Adenovirus Disease
Conditions
Keywords
AdV, Hematopoeitic Stem Cell Transplant, HSCT
Brief summary
This study was designed to assess the safety and efficacy of preemptive treatment with oral brincidofovir (BCV), as compared to placebo, for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia.
Detailed description
This was a Phase 2, randomized, multicenter, placebo-controlled study for pediatric and adult subjects who had undergone hematopoietic stem cell transplantation (HCT) and who had been identified as having asymptomatic adenovirus (AdV) viremia \[i.e., had detectable AdV DNA in plasma based on polymerase chain reaction testing performed at the local laboratory with no AdV disease symptoms\]. The primary objectives of the study were to assess the safety and tolerability of oral brincidofovir (BCV), and to estimate the treatment failure rate based on an efficacy endpoint with 2 different dosing regimens of oral BCV versus placebo.
Interventions
DRUGBrincidofovir
* Adult subjects: 200mg BCV administered as 50mg tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets). * Pediatric subjects: 4mg/kg BCV (not to exceed a total single dose of 200mg) administered using a 10 mg/mL liquid formulation taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).
OTHERPlacebo
Adult subjects: Matching placebo tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets). • Pediatric subjects: Matching liquid placebo taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Months to 75 Years
Healthy volunteers
No
Inclusion criteria
For inclusion into the study, subjects were required to fulfill all of the following criteria: 1. Were males or female aged ≥3 months to ≤75 years. 2. Received an allogeneic hematopoietic stem cell transplant (HCT). 3. Had positive serum adenovirus (AdV) PCR (\>100 copies/mL) as measured by the central laboratory (unless the subject developed AdV disease while participating in the prescreening activities and after concurrence from the Chimerix medical monitor or designee). 4. Was on dialysis during treatment if he/she had an estimated glomerular filtration rate (eGFR) ≤30 mL/minute. 5. Subject or guardian(s) were willing to comply with the protocol. 6. Subject or guardian(s) were willing and able to understand the informed consent/assent. 7. Female subjects of child-bearing potential must have had a negative pregnancy test and must have agreed to use 2 acceptable methods of birth control throughout the study with at least 1 being a barrier method. Sexually active males of procreation potential must have been able and willing to se a reliable and medically approved contraceptive method throughout the study. At least 1 barrier method of contraception must have been used.
Exclusion criteria
Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant AdV Infection | 12 weeks | The primary objective of this study was to evaluate the safety and efficacy of preemptive treatment with brincidofovir (BCV) versus placebo for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia. The outcome measure for the primary endpoint was treatment failure, a composite endpoint that consisted of the following: * Progression to probable AdV disease (other positive causes/agents have been ruled out and subject has disease-targeted organ-specific signs or symptoms) or definitive AdV disease (AdV detected in disease-targeted organ/system biopsy via antigen/immunohistochemistry, culture, and/or polymerase chain reaction and has at least 1 disease-targeted organ-specific sign or symptom); or * Increasing AdV viremia (defined as an increase from baseline in AdV viremia by ≥1 log10, confirmed on a second measurement, at least 1 week apart) and requiring discontinuation from blinded therapy. |
Countries
United States
Participant flow
Pre-assignment details
Randomized (blinded) subjects who considered treatment failures were offered open-label BCV therapy. These subjects followed the same schedule of assessments, beginning at Day 0 for up to 12 weeks followed by 4 weeks of post-treatment follow-up. Additionally, 4 subjects who had not been previously enrolled in the randomized (blinded) phase of the study were enrolled directly to the open-label arm.
Participants by arm
| Arm | Count |
|---|---|
| BCV BIW Randomized (Blinded) Phase
* Adult subjects: 200 mg brincidofovir (BCV) administered as four 50 mg tablets taken orally twice weekly (BIW).
* Pediatric subjects: 4 mg/kg BCV (not to exceed a total single dose of 200 mg) administered using a 10 mg/mL liquid formulation taken orally BIW (as 2 mg/kg). | 14 |
| BCV QW Randomized (Blinded) Phase
* Adult subjects: 200 mg brincidofovir (BCV) administered as four 50 mg tablets taken orally once weekly (QW).
* Pediatric subjects: 4 mg/kg BCV (not to exceed a total single dose of 200 mg) administered using a 10 mg/mL liquid formulation taken orally QW (as 4 mg/kg). | 16 |
| Placebo Randomized (Blinded) Phase
* Adult subjects: Matching placebo tablets taken orally once weekly (QW) or twice weekly (BIW).
* Pediatric subjects: Matching liquid placebo taken orally QW or BIW. | 18 |
| BCV Direct to Open-Label Subjects who were enrolled directly to open-label and had not been previously randomized (n=4) received 200 mg brincidofovir (BCV) administered as four 50 mg tablets taken orally twice weekly (BIW).
This number does not include subjects who were previously randomized and moved to open-label (n=8), as they are represented in their previously randomized arm. | 4 |
| Total | 52 |
Baseline characteristics
| Characteristic | BCV BIW | BCV QW | Placebo | BCV Direct to Open-Label | Total |
|---|---|---|---|---|---|
| Age, Continuous | 12.6 years STANDARD_DEVIATION 14.64 | 15.7 years STANDARD_DEVIATION 20.67 | 13.8 years STANDARD_DEVIATION 12.35 | 23.8 years STANDARD_DEVIATION 21.55 | 14.8 years STANDARD_DEVIATION 16.44 |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 7 Participants | 0 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 11 Participants | 4 Participants | 37 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 | 13 / 14 | 14 / 16 | 16 / 18 | 12 / 12 |
| serious Total, serious adverse events | 6 / 14 | 7 / 16 | 6 / 18 | 8 / 12 |
Outcome results
Primary
Number of Participants With Clinically Significant AdV Infection
The primary objective of this study was to evaluate the safety and efficacy of preemptive treatment with brincidofovir (BCV) versus placebo for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia. The outcome measure for the primary endpoint was treatment failure, a composite endpoint that consisted of the following: * Progression to probable AdV disease (other positive causes/agents have been ruled out and subject has disease-targeted organ-specific signs or symptoms) or definitive AdV disease (AdV detected in disease-targeted organ/system biopsy via antigen/immunohistochemistry, culture, and/or polymerase chain reaction and has at least 1 disease-targeted organ-specific sign or symptom); or * Increasing AdV viremia (defined as an increase from baseline in AdV viremia by ≥1 log10, confirmed on a second measurement, at least 1 week apart) and requiring discontinuation from blinded therapy.
Time frame: 12 weeks
Population: Intent-to-Treat Population, defined as all randomized subjects who took at least 1 dose of study drug. Note that the subjects who were enrolled directly to open-label and not randomized are not included in this data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCV BIW | Number of Participants With Clinically Significant AdV Infection | 3 Participants |
| BCV QW | Number of Participants With Clinically Significant AdV Infection | 6 Participants |
| Placebo | Number of Participants With Clinically Significant AdV Infection | 6 Participants |