The AdAPT Trial; Adenovirus After Allogeneic Pediatric Transplantation

• Sponsor: Chimerix (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03339401
• Collaborator: (none)
• Enrollment: 29
• Locations: 36
• Arms: 2
• Actual Duration (Months): 16.6
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adenovirus	Other: Standard of Care; Drug: Brincidofovir	Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study to Assess the Safety, Overall Tolerability, and Antiviral Activity of Brincidofovir Versus Standard of Care for Treatment of Adenovirus in High-risk Pediatric Allogeneic Hematopoietic Transplant Recipients
• Actual Study Start Date: Dec 22, 2017
• Actual Primary Completion Date: May 10, 2019
• Actual Study Completion Date: May 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brincidofovir 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.	Drug: Brincidofovir; Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.; Other Names: BCV
Other: Standard of Care 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.	Other: Standard of Care; 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.; Other Names: SoC

Outcome Measures

Primary Outcome Measures

1. Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL). [From randomization to 16 weeks post-randomization]

   The primary efficacy endpoint for this study was the time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia (log10 copies/mL) from randomization through Week 16 post-randomization. Due to the small number of subjects enrolled in the study, formal efficacy analyses were not performed. Individual subject AdV viremia profiles show the differential anti-adenoviral effect of brincidofovir (BCV) in comparison to standard of care (SoC) therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects were high-risk allogeneic hematopoietic cell transplant (HCT) recipients aged 2 months to <18 years (<26 years in the United States) who met adenovirus (AdV) viremia criteria within 7 days of randomization (Day 1), and all other eligibility criteria.

High-risk was defined as having received 1 of the following:

• A T cell-depleted graft:

• Ex vivo T cell depletion via positive selective (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 ≥30 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; or

• A cord blood graft from an unrelated donor with or without T cell depletion, or

• A T cell-replete graft from a haploidentical donor with high-dose cyclophosphamide (e.g., cumulative dose of ≥100 mg/kg) administered at any time post-transplant and prior to Day 1.

Subjects must have had qualifying AdV viremia within 100 days of transplant, which was defined as having either:

1. Confirmed AdV viremia of ≥1000 copies/mL on 2 consecutive AdV DNA polymerase chain reaction (PCR) test results drawn ≥48 hours apart from the designated central virology laboratory, with the second result being greater than the first; or

2. A single AdV viremia result of ≥10,000 copies/mL from the designated central virology laboratory Subjects who were previously treated with intravenous (IV) cidofovir (CDV) could have a cumulative exposure to IV CDV of no more than 10 mg/kg within 21 days prior to Day 1.

Written informed consent (and assent, where applicable) to participate in the study was obtained from each subject and his/her legal guardian(s) in accordance with national or local law and institutional practice.

Exclusion Criteria:

1. Any United States National Institutes of Health (NIH)/National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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/day over baseline [pre-transplant] diarrheal output), unless attributed to AdV, within 7 days prior to Day 1.

3. 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.

4. NIH Stage ≥2 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 acute GVHD of the gut (i.e., diarrhea >556 mL/m2/day for pediatric patients [or >1000 mL/day for young adults at centers in the United States only], or severe abdominal pain with or without ileus) within 7 days prior to Day 1.

6. Poor clinical prognosis (including active malignancy or use of vasopressors other than low dose (e.g., ≤5 µg/kg/min) dopamine for renal perfusion within 7 days prior to Day

8. Requirement for mechanical ventilation within 7 days prior to Day 1 or requirement for sustained oxygen delivery for >24 hours within 7 days prior to Day 1.

9. Concurrent HIV, active hepatitis B virus, or hepatitis C virus infection.

10. Specified out of range laboratory results (including alanine aminotransferase >5x the upper limit of normal [ULN], aspartate aminotransferase >5x ULN, total bilirubin >3 mg/dL [SI: >51 µmol/L], or prothrombin time-international normalized ratio >2x ULN) within 7 days prior to Day 1.

11. Estimated creatinine clearance <30 mL/min or use of renal replacement therapy within 7 days prior to Day 1.

12. Previous receipt of BCV at any time or receipt of CDV (IV or intravesicular) or letermovir within 48 hours prior to Day 1.

13. Received any anti-AdV-specific cell-based therapy within 6 weeks prior to Day 1 or previously received an anti-AdV vaccine at any time.

When applicable, female subjects of childbearing potential (i.e., not pre-menarche) were not pregnant or breastfeeding, and if sexually active, agreed to use 2 acceptable forms of contraception, 1 of which must have been a barrier method and the other a highly-effective method of contraception. Male subjects, if sexually active and capable of fathering a child, agreed to use a barrier method of contraception while enrolled in the study and for at least 90 days after the last dose of BCV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	University of California San Francisco	San Francisco	California	United States	94143
3	University of Chicago	Chicago	Illinois	United States	60637
4	Joseph M. Sanzari Childrens Hospital-Regional Cancer Care	Hackensack	New Jersey	United States	07601
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
6	Duke University Medical Center	Durham	North Carolina	United States	27705
7	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio	United States	45229
8	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
9	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
10	University of Washington-Seattle Childrens Hospital	Seattle	Washington	United States	98105
11	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
12	IHOPe-Institut d'Homatologie et d'Oncologie Pediatrique	Lyon		France	69008
13	Hopital Necker-Enfants Malades	Paris		France	75015
14	Hopital Universitaire Robert Debre	Paris		France	75019
15	Universitatsklinik fur Kinder-und Jugendmedizin	Tübingen	Baden-Wurttemberg	Germany	72076
16	Dr. von Haunersches Kinderspital, Abteilung fur Padiatrische	München	Bavaria	Germany	80337
17	Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum	Berlin		Germany	13353
18	Our Lady's Children Hospital	Dublin		Ireland	D12 N512
19	Fondazione MBBM-CTMO Pediatrico	Monza		Italy	20900
20	Ospedale Pediatrico Bambino Gesu	Roma		Italy	00165
21	Leiden University Medical Center (LUMC)	Leiden		Netherlands	2333
22	Princess Maxima Center Utrecht	Utrecht		Netherlands	3584
23	Uniwerstytecki Azpital Kliniczny we Wroclawiu	Wrocław	Dolnoslaskie	Poland	50-556
24	Hospital Sant Joan de Deu	Esplugues De Llobregat	Barcelona	Spain	08950
25	Hospital Infantil Universitario Nino Jesus	Madrid		Spain	28009
26	Royal Marsden Hospital	Sutton	Surrey	United Kingdom	SM2 5PT
27	Newcastle-upon-Tyne Hospitals-Great Childrens Hospital	Newcastle Upon Tyne	Tyneside	United Kingdom	NE1 4LP
28	Birmingham Childrens Hospital	Birmingham	West Midlands	United Kingdom	B4 6NH
29	Leeds Children's Hospital	Leeds	West Yorkshire	United Kingdom	LS1 3EX
30	Bristol Royal Hospital for Children	Bristol		United Kingdom	BS2 8BJ
31	Royal Hospital for Sick Children	Glasgow		United Kingdom	G51 4TF
32	University College London Hospital	London		United Kingdom	NW1 2BU
33	St Marys Hospital	London		United Kingdom	W2 1NY
34	Great Ormond Street Hospital for Children	London		United Kingdom	WCIN 3JH
35	Royal Manchester Childrens Hospital	Manchester		United Kingdom	M13 9WL
36	Sheffield Children's Hospital	Sheffield		United Kingdom	S10 2TH

Sponsors and Collaborators

• Chimerix

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 26, 2017

More Information

Publications

None provided.

• Responsible Party: Chimerix
• ClinicalTrials.gov Identifier: NCT03339401
• Other Study ID Numbers: CMX001-999
• First Posted: Nov 13, 2017
• Last Update Posted: Jan 25, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Chimerix: Adenovirus; Pediatric; Hematopoietic Cell Transplant; Brincidofovir; Standard of care
• Additional relevant MeSH terms: Adenoviridae Infections; Brincidofovir

Study Results

Participant Flow

Arm/Group Title	Brincidofovir	Standard of Care
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	20	9
COMPLETED	11	5
NOT COMPLETED	9	4

Baseline Characteristics

Arm/Group Title	Brincidofovir	Standard of Care	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	20	9	29
Age (Count of Participants)
<=18 years	20 100%	9 100%	29 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.1 (4.05)	5.9 (4.18)	5.3 (4.04)
Sex: Female, Male (Count of Participants)
Female	8 40%	5 55.6%	13 44.8%
Male	12 60%	4 44.4%	16 55.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5%	0 0%	1 3.4%
Not Hispanic or Latino	18 90%	8 88.9%	26 89.7%
Unknown or Not Reported	1 5%	1 11.1%	2 6.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 5%	1 11.1%	2 6.9%
Native Hawaiian or Other Pacific Islander	1 5%	0 0%	1 3.4%
Black or African American	0 0%	0 0%	0 0%
White	17 85%	4 44.4%	21 72.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 5%	4 44.4%	5 17.2%
Region of Enrollment (participants) [Number]
United States	4 20%	2 22.2%	6 20.7%
United Kingdom	12 60%	5 55.6%	17 58.6%
Italy	0 0%	1 11.1%	1 3.4%
France	3 15%	0 0%	3 10.3%
Germany	1 5%	1 11.1%	2 6.9%
Adenovirus in plasma (Count of Participants)
Count of Participants [Participants]	20 100%	9 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL).
Description	The primary efficacy endpoint for this study was the time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia (log10 copies/mL) from randomization through Week 16 post-randomization. Due to the small number of subjects enrolled in the study, formal efficacy analyses were not performed. Individual subject AdV viremia profiles show the differential anti-adenoviral effect of brincidofovir (BCV) in comparison to standard of care (SoC) therapy.
Time Frame	From randomization to 16 weeks post-randomization

Outcome Measure Data

Analysis Population Description

The time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia was not calculated because many of the viral response data were arbitrarily truncated/censored and individual subject AdV viremia profiles cannot be reported due to concerns with patient confidentiality.

Arm/Group Title	Brincidofovir	Standard of Care
Arm/Group Description	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.	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.
Measure Participants	0	0

Adverse Events

Time Frame	From randomization to 16 weeks post-randomization.
Adverse Event Reporting Description	Note: Other Adverse Events includes non-serious and serious adverse events.
Arm/Group Title	Brincidofovir		Standard of Care
Arm/Group Description	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.		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.
All Cause Mortality
	Brincidofovir		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/20 (20%)		1/9 (11.1%)
Serious Adverse Events
	Brincidofovir		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/20 (75%)		6/9 (66.7%)
Blood and lymphatic system disorders
Evans Syndrome	0/20 (0%)		1/9 (11.1%)
Haemolytic anaemia	1/20 (5%)		0/9 (0%)
Haemolytic uraemic syndrome	1/20 (5%)		0/9 (0%)
Cardiac disorders
Cardiac tamponade	1/20 (5%)		0/9 (0%)
Pericardial effusion	1/20 (5%)		0/9 (0%)
Gastrointestinal disorders
Abdominal distension	1/20 (5%)		0/9 (0%)
Abdominal pain	1/20 (5%)		0/9 (0%)
Diarrhoea	0/20 (0%)		1/9 (11.1%)
Gastric haemorrhage	1/20 (5%)		0/9 (0%)
Gastrointestinal haemorrhage	2/20 (10%)		0/9 (0%)
Vomiting	1/20 (5%)		0/9 (0%)
Unevaluable event	1/20 (5%)		0/9 (0%)
General disorders
Pyrexia	1/20 (5%)		3/9 (33.3%)
Hepatobiliary disorders
Venoocclusive liver disease	1/20 (5%)		0/9 (0%)
Infections and infestations
Adenovirus infection	1/20 (5%)		0/9 (0%)
Bacteraemia	1/20 (5%)		0/9 (0%)
Device related infection	2/20 (10%)		0/9 (0%)
Device related sepsis	1/20 (5%)		0/9 (0%)
Enterococcal bacteraemia	0/20 (0%)		1/9 (11.1%)
Gastroenteritis viral	0/20 (0%)		1/9 (11.1%)
Human herpesvirus 6 infection	0/20 (0%)		1/9 (11.1%)
Influenza	1/20 (5%)		0/9 (0%)
Lower respiratory tract infection fungal	0/20 (0%)		1/9 (11.1%)
Parainfluenzae virus infection	1/20 (5%)		0/9 (0%)
Pneumonia cytomegaloviral	0/20 (0%)		1/9 (11.1%)
Rhinovirus infection	2/20 (10%)		0/9 (0%)
Sepsis	1/20 (5%)		0/9 (0%)
Viral upper respiratory tract infection	1/20 (5%)		0/9 (0%)
Investigations
Astrovirus test positive	1/20 (5%)		0/9 (0%)
Blood creatinine abnormal	1/20 (5%)		0/9 (0%)
Body temperature increased	1/20 (5%)		0/9 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	1/20 (5%)		0/9 (0%)
Musculoskeletal and connective tissue disorders
Flank pain	0/20 (0%)		1/9 (11.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/20 (5%)		0/9 (0%)
Nervous system disorders
Encephalopathy	1/20 (5%)		0/9 (0%)
Product Issues
Device dislocation	1/20 (5%)		0/9 (0%)
Renal and urinary disorders
Acute kidney injury	1/20 (5%)		1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/20 (5%)		0/9 (0%)
Hypoxia	1/20 (5%)		0/9 (0%)
Respiratory failure	1/20 (5%)		1/9 (11.1%)
Other (Not Including Serious) Adverse Events
	Brincidofovir		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/20 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Anaemia	2/20 (10%)		0/9 (0%)
Evans Syndrome	0/20 (0%)		1/9 (11.1%)
Febrile neutropenia	2/20 (10%)		0/9 (0%)
Haemolytic uraemic syndrome	3/20 (15%)		0/9 (0%)
Neutropenia	2/20 (10%)		2/9 (22.2%)
Thrombotic microanglopathy	2/20 (10%)		0/9 (0%)
Cardiac disorders
Pericardial effusion	2/20 (10%)		0/9 (0%)
Endocrine disorders
Adrenal insufficiency	0/20 (0%)		1/9 (11.1%)
Gastrointestinal disorders
Abdominal pain	6/20 (30%)		1/9 (11.1%)
Anal fissure	0/20 (0%)		1/9 (11.1%)
Diarrhoea	7/20 (35%)		1/9 (11.1%)
Gastric haemorrhage	1/20 (5%)		1/9 (11.1%)
Nausea	4/20 (20%)		0/9 (0%)
Pneumatosis intestinalis	2/20 (10%)		0/9 (0%)
Vomiting	6/20 (30%)		1/9 (11.1%)
Gastrointestinal haemorrhage	2/20 (10%)		0/9 (0%)
General disorders
Mucosal inflammation	1/20 (5%)		1/9 (11.1%)
Pyrexia	8/20 (40%)		5/9 (55.6%)
Hepatobiliary disorders
Venoocclusive liver disease	2/20 (10%)		0/9 (0%)
Immune system disorders
Engraftment syndrome	2/20 (10%)		0/9 (0%)
Graft versus host disease	0/20 (0%)		2/9 (22.2%)
Graft versus host disease in skin	2/20 (10%)		2/9 (22.2%)
Infections and infestations
Adenovirus infection	3/20 (15%)		0/9 (0%)
Device related infection	2/20 (10%)		0/9 (0%)
Enterococcal bacteraemia	0/20 (0%)		1/9 (11.1%)
Epstein-Barr virus infection	0/20 (0%)		1/9 (11.1%)
Gastroenteritis viral	0/20 (0%)		1/9 (11.1%)
Human herpesvirus 6 infection	0/20 (0%)		1/9 (11.1%)
Influenza	2/20 (10%)		0/9 (0%)
Lower respiratory tract infection fungal	0/20 (0%)		1/9 (11.1%)
Pneumonia	0/20 (0%)		1/9 (11.1%)
Pneumonia cytomegaloviral	0/20 (0%)		1/9 (11.1%)
Rhinitis	0/20 (0%)		2/9 (22.2%)
Rhinovirus infection	2/20 (10%)		0/9 (0%)
Viral upper respiratory tract infection	1/20 (5%)		1/9 (11.1%)
Investigations
Alanine aminotransferase increased	2/20 (10%)		2/9 (22.2%)
Aspartate aminotransferase increased	1/20 (5%)		1/9 (11.1%)
Blood bilirubin increased	2/20 (10%)		1/9 (11.1%)
Blood creatinine increased	1/20 (5%)		1/9 (11.1%)
Blood magnesium decreased	0/20 (0%)		1/9 (11.1%)
Fluid balance positive	0/20 (0%)		1/9 (11.1%)
Gamma-glutamyltranferase increased	4/20 (20%)		2/9 (22.2%)
Haemoglobin decreased	0/20 (0%)		1/9 (11.1%)
Lipase increased	1/20 (5%)		1/9 (11.1%)
Liver function test increased	0/20 (0%)		1/9 (11.1%)
Platelet count decreased	1/20 (5%)		1/9 (11.1%)
Metabolism and nutrition disorders
Decreased appetite	3/20 (15%)		0/9 (0%)
Fluid overload	2/20 (10%)		0/9 (0%)
Hypokalaemia	2/20 (10%)		1/9 (11.1%)
Hypomagnesaemia	2/20 (10%)		0/9 (0%)
Hypophosphataemia	2/20 (10%)		1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Flank pain	0/20 (0%)		1/9 (11.1%)
Nervous system disorders
Encephalopathy	1/20 (5%)		1/9 (11.1%)
Headache	2/20 (10%)		0/9 (0%)
Renal and urinary disorders
Acute kidney injury	1/20 (5%)		1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)		1/9 (11.1%)
Hypoxia	2/20 (10%)		2/9 (22.2%)
Nasal congestion	0/20 (0%)		1/9 (11.1%)
Respiratory failure	1/20 (5%)		1/9 (11.1%)
Skin and subcutaneous tissue disorders
Dermatitis diaper	0/20 (0%)		1/9 (11.1%)
Dry skin	2/20 (10%)		1/9 (11.1%)
Rash	1/20 (5%)		2/9 (22.2%)
Rash generalised	0/20 (0%)		1/9 (11.1%)
Rash maculo-papular	1/20 (5%)		1/9 (11.1%)
Vascular disorders
Hypertension	2/20 (10%)		2/9 (22.2%)

Limitations/Caveats

The study was terminated in May 2019 due to poor subject accrual rates. As a result, statistical analyses were not performed. Limited demographic, efficacy, and safety data are provided for the 29 subjects who were enrolled as descriptive summaries.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Within 12 months after the end of the Study at all sites, if no publication of the overall multi-center results has been made, institutions are entitled to publish their locally obtained results, provided the Sponsor is given opportunity to review and comment. Institution publication may be delayed up to an additional 3 months to allow Sponsor to seek patent protection.