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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT03339401
Other study ID # CMX001-999
Secondary ID
Status Terminated
Phase Phase 2
First received
Last updated
Start date December 22, 2017
Est. completion date May 10, 2019

Study information

Verified date January 2021
Source Chimerix
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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).


Recruitment information / eligibility

Status Terminated
Enrollment 29
Est. completion date May 10, 2019
Est. primary completion date May 10, 2019
Accepts healthy volunteers No
Gender All
Age group 2 Months to 25 Years
Eligibility 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 a/ß 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 1. 7. 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. 8. Concurrent HIV, active hepatitis B virus, or hepatitis C virus infection. 9. 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. 10. Estimated creatinine clearance <30 mL/min or use of renal replacement therapy within 7 days prior to Day 1. 11. Previous receipt of BCV at any time or receipt of CDV (IV or intravesicular) or letermovir within 48 hours prior to Day 1. 12. 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.

Study Design


Related Conditions & MeSH terms


Intervention

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.
Drug:
Brincidofovir
Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.

Locations

Country Name City State
France IHOPe-Institut d'Homatologie et d'Oncologie Pediatrique Lyon
France Hopital Necker-Enfants Malades Paris
France Hopital Universitaire Robert Debre Paris
Germany Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum Berlin
Germany Dr. von Haunersches Kinderspital, Abteilung fur Padiatrische München Bavaria
Germany Universitatsklinik fur Kinder-und Jugendmedizin Tübingen Baden-Wurttemberg
Ireland Our Lady's Children Hospital Dublin
Italy Fondazione MBBM-CTMO Pediatrico Monza
Italy Ospedale Pediatrico Bambino Gesu Roma
Netherlands Leiden University Medical Center (LUMC) Leiden
Netherlands Princess Maxima Center Utrecht Utrecht
Poland Uniwerstytecki Azpital Kliniczny we Wroclawiu Wroclaw Dolnoslaskie
Spain Hospital Sant Joan de Deu Esplugues De Llobregat Barcelona
Spain Hospital Infantil Universitario Nino Jesus Madrid
United Kingdom Birmingham Childrens Hospital Birmingham West Midlands
United Kingdom Bristol Royal Hospital for Children Bristol
United Kingdom Royal Hospital for Sick Children Glasgow
United Kingdom Leeds Children's Hospital Leeds West Yorkshire
United Kingdom Great Ormond Street Hospital for Children London
United Kingdom St Marys Hospital London
United Kingdom University College London Hospital London
United Kingdom Royal Manchester Childrens Hospital Manchester
United Kingdom Newcastle-upon-Tyne Hospitals-Great Childrens Hospital Newcastle Upon Tyne Tyneside
United Kingdom Sheffield Children's Hospital Sheffield
United Kingdom Royal Marsden Hospital Sutton Surrey
United States University of Chicago Chicago Illinois
United States Cincinnati Childrens Hospital Medical Center Cincinnati Ohio
United States Duke University Medical Center Durham North Carolina
United States Joseph M. Sanzari Childrens Hospital-Regional Cancer Care Hackensack New Jersey
United States Children's Hospital of Los Angeles Los Angeles California
United States St. Jude Children's Research Hospital Memphis Tennessee
United States Medical College of Wisconsin Milwaukee Wisconsin
United States Memorial Sloan Kettering Cancer Center New York New York
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States University of California San Francisco San Francisco California
United States University of Washington-Seattle Childrens Hospital Seattle Washington

Sponsors (1)

Lead Sponsor Collaborator
Chimerix

Countries where clinical trial is conducted

United States,  France,  Germany,  Ireland,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL). 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. From randomization to 16 weeks post-randomization
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