Double-stranded DNA Virus
Conditions
Keywords
Cytomegalovirus, Adenovirus, Herpes simplex virus, Vaccinia virus, Variola virus
Brief 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.
Detailed description
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.
Interventions
DRUGBrincidofovir
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.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus | 3 months | Proportion of subjects who achieved a confirmed reduction in viral load for the primary dsDNA virus of ≥1 log10 copies/mL from baseline or to an undetectable level. Confirmation required the reduction in viral load (i.e., decrease of ≥ 1 log10 copies/mL from baseline or to undetectable levels) to be maintained at the next assessment for the subject to be considered a success. |
Countries
United States
Participant flow
Recruitment details
This was an expanded access study with the primary objective of providing brincidofovir (BCV) to subjects with serious or life-threatening conditions caused by double-stranded DNA viral infections. All subjects enrolled received BCV for up to 3 months until their clinical disease was resolved or stabilized and/or viral DNA testing was negative for 4 consecutive weeks, whichever was longer.
Participants by arm
| Arm | Count |
|---|---|
| BCV (≤4 mg/kg/Week) Pediatric subjects (≤12 years) who received BCV once or twice weekly. | 30 |
| BCV (>4 mg/kg/Week) Pediatric subjects (≤12 years) who received BCV once or twice weekly. | 38 |
| BCV (≤200 mg/Week) Adult/adolescent subjects (≥13 years) who received BCV once or twice weekly. | 102 |
| BCV (>200 mg/Week) Adult/adolescent subjects (≥13 years) who received BCV once or twice weekly. | 40 |
| Total | 210 |
Baseline characteristics
| Characteristic | BCV (≤4 mg/kg/Week) | BCV (>4 mg/kg/Week) | BCV (≤200 mg/Week) | BCV (>200 mg/Week) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 5.2 years STANDARD_DEVIATION 2.68 | 5.9 years STANDARD_DEVIATION 3.7 | 45.3 years STANDARD_DEVIATION 17.21 | 45.7 years STANDARD_DEVIATION 17.57 | 32.5 years STANDARD_DEVIATION 23.51 |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 41 Participants | 18 Participants | 87 Participants |
| Sex: Female, Male Male | 16 Participants | 24 Participants | 61 Participants | 22 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 37 / 38 | 101 / 102 | 40 / 40 |
| serious Total, serious adverse events | 27 / 30 | 32 / 38 | 80 / 102 | 35 / 40 |
Outcome results
Primary
Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus
Proportion of subjects who achieved a confirmed reduction in viral load for the primary dsDNA virus of ≥1 log10 copies/mL from baseline or to an undetectable level. Confirmation required the reduction in viral load (i.e., decrease of ≥ 1 log10 copies/mL from baseline or to undetectable levels) to be maintained at the next assessment for the subject to be considered a success.
Time frame: 3 months
Population: Only subjects who achieved a confirmed reduction in viral load for the primary dsDNA virus of ≥1 log10 copies/mL from baseline or to an undetectable level were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCV (≤4 mg/kg/Week) | Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus | 15 Participants |
| BCV (>4 mg/kg/Week) | Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus | 18 Participants |
| BCV (≤200 mg/Week) | Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus | 39 Participants |
| BCV (>200 mg/Week) | Number of Subjects Who Had a Sustained and Significant Reduction in Plasma Viral Load of Primary dsDNA Virus | 13 Participants |