Study to Assess the Safety and Efficacy of Brincidofovir in Treatment of Early Versus Late Adenovirus Infection
Condition: Adenovirus Infection
MeSH terms: Infections; Communicable Diseases; Adenoviridae Infections
Intervention: Brincidofovir
Intervention description: BCV administered twice weekly, dose depending on weight.
Intervention MeSH terms: Brincidofovir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 201.0
Sex: All
Minimum age: 2 Months
Healthy volunteers: No
Keywords: Adenovirus Infection

Summary:

      This was a Phase 3 open-label, non-randomized, multicenter study of oral brincidofovir (BCV)
      administered twice weekly for the treatment of adenovirus (AdV) infection detected during
      asymptomatic AdV viremia or during symptomatic AdV infection.
    

Eligibility criteria:

        Inclusion Criteria Subjects were required to meet all of the following criteria, as
        applicable, to be eligible to participate in this study.

          1. Were male or female, aged 2 months or older.

          2. Had either of the following:

               -  Disseminated adenovirus (AdV) disease; or

               -  An underlying immunocompromised state and were at risk of progression to
                  disseminated AdV disease.

             [Note: Subjects with symptomatic AdV infection (i.e., localized or disseminated AdV
             disease) could have been screening immediately, with brincidofovir (BCV) therapy
             initiated after receipt of the screening virology results from the designated central
             virology laboratory confirming study eligibility. Subjects with asymptomatic AdV
             infection (i.e., had no symptoms of AdV disease) could have been consented and
             screened only if they had at least 1 positive or detectable AdV DNA (quantitative [q])
             polymerase chain reaction (PCR) test (in any blood fluid or compartment) from the
             local virology laboratory, with treatment initiated only after confirmation of AdV
             positivity by 2 separate measurements at the designated central virology laboratory.
             Where the results from 2 AdV DNA (q)PCR measurements in plasma or non-plasma body
             fluid or compartment were needed to show that a subject was at risk of progression to
             disseminated AdV disease, the second measurement had to be resulted prior to the
             initiation of BCV therapy.]

          3. Were able to ingest and absorb oral medication (in the judgement of the investigator
             and based on lack of significant gastrointestinal [GI] events/medical history).

          4. If male of reproductive potential, were willing to use an acceptable contraceptive
             method(s) during sexual intercourse with a female partner of reproductive potential
             throughout the duration of this participation in the study and for at least 6 months
             after his last dose of BCV.

          5. If female of reproductive potential, i.e., not premenarche, postmenopausal, surgically
             sterile, or had documented ovarian failure, were willing to use 2 acceptable
             contraceptive methods, 1 of which must have been a barrier method, during sexual
             intercourse with a nonsterile male partner, throughout the duration of her
             participation in the study and for at least 6 months after her last dose of BCV.

          6. Were willing and able to understand and provide written informed consent to
             participate in the study. [Note: If the subject was under 18 years of age or was
             otherwise unable to legally give his or her informed consent to participate in the
             study, then written informed consent to participate had to be obtained from the
             parent(s) or legal guardian(s) of the subject or other legal personal
             representative(s), as applicable. In addition, in the case of minor subjects, the
             written assent of the subject to participate in the study was obtained where required
             by applicable institutional policy on the consenting of minor study participants.]

          7. The subject and his or her caregivers (as applicable) were willing and able to
             participate in all required study activities for the entire duration of the study
             (i.e., through completion of Week 36).

        Exclusion Criteria

        Subjects who met any of the following criteria (as applicable) were not eligible to
        participate in this study:

          1. If a female of reproductive potential, the subject was pregnant, planning to become
             pregnant during the study or within 6 months after their anticipated last BCV dose, or
             was nursing a child.

          2. Had hypersensitivity (not including renal dysfunction or eye disorder) to cidofovir
             (CDV) or to BCV or its formulation excipients.

          3. Had received treatment with another investigational drug within 14 days prior to Day 1
             unless prior approval was received from the Chimerix medical monitor (or designee).

          4. Were participating in another interventional clinical trial unless prior approval was
             received from the Chimerix medical monitor (or designee).

          5. Had previously received an anti-AdV vaccine or a cell-based anti-AdV therapy.

          6. Were receiving intravenous (IV) CDV, leflunomide, vidarabine, systemic ribavirin, or
             another investigational anti-AdV drug at Day 1. [Note: Subjects who were receiving
             treatment with IV CDV prior to enrollment had to discontinue IV CDV and wait until a
             minimum of 48 hours had elapsed from last IV CDV administration before initiating BCV
             therapy. All other drugs had to be discontinued prior to Day 1.]

          7. Were receiving digoxin or ketoconazole (other than topical formulations) at Day 1 or
             were anticipated to need treatment with either drug during the treatment phase of the
             study.

          8. Were infected with HIV, hepatitis B virus (HBV), and/or hepatitis C virus (HCV), had
             evidence of active viral replication within 6 months prior to screening, as
             demonstrated by detectable HIV or HCV RNA, or had detectable HBV DNA in blood, plasma
             or serum.

          9. Had end-stage renal disease, i.e., an estimated glomerular filtration rate <15 mL/min,
             unless receiving renal replacement therapy.

         10. Had a serum alanine aminotransferase or aspartate aminotransferase concentration >5 x
             the upper limit of normal (ULN), or a serum total bilirubin concentration >2 x the ULN
             and a serum direct (conjugated) bilirubin concentration >1.5 x the ULN, as reported by
             the central safety laboratory, unless, in the judgment of the investigator, the
             abnormality(ies) was/were related to the subject's AdV infection/disease.

         11. Had ongoing Grade 3 or higher diarrhea, unless, in the judgment of the investigator,
             the diarrhea was related to the subject's underlying AdV infection/disease.

         12. Had Stage 3 or higher graft versus host disease (GVHD) of the intestine (GI-GVHD or
             any other GI disease that would have, in the judgment of the investigator, precluded
             the subject from taking or absorbing oral medication (e.g., clinically active Crohn's
             disease, ischemic colitis, moderate or severe ulcerative colitis, small bowel
             resection, ileus, or any condition expected to require abdominal surgery during the
             course of study participation).

         13. Had any other condition, including abnormal laboratory values, that would have, in the
             judgment of the investigator, put the subject at increased risk by participating in
             the study, or would have interfered with the conduct or planned analyses of the study.