix Safety (or designee). 
Disease-specific signs and symptoms (including clinical laboratory abnormalities) that were 
ongoing before administration of the first dose of BCV (or randomization to SoC) should not be 
considered AEs unless they worsen (i.e., increase in frequency or severity by at least one 
CTCAE grade) after administration of the first BCV dose (or randomization to SoC).  In 
addition, unless fatal, AEs related to AdV infection (including viremia or viral load in other body 
fluids/compartments) or AdV disease do not need to be reported as AEs or SAEs for the 
purposes of this study; these events will be captured as part of the endpoints for the study. 
In addition, the following will NOT be considered AEs for the purposes of this study: 
1. Medical or surgical procedures (e.g., surgery, endoscopy, transfusion); the condition that 
requires the procedure is the AE 
2. Situations where an untoward medical occurrence had not occurred (e.g., hospitalization 
for elective surgery or social and/or convenience admissions) 
3. Overdose of BCV or concomitant medication without any signs or symptoms, unless the 
subject was hospitalized for observation 
4. Uncomplicated pregnancy 
5. An induced elective abortion to terminate a pregnancy without medical reason 
Subjects experiencing clinically significant AEs must be monitored periodically until symptoms 
subside or until there is a satisfactory explanation for the AE, whichever is later.  Additionally, 
clinically significant abnormal laboratory values should be monitored periodically using central 


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laboratory results until the abnormality resolves, returns to baseline levels, or is otherwise 
explained. 
11.9.2. 
Definition of Serious Adverse Event 
An SAE is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening (subject at immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in congenital anomaly/birth defect 
• Results in a persistent or significant disability or incapacity 
Important medical events that may not result in death, be life-threatening, or require/prolong 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Unless fatal, SAEs related to AdV infection or AdV disease 
do not need to be reported as SAEs for the purposes of this study; these events will be captured 
as part of the endpoints for the study. 
11.9.3. 
Recording Adverse Events 
AEs spontaneously reported by the subject, in response to an open question from study personnel 
and/or revealed by observation will be recorded during the study.  For each AE, the investigator 
will evaluate and report the onset date, resolution date, intensity (severity), causality (relatedness 
to BCV or other anti-AdV drug, as applicable), action taken (with BCV or other anti-AdV drug 
as well as other action taken), seriousness, outcome (if applicable), and whether it caused the 
subject to discontinue BCV or other anti-AdV drug. 
All AEs and SAEs should be recorded on the appropriate AE module of the eCRF.  The intensity 
(severity) of all AEs will be graded according to the NIH/NCI CTCAE grading scales.  The 
CTCAE scales provide unique clinical descriptions of severity for each AE based on the 
following general guideline: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL (see below) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLs 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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A copy of the full NIH/NCI CTCAE grading tables is provided in the SRM. 
Laboratory abnormalities are usually not recorded as AEs or SAEs.  However, laboratory 
abnormalities independent of the underlying medical condition that require medical or surgical 
intervention or lead to study drug interruption or discontinuation should be recorded as an AE, as 
well as an SAE, if applicable.  In addition, laboratory or other abnormal assessments 
(e.g., electrocardiogram, X-rays, or vital signs measurements) that are associated with signs 
and/or symptoms may be recorded as an AE or SAE if they meet the definitions described in 
Section 11.9.1 or Section 11.9.2, respectively.  The AE term should be reported in standard 
medical terminology whenever possible.  If a laboratory abnormality is part of a syndrome, the 
syndrome or diagnosis should be recorded as the AE, not the laboratory result (e.g., record 
anemia, not decreased hemoglobin as the AE).  For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the context of 
the underlying condition; this may or may not be in agreement with the grading of the numeric 
laboratory abnormality, e.g., anemia may be assessed as Grade 1 (mild) though the recorded 
hemoglobin falls within the range for a Grade 2 (moderate) value. 
11.9.4. 
Relationship to BCV or Other Anti-AdV Medication 
An investigator who is qualified in medicine must make the determination of relationship to 
BCV or other anti-AdV medication for each AE.  The investigator should decide whether, in his 
or her medical judgment, there is a reasonable possibility that the event may have been caused by 
BCV or other anti-AdV medication.  If no valid reason exists for suggesting a relationship, then 
the AE should be classified as “not related.”  If there is any valid reason, even if undetermined, 
for suspecting a possible cause-and-effect relationship between BCV or the other anti-AdV 
medication and the occurrence of the AE, then the AE should be considered “related.”   
The relationship to BCV or other anti-AdV medication should be assessed using clinical 
judgment and the following definitions: 
“Related”: A temporal relationship exists between the AE onset and administration of BCV 
or other anti-AdV medication that cannot be readily explained by the subject’s clinical state 
or concomitant therapies.  Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions or AE profile of BCV or 
other anti-AdV medication.  In case of cessation or reduction of the dose, the AE may abate 
or resolve and reappear upon re-challenge. 
“Not Related”: Evidence exists that the AE has an etiology other than BCV or other anti-
AdV medication.  For SAEs, an alternative causality must be provided (e.g., pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
Any medication(s), including those administered in the SoC arm, that are considered to have 
caused or contributed to a SAE must be recorded as suspect medication(s) on the SAE form.  
Additional instructions for completing the SAE form are provided in the SRM. 
11.9.5. 
Occurrence of Pregnancy and Reporting 
If a subject suspects that she is pregnant, a urine test will be performed at the site.  If the urine 
test is positive, BCV will be interrupted pending the results of a confirmatory blood/serum test.  
If the pregnancy is confirmed with a positive blood/serum test, then the subject will be 


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permanently discontinued from BCV, but should remain in the study and complete all remaining 
study assessments (with the exception of drug dosing and PK assessments), where possible.  If 
the female partner of a male subject becomes pregnant, the investigator will contact the Chimerix 
Medical Monitor (or designee) to discuss the most appropriate course of action, up to and 
including withdrawal of BCV. 
Should a pregnancy occur, including in the female partner of a male subject, it must be reported 
and recorded on a pregnancy report form.  However, pregnancy is not regarded as an AE for the 
purposes of this protocol, unless there is a suspicion that the study drug may have interfered with 
the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (i.e., spontaneous miscarriage, elective termination, normal birth 
or congenital abnormality) in female subjects and female partners of male subjects must be 
followed up and documented to the extent possible, even if the subject was discontinued from the 
study, provided appropriate consent is obtained from the pregnant subject or female partner.  All 
reports of congenital abnormalities/birth defects are to be considered SAEs.  Spontaneous 
miscarriages should also be reported and handled as SAEs.  Elective abortions without 
complications will not be regarded as AEs. 
Additional details regarding the reporting of pregnancies is provided in the SRM. 
11.9.6. 
Reporting Serious Adverse Events 
All SAEs must be recorded from the time of administration of the first dose of BCV (or the date 
of randomization for subjects randomized to SoC) until completion of the Week 36 assessment.  
In addition, any SAE that is considered to be related to BCV and discovered by the investigator 
at any time after the subject has completed the study should also be reported.  Study 
procedure-related SAE that occurs after a study participant has signed the ICF and prior to 
administration of the first dose of BCV (or randomization) should also be recorded as an SAE for 
the purposes of this protocol. 
All SAEs should be reported to Chimerix Safety (or designee).  The investigator should complete 
and forward the study-specific SAE Report Form to Chimerix Safety (or designee) according to 
the specific instructions provided in the SRM.  SAEs must be reported within 24 hours of 
learning of the event.  Additional follow-up information, if required or available, should be 
detailed on a follow-up SAE Report Form to Chimerix Safety (or designee) within 1 business 
day of receipt of the information, or as instructed by Chimerix Safety (or designee).  Responses 
to SAE queries should be provided to Chimerix Safety (or designee) within 1 business day of 
obtaining the information.  The additional information, including any responses to SAE queries, 
and any follow-up SAE Report Forms should be placed with the original SAE information and 
kept within the appropriate section of the study file.  More detailed information on reporting 
SAEs to Chimerix Safety (or designee) (including contact information) is provided in the SRM. 
Chimerix (or its designee) is responsible for notifying the relevant regulatory authority(ies) of 
certain events.  It is the investigator’s responsibility to notify the relevant EC of all SAEs that 
occur at his or her site.  Investigators and the DSMB Chair will also be notified of all 
unexpected, serious, drug-related events (i.e., 7- or 15-day expedited safety reports) that occur 
during the study.  Each site is responsible for notifying its EC of these expedited safety reports, 
in accordance with applicable site practices. 


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12. 
STATISTICS 
All summaries and analyses will be presented in tabular or graphical form.  Statistical methods 
will be described in detail in the Statistical Analysis Plan (SAP), which will be initially finalized 
as soon as possible during study enrollment with subsequent amendments clearly documenting 
changes to the plan throughout the study.  No amendments to the SAP will be made after the 
database lock for the primary analysis and subsequent changes will be presented as post hoc 
analyses.  All statistical analyses will be conducted using SAS® software, unless otherwise 
specified in the SAP. 
12.1. 
Determination of Sample Size 
A total of approximately 141 subjects will be enrolled into this study.  Sample size calculations 
were based on the primary endpoint, i.e., AAUC through Week 16.  Assuming the observed 
standard deviation of 1.03 log10 copies/mL in AAUC at Week 16 from a comparable subset of 
SoC subjects, the study has > 90% power with the currently planned sample size to demonstrate 
superiority of BCV vs. SoC, given that the true difference in means is > 0.6 log10 copies/mL 
(i.e., an effect size of ~ 0.58).  In addition, the overall mortality at Week 16 non-inferiority 
comparison will have > 80% power in the event that the expected mortality for SoC is 20% to 
30% and there is a true mortality advantage of 6% to 9% in favor of BCV (Feghoul 2015, 
Hiwarkar 2017, Mynarek 2014). 
12.2. 
Analysis Sets 
All subjects will be classified into Intent-to-Treat (ITT), modified Intent-to-Treat (mITT), Per 
Protocol (PP), Safety, and PK analysis sets.  The following definitions will be used: 
• ITT: The ITT analysis set will include all subjects who are randomized. 
• mITT: The mITT analysis set will include all subjects in the ITT analysis set with 
AdV viremia ≥ 1000 copies/mL measured by the designated central virology 
laboratory in the last sample on or prior to randomization.  Subjects randomized to 
BCV and not treated will be excluded from the mITT analysis set. 
• PP: The PP analysis set will include all subjects in the mITT analysis set who 
complete the study through Week 16 (or die prior to Week 16) and do not have any 
major protocol deviations (defined as significant inclusion/exclusion criteria violation 
or noncompliance that would be expected to impact the analysis of efficacy). 
• Safety: The safety analysis set will include all subjects who are randomized to and 
receive at least one dose of BCV, and all subjects who are randomized to SoC. 
• PK: The PK analysis set will include all subjects who are randomized to and receive 
at least one dose of BCV, and have at least one blood sample collected for analysis of 
plasma BCV concentrations. 
• Safety Exposure-Response: The safety exposure-response analysis set will include 
subjects who are in both the safety analysis set and the PK analysis set. 
• Efficacy Exposure-Response: The efficacy exposure-response analysis set will 
include subjects who are in both the mITT analysis set and the PK analysis set. 


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The ITT analysis set will be used to summarize all efficacy endpoints, including the primary 
endpoint/analysis.  The mITT and PP analysis sets will be determined prior to database lock for 
the primary analysis, and will be used for supportive primary efficacy analyses and possibly 
other selected endpoints to be defined in the SAP.  All efficacy analyses will use the randomized 
treatment assignment.  The safety analysis set will be used for all safety analyses and the PK 
analysis set will be used for all PK analyses. 
12.3. 
Interim Analyses 
No formal interim analyses are planned.  At least two safety reviews will be conducted by the 
DSMB.  The first safety review will be performed after the first 30 subjects enrolled have 
completed through Week 16 (or have died or are lost to follow-up).  The second safety review 
will be performed after the first 60 subjects enrolled have completed through Week 16 (or have 
died or are lost to follow-up).  In addition, safety and safety-exposure response will be monitored 
by the DSMB periodically, as described in Section 4.5.  There are no plans to stop the study for 
efficacy or futility; hence, no alpha-adjustment for DSMB monitoring is made. 
12.4. 
Efficacy Analyses 
12.4.1. 
Primary Efficacy Endpoint 
The primary AAUC analysis will utilize all randomized subjects (ITT) in an analysis of 
covariance (ANCOVA) with all stratification factors included in the model: T cell-depletion 
method (alemtuzumab or ex vivo cell selection vs. ATG), time from HCT to randomization 
(< 28 days vs. ≥ 28 days), and baseline AdV viremia (continuous log10 copies/mL).  These 
stratification factors have been selected as those that are clearly related to time to immune 
reconstitution (time from HCT to confirmed AdV viremia > 1000 copies/mL and thus 
randomization, procedural differences in depth and duration of immune suppression by 
T cell-depletion method) with resulting expected differences in clearance of viremia, and/or 
association with mortality (peak viral load).  Regarding baseline AdV viremia, subjects will be 
stratified at the time of randomization according to ≥ 10,000 vs. < 10,000 copies/mL; however, 
this factor will be included in the analysis as a continuous covariate in order to improve power in 
determining a treatment effect.  In the ANCOVA, AdV viremia values that are undetectable will 
be imputed at 99 copies/mL (i.e., one less than the lower limit of detection of 100 copies/mL) 
and values that are detected, but not quantifiable (BLQ) will be imputed at 189 copies/mL 
(i.e., one less than the lower limit of quantification of 190 copies/mL). 
Subjects who die or are lost to follow-up (i.e., drop-outs) prior to Week 16 are accounted for 
inherently in the AAUC approach by truncating their follow-up period, thereby normalizing 
AUC over time of follow-up (Li 2012).  It should be noted that subjects lost to follow-up are 
anticipated to be zero or negligible, and approximately 16% to 24% of subjects are expected to 
die by Week 16.  Regardless, the primary analysis will be supplemented by a number of planned 
sensitivity analyses to assess the impact of subjects who die prior to Week 16 and other potential 
influential elements on the primary inference and to allow for a more comprehensive assessment 
of efficacy. 


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The first three approaches are proposed to account for these subjects in a typical missing data 
framework: 
• Jump to reference imputation, where the missing part of the trajectory is imputed 
from the control group average (Kenward 2015). 
• Multiple imputation, where the missing part of the trajectory is imputed based on a 
model (Rubin 1978).  This imputation is repeated to create multiple simulated data 
sets (e.g., 5-times the number of deaths plus drop-outs).  Each of these simulated data 
sets is analyzed independently and the results from these analyses are pooled to yield 
a final inference. 
• Undetectable imputation, where the missing part of the trajectory is imputed as 
undetectable. 
In addition to the above, three other supportive analyses are proposed to directly account for 
subjects who die prior to Week 16: 
• Baseline imputation, where the missing part of the trajectory for deaths only is 
imputed at the baseline value for the subject. 
• Analysis of time below the detection limit, whereby subjects who die are considered 
to be above the detection limit after death.  This approach will be repeated using time 
below 1000 copies/mL, which is a clinically-meaningful level of viremia often 
signaling viral control vs. need to address in clinical practice. 
• Generalized pairwise comparisons of prioritized outcomes (Buyse 2010).  In this 
approach, all BCV subjects are compared with all SoC subjects in the same stratum.  
Comparisons will be made based on the following hierarchy: 
− Alive or dead at Week 16 
− If both die before Week 16, compare time to death 
− If both are alive at Week 16, compare AAUC 
Each comparison yields a favorable, unfavorable, or neutral result.  The “proportion 
in favor of treatment” (Δ) is the net difference between the number of favorable pairs 
and the number of unfavorable pairs divided by the total number of pairs.  The null 
hypothesis H0: Δ=0 is tested using a randomization test. 
Another important factor that may influence the primary inference is the imputation of 
undetectable and BLQ AdV viremia values, with additional sensitivity analyses conducted in 
order to assess the potential impact of this imputation: 
• Impute all undetectable/BLQ values at 1 copy/mL (i.e., 0 log10 c/mL) 
• Impute all undetectable/BLQ values at 189 copies/mL 
• Impute all values < 1000 copies/mL at 1 copy/mL 
In addition, a supportive analysis of overall mortality (adjusting for advanced baseline disease, 
Matthes-Martin 2008) will examine the non-inferiority of BCV treatment to SoC.  No negative 
impact on mortality will be concluded if the upper bound of the one-sided 95% confidence 


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interval (CI) for the absolute difference between BCV mortality and SoC mortality is < 10%.  
The proposed sample size will have > 80% power to demonstrate this conclusion, assuming SoC 
mortality in the expected range of 20% to 30% and a risk difference of 6% to 9% in favor of 
BCV (Feghoul 2015, Hiwarkar 2017, Mynarek 2014).  In the event this supportive analysis 
concludes non-inferiority and the primary endpoint is met, superiority for overall mortality at 
Week 16 will be tested at alpha 0.05.  Non-relapse mortality will be assessed in a similar fashion. 
12.4.2. 
Secondary Efficacy Endpoints 
Continuous secondary efficacy analyses will use the same method used for the primary analysis. 
Dichotomous secondary efficacy analyses will be analyzed using a Cochran-Mantel-Haenszel 
test stratified by each of the stratification factors.  Number of failures and failure rates will be 
presented for each treatment arm.  Cochran-Mantel-Haenszel p-values, estimated common odds 
ratios, and corresponding approximate 95% CIs will be presented for each comparison.  The 
Breslow-Day test will be used to test the homogeneity of the odds ratios.  Missing data will be 
imputed as failure. 
Most time-to-event analyses will be performed using Kaplan-Meier methods/plots and Cox 
models.  P-values and hazard ratios along with their 95% CIs will be presented for each 
treatment comparison.  Missing data will be censored, generally at the earlier of the end of study 
for each subject or the time point for the specific analysis. 
Non-relapse mortality will be analyzed with relapse as a competing risk adjusted for baseline 
strata, with corresponding cumulative incidence plots, Fine-Gray models, and cause-specific and 
sub-distribution hazard ratios with corresponding 95% CIs. 
12.5. 
Virology Analyses 
Only data analyzed by the designated central virology laboratories will be used for any viral load 
analyses. 
12.6. 
Safety Analyses 
All safety analyses will be presented by randomized treatment arm using the safety analysis set.  
Inferential analyses will generally not be performed for safety endpoints; exceptions are defined 
herein or will be defined in the SAP. 
12.6.1. 
Adverse Events 
On-study AEs are those events that occur from Day 1 through Week 16.  Only on-study AEs are 
summarized unless otherwise specified. 
For the BCV arm, TEAEs are those events that begin on or after the date of the first dose of 
study drug and on or before 7 days after the date of the last dose of study drug.  For the SoC arm, 
TEAEs are those that begin on or after Day 1 and on or before 7 days after the date of the last 
dose of anti-AdV therapy (or Week 16 if no anti-AdV therapy was used in SoC arm. 
Follow-up AEs are those that begin beyond 7 days after the last dose of study drug through 
Week 16. 


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Summaries (number and percent of subjects) of AEs by system organ class and preferred term 
will be provided as follows: 
• TEAEs 
• ≥ CTCAE Grade 3 TEAEs 
• Treatment-emergent SAEs 
• Treatment-related AEs 
• ≥ CTCAE Grade 3 treatment-related AEs 
• Treatment-related SAEs 
• AEs resulting in permanent BCV or other anti-AdV drug discontinuation 
• AEs requiring BCV or other anti-AdV drug interruption 
• AEs requiring dose modification or consolidation of BCV or other anti-AdV drug 
• On-study AEs 
• ≥ CTCAE Grade 3 on-study AEs 
• On-study SAEs 
• Follow-up AEs 
• ≥ CTCAE Grade 3 follow-up AEs 
• Follow-up SAEs 
• SAEs starting after Week 16 
• AEs beginning after Week 16 and leading to death 
12.6.2. 
Laboratory Results 
Descriptive statistics (N, mean, standard deviation [SD], median, first and third quartiles [Q1, 
Q3], minimum, and maximum) will be provided for each continuous laboratory test by treatment 
arm.  Values will be summarized at baseline, at each on-treatment time point, for the minimum 
and maximum on-treatment values, for the last on-treatment value, and for the last on-study 
value.  These results will also be presented as boxplots. 
Dichotomous laboratory endpoints will be descriptively analyzed using counts and percentages. 
12.7. 
Pharmacokinetic and Exposure-Response Analyses 
Plasma BCV concentrations will be listed and summarized using descriptive statistics (including 
N, mean, SD, percent coefficient of variation [%CV], median, minimum, and maximum).  
Concentrations that are BLQ will be treated as zero (0) for the purposes of descriptive statistics. 
The plasma BCV concentration-time data will be included in a population PK analysis to 
characterize plasma BCV PK, evaluate the impact of covariates of interest, and derive individual 
post hoc PK exposure parameters (plasma BCV AUC and Cmax).  An existing population PK 
model developed with data from six previous BCV studies (CMX001-115, CMX001-201, 


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CMX001-301, CMX001-202, CMX001-304, and CMX001-350) will be applied.  If necessary, 
additional modelling may be completed with data from only this study or by combining data 
from this study with data from previous studies.  Population PK analyses will be completed in 
NONMEM®.  A Population PK analysis plan will be written separately from the study SAP. 
The post hoc plasma BCV AUC and Cmax estimates from the population PK model will be used 
to characterize the potential impact of plasma BCV exposure on clinical safety, virologic, and 
mortality endpoints, and to evaluate the modifying influence of various covariates of interest on 
these relationships and endpoints.  Data from this study may be analyzed alone or in combination 
with data from previous studies for exposure-response analyses.  Exposure-response analysis 
may include time-to-event, logistic regression, linear regression, and/or nonlinear regression 
models, and analyses will be completed in R, S-plus, and/or SAS.  An exposure-response 
analysis plan will be written separately from the study SAP. 
12.8. 
Other Analyses 
12.8.1. 
Subject Enrollment and Analysis Sets 
The number and percent of subjects randomized in each country and by each investigator will be 
summarized overall and by treatment arm.  The denominator for this calculation will be the 
number of ITT subjects. 
A summary of analysis sets will present the number of subjects screened, randomized, and 
included in each analysis set (with summary of reasons for exclusion from each analysis set) by 
treatment arm. 
12.8.2. 
Demographics and Baseline Characteristics 
Subject demographic data (e.g., age, sex, race, and ethnicity) and baseline characteristics 
(e.g., body weight, height, body mass index, AdV viral load, disease for which HCT was 
conducted, pre-transplant conditioning regimen, source of graft, type of graft) will be 
summarized by treatment arm and overall using descriptive statistics (N, mean, SD, median, Q1, 
Q3, minimum, and maximum) for continuous data and using the number and percent of subjects 
for categorical data.  Age is calculated in years at the date of randomization.  Summaries of 
demographic data and baseline characteristics will be provided for the ITT, mITT, PP, and safety 
analysis sets. 
12.8.3. 
Prior and Concomitant Medications 
Medications started prior to Day 1 and those taken on or after Day 1 will be summarized 
separately (number and percentage of subjects) by treatment arm, Anatomical Therapeutic 
Chemical classification second-level category, and World Health Organization generic name, 
using the safety analysis set. 
12.8.4. 
Study Drug Exposure/Compliance 
Duration of exposure to BCV will be defined as: last dose date – first dose date + 1, regardless of 
temporary interruptions in study drug administration, and will be expressed in days.  Duration of 
exposure to BCV will be summarized using descriptive statistics (N, mean, SD, median, Q1, Q3, 
minimum, and maximum) and as the number and percent of subjects exposed for BIW durations 


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(decreasing cumulative) for the safety analysis set.  Other measures of exposure/compliance may 
be presented as defined in the SAP. 
12.8.5. 
Subject Disposition 
A summary of subject disposition will be provided by treatment arm using the ITT analysis set.  
This summary will present the number and percent of subjects who: 
• complete the study through Week 16 
• do not complete the study through Week 16 (with summary of reasons) 
12.9. 
Subgroup Analyses 
The primary and all-cause mortality endpoints will be analyzed by various subgroups, including, 
but not limited to, each of the stratification factors, sex, age, race, transplant characteristics, 
underlying disease (malignant, non-malignant), advanced disease status, and investigator’s 
intended SoC selected at the time of randomization.  Multivariate modelling will be considered 
and defined in the SAP. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. 
Quality Controls and Study Monitoring 
Quality controls are incorporated into project management activities conducted by Chimerix (or 
its designee), including the monitoring and verification of clinical and safety data. 
Each investigational site will be subject to an assessment of the adequacy of site facilities, 
including responsibilities as related to the study and protocol requirements. 
The progress of the study will be monitored by periodic onsite visits and frequent 
communications between Chimerix (or designee) and the investigator.  A monitor assigned to the 
investigational site is responsible for assessment of the progress of the study, review and 
verification of study data collected, and identifying and assisting in resolution of issues. The 
objectives of monitoring procedures are to verify that study data are accurate, authentic and 
complete; that the safety and rights of subjects are being protected; and, that the study is 
conducted in accordance with the approved protocol (including any amendments), International 
Conference on Harmonisation (ICH) GCP and applicable regulatory requirements. 
The investigator and study staff will allocate time to the monitor as required during on-site 
monitoring visits.  The monitor will continue to support the investigational site between 
monitoring visits. 
13.2. 
Quality Assurance Audits and Regulatory Inspections 
Authorized representatives of Chimerix (or its designee), a regulatory authority, or the applicable 
EC may visit the site to perform audits or inspections, including source data verification.  The 
purpose of such an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, and applicable 
regulatory requirements.  If such an audit or inspection occurs, the investigator will allow the 
auditor(s) or inspector(s) direct access to all source documents, eCRFs, and other study 
documentation for source data check and/or on-site audit/inspection, and will allocate his or her 
time and the time of his or her staff to the auditor or inspector, as required.  The investigator 
should notify Chimerix immediately if contacted by a regulatory agency intending to conduct an 
inspection. 


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14. 
ETHICS 
14.1. 
Ethics Review 
This protocol, the informed consent document, relevant supporting information, and all types of 
subject recruitment or advertisement information must be approved by the appropriate EC before 
the study is initiated.  Any amendments to the protocol must also be approved, where necessary, 
by the EC prior to implementing changes in the study.  Documentation of these approvals must 
be provided to Chimerix (or designee) prior to the initiation of the amendment. 
The investigator’s responsibilities regarding the EC are as follows:  
• Obtain EC approval of the protocol, informed consent document, and any 
advertisements for subject recruitment prior to their use.  Maintaining this 
documentation in the site’s study file. 
• Obtain EC approval for any protocol amendments and revisions to the informed 
consent document before implementing the changes.  Maintaining this documentation 
in the study file. 
• Provide the EC with any required information before or during the study. 
• Submit progress reports to the EC, as required, during the conduct of the study; 
request re-review and approval of the study, as needed; provide copies of all EC 
re-approvals and relevant communication to Chimerix (or designee). 
• Notify the EC within the required timeframe of all serious and unexpected AEs 
related to the study drug that are reported to you by Chimerix (or designee).  The 
investigator is responsible for updating the EC on the progress of the study and of any 
changes made to the protocol at least once a year or at regular intervals as required.  
The investigator must also keep the EC informed of any AEs at the site, according to 
the EC policy. 
• Notify the EC of protocol deviations according to the EC’s policy.  Maintaining this 
documentation in the site’s study file. 
14.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP and applicable regulatory requirements 
in the respective territory where the study is conducted. 
14.3. 
Written Informed Consent/Assent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation in layman’s terms regarding the nature of 
the study, along with the purpose, methods, objectives, and any potential risks or benefits. 
Written assent should be obtained from minor subjects in accordance with institution practice 
using an assent form that summarizes the study in age-appropriate language, as approved by the 
EC. 


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The informed consent document shall also contain the subject's authorization for the use and 
disclosure of his/her protected health information (PHI) in connection with the study.  The 
authorization shall include at a minimum a clear description of the following:  the duration of the 
authorization, the subject's right of access to the PHI (or any suspension thereof during the 
course of the study), type of information to be used/disclosed in the study, the names or classes 
of parties that may use or disclose the PHI, the purpose of the use/disclosure of PHI, the extent of 
the subject's right to revoke the authorization, the extent to which participation in the study is 
conditioned on signing the authorization, and the potential for re-disclosure of PHI. 
The informed consent/assent document must be appropriately signed and dated by the subject or 
the subject’s legally authorized representative and the person obtaining the consent (if required 
by the EC) prior to conducting/obtaining any study-related assessments including the 
discontinuation of any medications prohibited for the study. 
If the informed consent/assent document(s) is amended during the study (e.g., new safety 
information), the investigator must follow all applicable regulatory requirements pertaining to 
approval of the amended informed consent/assent document(s) by the EC prior to use.  All new 
subjects enrolling in the study should be consented with the amended, approved informed 
consent/assent document(s), including ongoing subjects in treatment as directed by the EC. 
The investigator must maintain the original and any amended signed and dated informed consent 
document(s) and/or assent form(s) as applicable.  A copy of the signed informed consent 
document(s) or assent form(s) must be given to the subject or the subject’s legally authorized 
representative. 


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15. 
DATA HANDLING AND RECORD-KEEPING 
15.1. 
Data Collection 
All observations relating to the study will be recorded by site personnel in source documents.  In 
addition, eCRFs will be provided for this study.  An eCRF must be completed for every subject 
entered into the study.  The eCRF must be completed according to the eCRF completion 
guidelines.  After each subject has completed the study, the investigator must review and 
electronically sign the eCRFs indicating that (s)he has reviewed the completed eCRFs and 
pertinent clinical data for the subject and that, to the best of his/her knowledge, all data recorded 
in the eCRFs accurately reflects the subject’s performance in the study. 
15.2. 
Inspection of Records 
Chimerix (or its designee) will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records related to study conduct. 
15.3. 
Retention of Records 
Essential documents maintained in conduct of the study should be retained for one of the 
following time periods: 
• At least 2 years after approval of the last marketing application, 
OR 
• At least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
These documents should be retained for a longer period (e.g., 15 years or more), however, if 
required by applicable local or country-specific regulatory requirements or by an agreement with 
Chimerix.  It is the responsibility of Chimerix to inform the investigator/institution as to when 
these documents no longer need to be retained.  If it becomes necessary for Chimerix or any 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
15.4. 
Confidentiality 
Subject names will remain confidential and will not be supplied to Chimerix or its designee.  If 
the subject name appears on any other document collected (e.g., clinic discharge summary), it 
must be redacted before the document is transmitted to Chimerix or its designee.  All study 
findings will be stored in electronic databases.  Subjects will give explicit permission for 
representatives of Chimerix or its designee, regulatory authorities, and the relevant EC to inspect 
their medical records to verify the information collected.  Subjects will be informed that all 
personal information made available for inspection will be handled in the strictest confidence 
and in accordance with Health Insurance Portability and Accountability Act (HIPAA; in USA) or 
national data protection/privacy laws (outside of the USA). 


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Individual subject medical information obtained during this study is confidential and its 
disclosure to third parties other than those mentioned in the preceding paragraph is prohibited.  
Medical information obtained during this study may be provided to the subject’s personal 
physician or other appropriate medical personnel when required in connection with the subject’s 
continued health and welfare and with the subject’s prior knowledge and permission. 


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16. 
PUBLICATION POLICY 
It is the intention of Chimerix to publish the results of this study in their entirety within a 
reasonable period of time following the completion of the study.  Chimerix will determine when 
and where data will be first disclosed. 
Details of this study protocol will be posted to a publically accessible register(s) to the extent 
required by applicable laws and regulations prior to the first subject enrolling into the study, or 
as regional applicable. 
All information generated from this study is the proprietary property of Chimerix.  Chimerix 
reserves the right, among other things, to: 
• Modify or amend study material to ensure that no confidential or proprietary 
information is disclosed. 
• Ensure that the reported data are factually correct. 
• Utilize the information generated from or as a result of this study in any manner it 
deems appropriate, including but not limited to regulatory submissions, annual 
reports, and other scientific or business affairs of the company. 
• Modify the publication or disclosure or delay it a sufficient time to allow Chimerix to 
seek patent protection of any invention contained therein. 
Please refer to the separate agreement for this research for further specifics on publication. 


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17. 
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Kenward, MG. Controlled multiple imputation methods for sensitivity analyses in longitudinal 
clinical trials with dropout and protocol deviation. Clin Invest (Lond.) 2015;5(3):311-20. 
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(CMV) after allogeneic hematopoietic cell transplantation (HCT) in CMV-seropositive patients: 
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Matthes-Martin S, Feuchtinger T, Shaw PJ, et al. European guidelines for diagnosis and 
treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 
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McDonald GB, Tabellini L, Storer BE, et al. Plasma biomarkers of acute GVHD and nonrelapse 
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2;126(1):113-20. 
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obstructive uropathy and necrotizing tubulointerstitial nephritis in a bone marrow transplant 
recipient. Bone Marrow Transplant. 2003 Jun;31(12):1173-6. 


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Mynarek M, Ganzenmueller T, Mueller-Heine A, et al. Patient, virus, and treatment-related risk 
factors in pediatric adenovirus infection after stem cell transplantation: results of a routine 
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transplant recipient with severe adenovirus pneumonia. J Heart Lung Transplant. 2008 
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Runde V, Ross S, Trenschel R, et al. Adenoviral infection after allogeneic stem cell 
transplantation (SCT): report on 130 patients from a single SCT unit involved in a prospective 
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Symeonidis N, Jakubowski A, Pierre-Louis S, et al. Invasive adenoviral infections in 
T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of 
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Williams KM, Agwu AL, Dabb AA, et al. A clinical algorithm identifies high risk pediatric 
oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral 
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hematopoietic stem cell transplant patients. Transplantation. 2006 May 27;81(10):1398-404. 


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APPENDIX 1. ACUTE GRAFT VERSUS HOST DISEASE NIH STAGING 
SCALE 
The following table, adapted from the Center for International Blood & Marrow Transplant 
Research (CIBMTR): 2100 Post-HCT Follow-up Form, Question 169 
(https://www.cibmtr.org/manuals/fim/1/en/topic/f2100-q131-233), should be used for staging 
acute GVHD. 
Table 12: 
NIH Staging of Acute GVHD by Extent of Organ Involvement 
Stage 
Extent of Organ Involvement 
Skina 
Liver 
(Total Bilirubin)b 
Gut 
(Stool Output)c 
0 
No GVHD rash 
< 2 mg/dL 
[SI: < 34 μmol/L] 
< 280 mL/m2/day or 
< 10 mL/kg/day 
1 
Rash on < 25% BSA 
2 to 3 mg/dL 
[SI: 34 to 51 μmol/L] 
280 to 555 mL/m2/day or 
10 to 19.9 mL/kg/day or 
persistent nausead 
2 
Rash on 25 to 50% BSA 
> 3 to 6 mg/dL 
[SI: > 51 to 103 μmol/L] 
556 to 833 mL/m2/day or 
20 to 30 mL/kg/day 
3 
Rash on > 50% BSA 
> 6 to 15 mg/dL 
[SI: > 103 to 257 μmol/L] 
> 833 mL/m2/day or 
> 30 mL/kg/day 
4 
Generalized erythroderma 
with bullous formation 
> 15 mg/dL 
[SI: > 257 μmol/L] 
Severe abdominal pain with or 
without ileus, and/or grossly blood 
stool 
a Use “Rule of Nines” (see Table 13 below) or burn chart to determine extent of rash. 
b Range given as total bilirubin.  Downgrade one stage if an additional cause of elevated bilirubin has been 
documented. 
c Range given as volume of diarrhea based on body surface area (BSA) or body weight in kilograms.  Downgrade 
one stage if an additional cause of diarrhea has been documented 
d Persistent nausea with histologic evidence of GVHD of the stomach or duodenum. 
 
Table 13: 
Percent Body Surfaces 
Body Area 
Percent 
Total Percentage 
Each arm 
9% 
18% 
Each leg 
18% 
36% 
Chest & Abdomen 
18% 
18% 
Back 
18% 
18% 
Head 
9% 
9% 
Pubis 
1% 
1% 
 


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APPENDIX 2. BCV DOSING TABLES 
Separate dosing tables are provided for subjects receiving BCV with concurrent cyclosporine 
(Table 14) and for subjects receiving BCV without concurrent cyclosporine (Table 15). 
Please verify that you are using the correct table for each individual subject. 
Both tables present the volume of BCV oral suspension (in mL) to be administered for BIW 
administration (second columns) and QW administration (fourth column) in the event that the 
BCV dose is consolidated in response to a treatment-emergent toxicity. 
Look down the table for the appropriate weight range for your subject based on his or her lowest 
recorded body weight measurement (in kilograms) in the 30-day period prior to Day 1. 
Note: A 5-mL dosing syringe is recommended for BCV doses ≤ 50 mg (i.e., ≤ 5 mL), and a 
10-mL dosing syringe is recommended for BCV doses > 50 mg (i.e., > 5 mL). 


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Table 14 
BCV Suspension Volume by Dosing Weight for Subjects Receiving 
Concurrent Cyclosporine 
BCV BIW: 1.4 mg/kg dose 
BCV QW: 2.8 mg/kg dose 
(Dose Consolidation) 
Dosing weight (kg)a 
BCV Suspension Volume 
Dosing weight (kg)a 
BCV Suspension Volume 
5 to 5.3 
0.7 mL 
5 to 5.3 
1.4 mL 
5.4 to 6.1 
0.8 mL 
5.4 to 6.1 
1.6 mL 
6.2 to 6.8 
0.9 mL 
6.2 to 6.8 
1.8 mL 
6.9 to 7.5 
1 mL 
6.9 to 7.5 
2 mL 
7.6 to 8.2 
1.1 mL 
7.6 to 8.2 
2.2 mL 
8.3 to 8.9 
1.2 mL 
8.3 to 8.9 
2.4 mL 
9 to 9.6 
1.3 mL 
9 to 9.6 
2.6 mL 
9.7 to 10.3 
1.4 mL 
9.7 to 10.3 
2.8 mL 
10.4 to 11.1 
1.5 mL 
10.4 to 11.1 
3 mL 
11.2 to 11.8 
1.6 mL 
11.2 to 11.8 
3.2 mL 
11.9 to 12.5 
1.7 mL 
11.9 to 12.5 
3.4 mL 
12.6 to 13.6 
1.8 mL 
12.6 to 13.6 
3.6 mL 
13.7 to 15 
2 mL 
13.7 to 15 
4 mL 
15.1 to 16.4 
2.2 mL 
15.1 to 16.4 
4.4 mL 
16.5 to 17.8 
2.4 mL 
16.5 to 17.8 
4.8 mL 
17.9 to 19.3 
2.6 mL 
17.9 to 19.3 
5.2 mL 
19.4 to 20.7 
2.8 mL 
19.4 to 20.7 
5.6 mL 
20.8 to 22.2 
3 mL 
20.8 to 22.2 
6 mL 
22.3 to 23.6 
3.2 mL 
22.3 to 23.6 
6.4 mL 
23.7 to 25 
3.4 mL 
23.7 to 25 
6.8 mL 
25.1 to 26.4 
3.6 mL 
25.1 to 26.4 
7.2 mL 
26.5 to 27.8 
3.8 mL 
26.5 to 27.8 
7.6 mL 
27.9 to 29.3 
4 mL 
27.9 to 29.3 
8 mL 
29.4 to 30.7 
4.2 mL 
29.4 to 30.7 
8.4 mL 
30.8 to 33.9 
4.5 mL 
30.8 to 33.9 
9 mL 
34 to 37.5 
5 mL 
34 to 37.5 
10 mL 
37.6 to 41.1 
5.5 mL 
37.6 to 41.1 
11 mL 
41.2 to 44.6 
6 mL 
41.2 to 44.6 
12 mL 
44.7 to 47.9 
6.5 mL 
44.7 to 47.9 
13 mL 
≥ 48 
7 mL 
≥ 48 
14 mL 
a Dosing weight = lowest body weight (in kilograms) within 30 days prior to Day 1. 
Abbreviations: BCV = brincidofovir; BIW = twice weekly; QW = once weekly 


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Table 15 
BCV Suspension Volume by Dosing Weight for Subjects NOT Receiving 
Concurrent Cyclosporine 
BCV BIW: 2 mg/kg dose 
BCV QW: 4 mg/kg dose 
(Dose Consolidation) 
Dosing weight (kg)a 
BCV Suspension Volume 
Dosing weight (kg)a 
BCV Suspension Volume 
5 to 5.2 
1 mL 
5 to 5.2 
2 mL 
5.3 to 5.7 
1.1 mL 
5.3 to 5.7 
2.2 mL 
5.8 to 6.2 
1.2 mL 
5.8 to 6.2 
2.4 mL 
6.3 to 6.7 
1.3 mL 
6.3 to 6.7 
2.6 mL 
6.8 to 7.2 
1.4 mL 
6.8 to 7.2 
2.8 mL 
7.3 to 7.7 
1.5 mL 
7.3 to 7.7 
3 mL 
7.8 to 8.2 
1.6 mL 
7.8 to 8.2 
3.2 mL 
8.3 to 8.7 
1.7 mL 
8.3 to 8.7 
3.4 mL 
8.8 to 9.5 
1.8 mL 
8.8 to 9.5 
3.6 mL 
9.6 to 10.5 
2 mL 
9.6 to 10.5 
4 mL 
10.6 to 11.5 
2.2 mL 
10.6 to 11.5 
4.4 mL 
11.6 to 12.5 
2.4 mL 
11.6 to 12.5 
4.8 mL 
12.6 to 13.5 
2.6 mL 
12.6 to 13.5 
5.2 mL 
13.6 to 14.5 
2.8 mL 
13.6 to 14.5 
5.6 mL 
14.6 to 15.5 
3 mL 
14.6 to 15.5 
6 mL 
15.6 to 16.5 
3.2 mL 
15.6 to 16.5 
6.4 mL 
16.6 to 17.5 
3.4 mL 
16.6 to 17.5 
6.8 mL 
17.6 to 18.5 
3.6 mL 
17.6 to 18.5 
7.2 mL 
18.6 to 19.5 
3.8 mL 
18.6 to 19.5 
7.6 mL 
19.6 to 20.5 
4 mL 
19.6 to 20.5 
8 mL 
20.6 to 21.5 
4.2 mL 
20.6 to 21.5 
8.4 mL 
21.6 to 23.7 
4.5 mL 
21.6 to 23.7 
9 mL 
23.8 to 26.2 
5 mL 
23.8 to 26.2 
10 mL 
26.3 to 28.7 
5.5 mL 
26.3 to 28.7 
11 mL 
28.8 to 31.2 
6 mL 
28.8 to 31.2 
12 mL 
31.3 to 33.7 
6.5 mL 
31.3 to 33.7 
13 mL 
33.8 to 36.2 
7 mL 
33.8 to 36.2 
14 mL 
36.3 to 38.7 
7.5 mL 
36.3 to 38.7 
15 mL 
38.8 to 41.2 
8 mL 
38.8 to 41.2 
16 mL 
41.3 to 43.7 
8.5 mL 
41.3 to 43.7 
17 mL 
43.8 to 46.2 
9 mL 
43.8 to 46.2 
18 mL 
46.3 to 47.9 
9.5 mL 
46.3 to 47.9 
19 mL 
≥ 48 
10 mL 
≥ 48 
20 mL 
a Dosing weight = lowest body weight (in kilograms) within 30 days prior to Day 1. 
Abbreviations: BCV = brincidofovir; BIW = twice weekly; QW = once weekly 


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APPENDIX 3. FLOW CHART FOR BRINCIDOFOVIR DOSING 
ALGORITHM 
 
Abbreviations: AdV = adenovirus; BCV = brincidofovir; c/mL = copies per milliliter; UND = undetectable 


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APPENDIX 4. FLOW CHART FOR BRINCIDOFOVIR TOXICITY 
MANAGEMENT 
 
Abbreviations: BCV = brincidofovir; QW = once weekly 


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APPENDIX 5. DEFINITIONS FOR PROBABLE OR DEFINITIVE 
ADENOVIRUS INFECTION OR DISEASE 
Table 16: 
Definitions and Criteria for Probable or Definitive Adenovirus Disease 
Probable 
Definitive 
Cardiac AdV Infection or Disease 
• 
AdV detected by viral blood culture, or by a 
positive or detectable AdV DNA PCR value in 
blood or plasma 
• 
AND other causes (e.g., HIV, bacterial infection) 
ruled out 
• 
AND at least one of the following suggestive 
signs/symptoms: 
− 
dyspnea 
− 
chest pain 
− 
peripheral edema 
• 
AND confirmation of heart enlargement or 
pericardial effusion by imaging 
• 
AdV detected on cardiac or pericardium biopsy 
via antigen/IHC, culture, or PCR 
• 
AND at least one of the following suggestive 
signs/symptoms: 
− 
dyspnea 
− 
chest pain 
− 
peripheral edema 
• 
AND confirmation of heart enlargement or 
pericardial effusion by imaging 
Gastrointestinal AdV Infection or Disease 
• 
AdV isolated from intestinal biopsy by PCR 
OR 
• 
AdV detected by viral culture, or by AdV DNA 
PCR (positive or detectable value) in both stool 
and blood (with plasma ≥ 1000 copies/mL) 
• 
AND other causative agents (e.g., bacterial, viral, 
amoebic) ruled out 
• 
AND endoscopic evidence of lesions (macroscopic 
or microscopic) not attributed to GVHD 
(i.e., biopsy-proven) 
• 
AND suggestive signs or symptoms (e.g., diarrhea, 
abdominal pain, ileus, vomiting, GI hemorrhage) 
• 
AdV detected on intestinal biopsy via 
antigen/IHC, culture or PCR 
• 
AND EITHER: 
− 
Suggestive signs or symptoms 
(e.g., diarrhea, abdominal pain, ileus, 
vomiting, GI hemorrhage) and 
− 
Endoscopic evidence of lesions 
(macroscopic or microscopic) not 
attributed to GVHD 
OR 
• 
Cytopathic adenoviral aspect identified on biopsy 


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Table 16: 
Definitions and Criteria for Probable or Definitive Adenovirus Disease 
(Continued) 
Probable 
Definitive 
Hepatic AdV Infection or Disease 
• 
AdV detected by viral blood culture, or by a 
plasma AdV DNA PCR ≥ 1000 copies/mL 
• 
AND other causative agents (e.g., hepatitis 
viruses) and causes (e.g., drug-induced, GVHD) 
ruled out 
• 
AND at least one of the following confirmed 
laboratory abnormalities: 
− 
ALT > 5x ULN 
− 
AST > 5x ULN 
− 
serum total bilirubin > 5x ULN 
• 
AdV identified via hepatic biopsy via 
antigen/IHC or culture  
• 
AND at least one of the following confirmed 
laboratory abnormalities: 
− 
ALT > 5x ULN 
− 
AST > 5x ULN 
− 
serum total bilirubin > 5x ULN 
Central Nervous System AdV Infection or Disease 
• 
AdV detected by viral blood culture, or by a 
positive or detectable AdV DNA PCR value in 
blood or plasma 
• 
AND other causes (e.g., bacterial, amoebic and 
stroke/infarct/CSF leak) ruled out 
• 
AND at least two of the following: 
− 
Abnormal CSF 
− 
Focal deficit 
− 
Cognitive impairment 
− 
Visual symptoms 
− 
Seizure 
− 
Evidence of lesions by CT scan or MRI 
• 
AdV identified in CSF via antigen/IHC, culture 
or PCR 
• 
AND at least one of the following 
signs/symptoms of encephalitis: 
− 
Abnormal CSF 
− 
Focal deficit 
− 
Cognitive impairment 
− 
Visual symptoms 
− 
Seizure 
− 
Evidence of lesions by CT scan or MRI 
 
 


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Table 16: 
Definitions and Criteria for Probable or Definitive Adenovirus Disease 
(Continued) 
Probable 
Definitive 
Renal AdV Infection or Disease 
• 
AdV detected by viral culture, or by AdV DNA 
PCR (positive or detectable value) in both urine 
and blood (with plasma ≥ 1000 copies/mL) 
• 
AND other causes (e.g., bacterial, drug-induced) 
ruled out 
• 
AND at least one of the following: 
− 
Suggestive signs or symptoms (impaired 
renal function, proteinuria, microscopic 
hematuria, dysuria) 
− 
Enlarged kidney on imaging 
− 
Renal/bladder obstruction  
• 
AdV identified via renal or bladder biopsy via 
antigen/IHC or culture 
• 
AND at least one of the following: 
− 
Suggestive signs or symptoms (impaired 
renal function, proteinuria, microscopic 
hematuria, dysuria) 
− 
Enlarged kidney on imaging 
− 
Renal/bladder obstruction 
Respiratory AdV Infection or Disease 
• 
AdV identified in nasopharyngeal secretions, 
sputum, BAL, or endotracheal aspirate (culture, 
antigen or by PCR) 
• 
AND plasma AdV DNA PCR ≥ 1000 copies/mL 
• 
AND no bacterial, fungal or other probable 
causative agent identified/cultured 
• 
AND both of the following: 
− 
Suggestive signs or symptoms (cough, 
tachypnea, desaturation)  
− 
CT scan or x-ray with infiltrates 
• 
AdV identified in lung biopsy via PCR, culture, 
or via antigen/IHC methods 
• 
AND no bacterial, fungal or other probable 
causative agent identified/cultured 
• 
AND both of the following: 
− 
Suggestive signs or symptoms (cough, 
tachypnea, desaturation)  
− 
CT scan or x-ray with infiltrates 
Abbreviations: AdV = adenovirus; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BAL = bronchoalveolar lavage; CSF = cerebrospinal fluid; CT = computed tomography; DNA = deoxyribonucleic 
acid; GI = gastrointestinal; GVHD = graft versus host disease; HIV = human immunodeficiency virus; 
IHC = immunohistochemistry; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; 
ULN = upper limit of normal 
 


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APPENDIX 6. HCT COMORBIDITY INDEX SCALE 
The following table, adapted from Sorror et al (Sorror 2005), should be used for assessing HCT comorbidities. 
Table 17: 
Definitions of HCT Comorbidities 
HCT Comorbidity 
Definition 
Score 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmia 
1 
Cardiac 
Coronary artery diseasea, congestive heart failure, myocardial infarction, or EF ≤ 50% 
1 
Inflammatory bowel disease 
Crohn’s disease or ulcerative colitis 
1 
Diabetes 
Requiring treatment with insulin or oral hypoglycemic medication, but not diet alone 
1 
Cerebrovascular disease 
Transient ischemic attack or cerebrovascular accident 
1 
Psychiatric disturbance 
Depression or anxiety requiring psychiatric consult or treatment 
1 
Hepatic, mild 
Chronic hepatitis, bilirubin > ULN to 1.5x ULN, ALT > ULN to 2.5x ULN, or AST > ULN to 2.5x ULN 
1 
Obesity 
Body mass index ≥ 35 kg/m2 
1 
Infection 
Requiring continuation of antimicrobial treatment after Day 0 (Day 0 = day of transplant) 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 
2 
Peptic ulcer 
Requiring treatment 
2 
Renal, moderate to severe 
Serum creatinine > 2 mg/dL (SI: 177 μmol/L), on dialysis, or prior renal transplantation 
2 
Pulmonary, moderate 
DLco and/or FEV1 66% to 80% or dyspnea on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient’s past history, excluding non-melanoma skin cancer 
3 
Heart valve disease 
Except mitral valve prolapse 
3 
Pulmonary, severe 
DLco and FEV1 ≤ 65% or dyspnea at rest or requiring oxygen 
3 
Hepatic, moderate or severe 
Liver cirrhosis, bilirubin > 1.5x ULN, ALT > 2.5x ULN, or AST > 2.5x ULN 
3 
a One or more vessel-coronary artery stenosis requiring medical treatment, stent or bypass graft. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTD = connective tissue disorder; DLco = diffusion capacity of carbon 
monoxide; EF = ejection fraction; FEV1 = forced expiratory volume in the first second; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; 
ULN = upper limit of normal reference range. 


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APPENDIX 7. PELOD SCORE 
The following table, reproduced from Leteurtre et al (Leteurtre 2003), should be used for 
calculating the PELOD score. 
Table 18: 
PELOD Scoring System 
Organ 
Dysfunction 
Variable 
Scoring System 
0 
1 
10 
20 
Neurologicala 
Glasgow coma score 
12 to 15 
7 to 11 
4 to 6 
3 
 
 
AND 
 
OR 
 
 
Pupillary reactions 
both reactive 
NA 
both fixed 
NA 
Cardiovascularb 
Heart rate (beats/min) 
 
 
 
 
 
< 12 years of age 
≤ 195 
NA 
> 195 
NA 
 
≥ 12 years 
≤ 150 
NA 
> 150 
NA 
 
 
AND 
 
OR 
 
 
Systolic blood pressure (mm Hg) 
 
 
 
 
 
< 1 month of age 
> 65 
NA 
35 to 65 
< 35 
 
1 month to < 1 year 
> 75 
NA 
35 to 75 
< 35 
 
1 to < 12 years 
> 85 
NA 
45 to 85 
< 45 
 
≥ 12 years 
> 95 
NA 
55 to 95 
< 55 
Renal 
Creatinine (µmol/L) 
 
 
 
 
 
< 7 days of age 
< 140 
NA 
≥ 140 
NA 
 
7 days to < 1 year 
< 55 
NA 
≥ 55 
NA 
 
1 to < 12 years 
< 100 
NA 
≥ 100 
NA 
 
≥ 12 years 
< 140 
NA 
≥ 140 
NA 
Respiratoryc 
PaO2 (kPa)/FIO2 ratio 
> 9.3 
NA 
≤ 9.3 
NA 
 
 
AND 
 
OR 
 
 
PaCO2 (kPa) 
≤ 11.7 
NA 
> 11.7 
NA 
 
 
AND 
 
 
 
 
Mechanical ventilation 
No 
Yes 
NA 
NA 
Hematological 
White blood cell count (x109/L) 
≥ 4.5 
1.5 to 4.4. 
< 1.5 
NA 
 
 
AND 
OR 
 
 
 
Platelets (x109/L) 
≥ 35 
< 35 
NA 
NA 
Hepatic 
Aspartate aminotransferase (IU/L) 
< 950 
≥ 950 
NA 
NA 
 
 
AND 
OR 
 
 
 
Prothrombin timed (or INR) 
> 60 (< 1.40) 
≤ 60 (≥ 1.40) 
NA 
NA 


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a Glasgow coma score: use lowest value. If patient is sedated, record estimated Glasgow coma score before 
sedation.  Assess patient only with known or suspected acute central nervous system disease.  Pupillary reactions: 
non-reactive pupils must be > 3 mm.  Do not assess after iatrogenic pupillary dilatation. 
b Heart rate and systolic blood pressure: do not assess during crying or iatrogenic agitation. 
c PaO2: use arterial measurement only.  PaO2/FIO2 ratio, which cannot be assessed in patients with intracardiac 
shunts, is considered as normal in children with cyanotic heart disease.  PaCO2 may be measured from arterial, 
capillary, or venous samples.  Mechanical ventilation: the use of mask ventilation is not counted as mechanical 
ventilation. 
d Percentage of activity. 
Abbreviations: FIO2 = fraction of inspired oxygen; INR = international normalized ratio; NA = not applicable; 
PaCO2 = arterial carbon dioxide pressure; PaO2 = arterial oxygen pressure. 


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APPENDIX 8. BRISTOL STOOL FORM SCALE 
Bristol stool form scale created by Heaton and Lewis at the University of Bristol, UK.  
Originally published in Scan J Gastroenterol. 1997;32(9):920-4.