Study to Assess Brincidofovir Treatment of Serious Diseases or Conditions Caused by Double-stranded DNA Viruses

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.

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 with a life-threatening or serious disease or condition caused by infection with any dsDNA virus(es), who met the protocol eligibility criteria and who were approved by the Chimerix Medical Monitor were enrolled in this open-label treatment study. During the course of the study, the viral disease indications were narrowed in Amendment 2 to cytomegalovirus, adenovirus, herpes simplex virus, vaccinia virus, variola virus, or monkeypox virus to focus on indications that were under study in controlled clinical trials of oral BCV and on viral disease with few, if any, options for treatment. However, subjects with other viral disease indications may have been enrolled with the approval of the Chimerix Medical Monitor.

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. Subjects who met criteria for resolution of viral disease may have: 1) discontinued BCV; 2) reduced the dose or dosing frequency of BCV; or 3) continued BCV QW or BIW, depending on the investigator's assessment of the risk of relapse and following discussion with the Chimerix medical monitor.

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.