Adenovirus
Conditions
Keywords
Adenovirus, Pediatric, Hematopoietic Cell Transplant, Brincidofovir, Standard of care
Brief summary
This study was designed to assess the safety, overall tolerability, and antiviral activity of short course brincidofovir (BCV) therapy, as compared with current standard of care (SoC), for the treatment of adenovirus (AdV) infections in high-risk (i.e., T cell depleted) pediatric allogeneic hematopoietic cell transplant (HCT) recipients. A virologic response-driven approach to the duration of treatment was to be evaluated, in which subjects randomized to BCV therapy were to be treated until AdV viremia was confirmed as undetectable or until a maximum of 16 weeks of therapy, whichever occurred first. The formulation of BCV used in this study was oral tablet/suspension.
Detailed description
This was a randomized, open-label, multi-center study of the safety, overall tolerability, and antiviral activity of BCV, as compared with SoC, in pediatric (and young adults in the United States) recipients of high-risk (i.e., T cell-depleted and/or unrelated cord blood graft, or a T cell-replete graft from ahaploidentical donor with post-transplant cyclophosphamide administration) allogeneic HCT. Subjects with AdV detected in plasma after their qualifying transplant could be screened for participation in the study. Subjects who met all applicable entry criteria were randomized in a 2:1 ratio to receive either BCV or SoC (i.e., investigator-assigned therapy). The formulation of BCV used in this study was oral tablet/suspension. Subjects were randomized within 100 days post-transplant; for study purposes, the day of randomization was defined as Day 1. During randomization, subjects were stratified based on the following variables: last AdV viremia (≥10,000 copies/mL versus \<10,000 copies/mL) measurement available from the designated central virology laboratory prior to randomization, time from transplant to randomization (≥28 days versus \<28 days), and T cell-depletion methodology (receipt of alemtuzumab or ex vivo depletion versus receipt of anti-thymocyte globulin \[ATG\] or no T cell depletion).
Interventions
OTHERStandard of Care
Local institutional standard of care (SoC) (i.e., investigator-assigned therapy) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.
DRUGBrincidofovir
Brincidofovir (BCV) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Months to 25 Years
Healthy volunteers
No
Inclusion criteria
Subjects were high-risk allogeneic hematopoietic cell transplant (HCT) recipients aged 2 months to \<18 years (\<26 years in the United States) who met adenovirus (AdV) viremia criteria within 7 days of randomization (Day 1), and all other eligibility criteria. High-risk was defined as having received 1 of the following: * A T cell-depleted graft: * Ex vivo T cell depletion via positive selective (e.g., CD34+ cell) or negative selection (e.g., T cell receptor α/β or CD3+ cell removal by column filtration); or * Serotherapy with ATG (cumulative dose of ≥3 mg/kg rabbit-derived ATG or ≥30 mg/kg of equine-derived ATG) administered within 10 days prior to transplant or at any time post-transplant and prior to Day 1; or * Serotherapy with alemtuzumab administered within 30 days prior to transplant or at any time post-transplant and prior to Day 1; or * A cord blood graft from an unrelated donor with or without T cell depletion, or * A T cell-replete graft from a haploidentical donor with high-dose cyclophosphamide (e.g., cumulative dose of ≥100 mg/kg) administered at any time post-transplant and prior to Day 1. Subjects must have had qualifying AdV viremia within 100 days of transplant, which was defined as having either: 1. Confirmed AdV viremia of ≥1000 copies/mL on 2 consecutive AdV DNA polymerase chain reaction (PCR) test results drawn ≥48 hours apart from the designated central virology laboratory, with the second result being greater than the first; or 2. A single AdV viremia result of ≥10,000 copies/mL from the designated central virology laboratory Subjects who were previously treated with intravenous (IV) cidofovir (CDV) could have a cumulative exposure to IV CDV of no more than 10 mg/kg within 21 days prior to Day 1. Written informed consent (and assent, where applicable) to participate in the study was obtained from each subject and his/her legal guardian(s) in accordance with national or local law and institutional practice.
Exclusion criteria
1. Any United States National Institutes of Health (NIH)/National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 diarrhea (i.e., life-threatening consequences with urgent intervention indicated) within 7 days prior to Day 1. 2. Any CTCAE Grade 2 or 3 diarrhea (i.e., increase of ≥4 stools/day over baseline \[pre-transplant\] diarrheal output), unless attributed to AdV, within 7 days prior to Day 1. 3. NIH Stage 4 acute graft versus host disease (GVHD) of the skin (i.e., generalized erythroderma with bullous formation) within 7 days prior to Day 1. 4. NIH Stage ≥2 acute GVHD of the liver (i.e., bilirubin \>3 mg/dL \[SI: \>51 µmol/L\]) within 7 days prior to Day 1. 5. NIH Stage ≥2 acute GVHD of the gut (i.e., diarrhea \>556 mL/m2/day for pediatric patients \[or \>1000 mL/day for young adults at centers in the United States only\], or severe abdominal pain with or without ileus) within 7 days prior to Day 1. 6. Poor clinical prognosis (including active malignancy or use of vasopressors other than low dose (e.g., ≤5 µg/kg/min) dopamine for renal perfusion within 7 days prior to Day 1. 7. Requirement for mechanical ventilation within 7 days prior to Day 1 or requirement for sustained oxygen delivery for \>24 hours within 7 days prior to Day 1. 8. Concurrent HIV, active hepatitis B virus, or hepatitis C virus infection. 9. Specified out of range laboratory results (including alanine aminotransferase \>5x the upper limit of normal \[ULN\], aspartate aminotransferase \>5x ULN, total bilirubin \>3 mg/dL \[SI: \>51 µmol/L\], or prothrombin time-international normalized ratio \>2x ULN) within 7 days prior to Day 1. 10. Estimated creatinine clearance \<30 mL/min or use of renal replacement therapy within 7 days prior to Day 1. 11. Previous receipt of BCV at any time or receipt of CDV (IV or intravesicular) or letermovir within 48 hours prior to Day 1. 12. Received any anti-AdV-specific cell-based therapy within 6 weeks prior to Day 1 or previously received an anti-AdV vaccine at any time. When applicable, female subjects of childbearing potential (i.e., not pre-menarche) were not pregnant or breastfeeding, and if sexually active, agreed to use 2 acceptable forms of contraception, 1 of which must have been a barrier method and the other a highly-effective method of contraception. Male subjects, if sexually active and capable of fathering a child, agreed to use a barrier method of contraception while enrolled in the study and for at least 90 days after the last dose of BCV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL). | From randomization to 16 weeks post-randomization | The primary efficacy endpoint for this study was the time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia (log10 copies/mL) from randomization through Week 16 post-randomization. Due to the small number of subjects enrolled in the study, formal efficacy analyses were not performed. Individual subject AdV viremia profiles show the differential anti-adenoviral effect of brincidofovir (BCV) in comparison to standard of care (SoC) therapy. |
Countries
France, Germany, Ireland, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Brincidofovir Brincidofovir (BCV) for the treatment of adenovirs (AdV) infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.
Brincidofovir (BCV) treatment began no later than 100 days post-transplant and was to continue for a maximum of 16 weeks. Brincidofovir (BCV) was discontinued once AdV viremia was confirmed undetectable.
Subjects who did NOT receive concurrent cyclosporine on Day 1:
* If ≥48kg body weight, one 100mg oral tablet BIW (or 10mL of 10mg/mL oral suspension if unable to take tablets).
* If \<48kg body weight, 2mg/kg oral volume of 10mg/mL oral suspension BIW.
Subjects who received cyclosporine on Day 1 (or initiated cyclosporine at any time):
* 1.4mg/kg (maximum of 70mg) oral volume of 10mg/mL oral suspension BIW.
* 2mg/kg (maximum of 100mg) oral volume of 10mg/mL oral suspension BIW if discontinued cyclosporine. | 20 |
| Standard of Care Local institutional standard of care (SoC) (i.e., investigator-assigned therapy) for the treatment of adenovirus infection in high-risk pediatric allogeneic hematopoietic cell transplant (HCT) recipients.
Management of these subjects was prescribed by the investigator as being in the best interests of the subject and may have included a watch-and-wait approach, with or without decreased immunosuppression (ergo, no treatment), or treatment administration with other available antivirals, most commonly cidofovir intravenously.
Decisions regarding SoC, including administration of therapy, dose and regimen of therapy, modification of immunosuppression, and monitoring was the responsibility of the clinical team caring for the subject, according to institutional guidelines, local practices, and applicable guidelines for the management of AdV infection. | 9 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Investigator Decision | 1 | 0 |
| Overall Study | Study terminated | 4 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Brincidofovir | Standard of Care | Total |
|---|---|---|---|
| Adenovirus in plasma | 20 Participants | 9 Participants | 29 Participants |
| Age, Categorical <=18 years | 20 Participants | 9 Participants | 29 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 5.1 years STANDARD_DEVIATION 4.05 | 5.9 years STANDARD_DEVIATION 4.18 | 5.3 years STANDARD_DEVIATION 4.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 8 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 17 Participants | 4 Participants | 21 Participants |
| Region of Enrollment France | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Germany | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 12 participants | 5 participants | 17 participants |
| Region of Enrollment United States | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 12 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 20 | 1 / 9 |
| other Total, other adverse events | 20 / 20 | 9 / 9 |
| serious Total, serious adverse events | 15 / 20 | 6 / 9 |
Outcome results
Primary
Time-averaged Area Under the Concentration-time Curve for Plasma Adenovirus Viremia (Log10 Copies/mL).
The primary efficacy endpoint for this study was the time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia (log10 copies/mL) from randomization through Week 16 post-randomization. Due to the small number of subjects enrolled in the study, formal efficacy analyses were not performed. Individual subject AdV viremia profiles show the differential anti-adenoviral effect of brincidofovir (BCV) in comparison to standard of care (SoC) therapy.
Time frame: From randomization to 16 weeks post-randomization
Population: The time-averaged area under the concentration-time curve for plasma adenovirus (AdV) viremia was not calculated because many of the viral response data were arbitrarily truncated/censored and individual subject AdV viremia profiles cannot be reported due to concerns with patient confidentiality.