The AdAPT Trial; Adenovirus After Allogeneic Pediatric Transplantation
Condition: Adenovirus
MeSH terms: Adenoviridae Infections
Intervention: Standard of Care; Brincidofovir
Intervention description: 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.; Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.
Intervention MeSH terms: Brincidofovir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 2 Months
Maximum age: 25 Years
Healthy volunteers: No
Keywords: Adenovirus; Pediatric; Hematopoietic Cell Transplant; Brincidofovir; Standard of care

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.
    

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.