Study to Assess Brincidofovir Treatment of Serious Diseases or Conditions Caused by Double-stranded DNA Viruses
Condition: Double-stranded DNA Virus
MeSH terms: Virus Diseases
Intervention: Brincidofovir
Intervention description: Brincidofovir (BCV) was administered orally either once or twice weekly for up to 3 months. Treatment may have been extended for an additional 3 months depending a satisfactory review of safety parameters. Subjects could not receive more than a total of 6 months of treatment with BCV without prior approval.
Intervention MeSH terms: Brincidofovir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 210.0
Sex: All
Healthy volunteers: No
Keywords: Cytomegalovirus; Adenovirus; Herpes simplex virus; Vaccinia virus; Variola virus

Summary:

      This was a multicenter, open-label study of oral brincidofovir (BCV) treatment of serious
      disease or conditions caused by double-stranded DNA (dsDNA) virus(es). Subjects received
      either a weight-based or a fixed dose of oral BCV once weekly (QW) or twice weekly (BIW) for
      up to 3 months until clinical disease was resolved or stabilized and/or viral DNA by
      polymerase chain reaction testing was negative for 4 consecutive weeks, whichever was longer.
      Under the first protocol amendment, adults and adolescents (≥13 years) received 200 mg or 300
      mg BCV BIW (not to exceed 4 mg/kg total weekly dose) depending on the difficulty of treating
      their disease (i.e., Group 1 or Group 2, respectively), and pediatric subjects (≤12 years)
      received 4 mg/kg BCV BIW. Under the second protocol amendment, adults and adolescents (≥13
      years), regardless of viral infection/disease, had a maximum weekly dose of 200 mg, i.e., 200
      mg QW or 100 mg BIW; not to exceed 4mg/kg total weekly dose. Pediatric subjects (≤12 years),
      regardless of viral infection/disease, had a maximum weekly dose of 4 mg/kg, i.e., 4 mg/kg QW
      or 2 mg/kg BIW; not to exceed 200 mg.
    

Eligibility criteria:

        Inclusion Criteria

        Subjects were required to meet all of the following inclusion criteria in order to
        participate in the study:

          1. Had an immediately life-threatening or serious disease or condition caused by
             infection with a double-stranded DNA virus (including subjects with recurrent viral
             disease). [Note: During the course of the study, the viral disease indications were
             narrow to focus on indications that were under study in controlled clinical trials of
             brincidofovir (BCV) and on viral diseases that had few, if any, options for treatment,
             including cytomegalovirus (CMV), adenovirus (AdV), herpes simplex virus (HSV),
             vaccinia virus (VAVC), variola virus (VARV) or monkeypox viruses(s).]

          2. Had a life expectancy of at least 2 weeks and commitment to continuation of supportive
             care for at least 4 weeks.

          3. Were able to ingest and absorb oral medication (in the judgment of the investigator
             and based on lack of significant gastrointestinal [GI] pathology such as small bowel
             resection or ileus). [Note: Use of total parenteral nutrition was not in and of itself
             exclusionary as long as the reason for use did not disqualify the subject based on
             this criterion.]

          4. Were willing and able to understand and provide written informed consent. [Note: For
             minors or those incapable of providing written informed consent (i.e., incapacitated),
             consent was provided by a parent or legal guardian or representative who could
             understand and provide written informed consent.]

          5. Were willing and able, to the best of his or her (or parent/guardian) knowledge, to
             participate in all required study activities for the duration of the study.

          6. If female of reproductive potential, agreed to use 2 acceptable methods of birth
             control throughout the study with at least 1 being a barrier method.

          7. In the judgment of the investigator, subjects for whom no comparable or satisfactory
             therapeutic alternative was available

        Exclusion Criteria

        Subjects were not to be enrolled if they met any of the following exclusion criteria:

          1. Were pregnant or currently nursing.

          2. Had hypersensitivity to cidofovir or BCV.

          3. Had a long-term prognosis that included a poor likelihood of survival due to
             irreversible organ failure including, for example, subjects with frank hepatic failure
             and adults with Grade 4 graft versus host disease of the GI tract.

          4. Were eligible for enrollment and able to participate in a clinical trial evaluating
             BCV. [Note: Per the FDA guidance, subjects eligible and able to participate in a
             controlled clinical study evaluating BCV were not eligible for participation in this
             study. Subjects who did not meet eligibility criteria for a controlled BCV clinical
             study or who were unable to participate because, for example, of logistical or other
             issues were eligible to participate in this study. The investigator verified that
             his/her subjects met this criterion on the Eligibility electronic case report form. A
             subject simply preferring enrollment in this study over a BCV controlled clinical
             trial did not qualify for enrollment in this study.]

          5. Had any other condition that would have, in the judgment of the investigator, put the
             subject at increased risk during participation in the study or interfered with the
             conduct of the study.

          6. Had a serum total bilirubin value >5 x the upper limit of normal reference range,
             taking into account the age and/or gender of the subject. [Note: In order to avoid any
             unwarranted delay to the start of BCV treatment, compliance with this exclusion
             criterion may have been determined based on the results of testing performed at a
             local safety laboratory, rather than waiting for results from the designated central
             safety laboratory. If relying on local safety laboratory test results, the blood
             sample must have been collected no more than 7 days prior to the scheduled first dose
             administration on Day 0, otherwise it was repeated. A subject whose elevated bilirubin
             was due to the underlying viral disease may still have been enrolled into the study if
             the participation of the subject was prospectively approved by the Chimerix Medical
             Monitor.]

        Subjects with acute or chronic renal impairment, pediatric and adolescent subjects, and
        subjects aged 65 years and older were included in this study. Subjects with hepatic
        impairment were included unless the investigator judged that the subject had irreversible
        hepatic compromise.