Clinical trial NCT03339401: The AdAPT Trial; Adenovirus After Allogeneic Pediatric Transplantation
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Adenovirus
Keywords: Adenovirus
Pediatric
Hematopoietic Cell Transplant
Brincidofovir
Standard of care
Lead sponsor: Chimerix
Sponsor class: INDUSTRY
First posted: 2017-11-13
Enrollment: 29
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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 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.

Primary outcomes:
measure: Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL).
timeFrame: From randomization to 16 weeks post-randomization
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Hackensack
country: United States
facility: Joseph M. Sanzari Childrens Hospital-Regional Cancer Care
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Seattle
country: United States
facility: University of Washington-Seattle Childrens Hospital
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Lyon
country: France
facility: IHOPe-Institut d'Homatologie et d'Oncologie Pediatrique
city: Paris
country: France
facility: Hopital Necker-Enfants Malades
city: Paris
country: France
facility: Hopital Universitaire Robert Debre
city: Tübingen
country: Germany
facility: Universitatsklinik fur Kinder-und Jugendmedizin
state: Baden-Wurttemberg
city: München
country: Germany
facility: Dr. von Haunersches Kinderspital, Abteilung fur Padiatrische
state: Bavaria
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum
city: Dublin
country: Ireland
facility: Our Lady's Children Hospital
city: Monza
country: Italy
facility: Fondazione MBBM-CTMO Pediatrico
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Leiden
country: Netherlands
facility: Leiden University Medical Center (LUMC)
city: Utrecht
country: Netherlands
facility: Princess Maxima Center Utrecht
city: Wrocław
country: Poland
facility: Uniwerstytecki Azpital Kliniczny we Wroclawiu
state: Dolnoslaskie
city: Esplugues De Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: Surrey
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle-upon-Tyne Hospitals-Great Childrens Hospital
state: Tyneside
city: Birmingham
country: United Kingdom
facility: Birmingham Childrens Hospital
state: West Midlands
city: Leeds
country: United Kingdom
facility: Leeds Children's Hospital
state: West Yorkshire
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: St Marys Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
Study officials:
References: