Adenovirus Infection
Conditions
Keywords
Adenovirus Infection
Brief summary
This was a Phase 3 open-label, non-randomized, multicenter study of oral brincidofovir (BCV) administered twice weekly for the treatment of adenovirus (AdV) infection detected during asymptomatic AdV viremia or during symptomatic AdV infection.
Detailed description
This was a Phase 3 open-label, non-randomized, multicenter study of the safety, tolerability, and efficacy of oral brincidofovir (BCV) when administered twice weekly for the treatment of disseminated adenovirus (AdV) disease and for the treatment of AdV infection when treatment was initiated in subjects who were at risk of progression to disseminated disease (i.e., during the asymptomatic or localized phases of infection).
Interventions
DRUGBrincidofovir
BCV administered twice weekly, dose depending on weight.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Months to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects were required to meet all of the following criteria, as applicable, to be eligible to participate in this study. 1. Were male or female, aged 2 months or older. 2. Had either of the following: * Disseminated adenovirus (AdV) disease; or * An underlying immunocompromised state and were at risk of progression to disseminated AdV disease. \[Note: Subjects with symptomatic AdV infection (i.e., localized or disseminated AdV disease) could have been screening immediately, with brincidofovir (BCV) therapy initiated after receipt of the screening virology results from the designated central virology laboratory confirming study eligibility. Subjects with asymptomatic AdV infection (i.e., had no symptoms of AdV disease) could have been consented and screened only if they had at least 1 positive or detectable AdV DNA (quantitative \[q\]) polymerase chain reaction (PCR) test (in any blood fluid or compartment) from the local virology laboratory, with treatment initiated only after confirmation of AdV positivity by 2 separate measurements at the designated central virology laboratory. Where the results from 2 AdV DNA (q)PCR measurements in plasma or non-plasma body fluid or compartment were needed to show that a subject was at risk of progression to disseminated AdV disease, the second measurement had to be resulted prior to the initiation of BCV therapy.\] 3. Were able to ingest and absorb oral medication (in the judgement of the investigator and based on lack of significant gastrointestinal \[GI\] events/medical history). 4. If male of reproductive potential, were willing to use an acceptable contraceptive method(s) during sexual intercourse with a female partner of reproductive potential throughout the duration of this participation in the study and for at least 6 months after his last dose of BCV. 5. If female of reproductive potential, i.e., not premenarche, postmenopausal, surgically sterile, or had documented ovarian failure, were willing to use 2 acceptable contraceptive methods, 1 of which must have been a barrier method, during sexual intercourse with a nonsterile male partner, throughout the duration of her participation in the study and for at least 6 months after her last dose of BCV. 6. Were willing and able to understand and provide written informed consent to participate in the study. \[Note: If the subject was under 18 years of age or was otherwise unable to legally give his or her informed consent to participate in the study, then written informed consent to participate had to be obtained from the parent(s) or legal guardian(s) of the subject or other legal personal representative(s), as applicable. In addition, in the case of minor subjects, the written assent of the subject to participate in the study was obtained where required by applicable institutional policy on the consenting of minor study participants.\] 7. The subject and his or her caregivers (as applicable) were willing and able to participate in all required study activities for the entire duration of the study (i.e., through completion of Week 36).
Exclusion criteria
Subjects who met any of the following criteria (as applicable) were not eligible to participate in this study: 1. If a female of reproductive potential, the subject was pregnant, planning to become pregnant during the study or within 6 months after their anticipated last BCV dose, or was nursing a child. 2. Had hypersensitivity (not including renal dysfunction or eye disorder) to cidofovir (CDV) or to BCV or its formulation excipients. 3. Had received treatment with another investigational drug within 14 days prior to Day 1 unless prior approval was received from the Chimerix medical monitor (or designee). 4. Were participating in another interventional clinical trial unless prior approval was received from the Chimerix medical monitor (or designee). 5. Had previously received an anti-AdV vaccine or a cell-based anti-AdV therapy. 6. Were receiving intravenous (IV) CDV, leflunomide, vidarabine, systemic ribavirin, or another investigational anti-AdV drug at Day 1. \[Note: Subjects who were receiving treatment with IV CDV prior to enrollment had to discontinue IV CDV and wait until a minimum of 48 hours had elapsed from last IV CDV administration before initiating BCV therapy. All other drugs had to be discontinued prior to Day 1.\] 7. Were receiving digoxin or ketoconazole (other than topical formulations) at Day 1 or were anticipated to need treatment with either drug during the treatment phase of the study. 8. Were infected with HIV, hepatitis B virus (HBV), and/or hepatitis C virus (HCV), had evidence of active viral replication within 6 months prior to screening, as demonstrated by detectable HIV or HCV RNA, or had detectable HBV DNA in blood, plasma or serum. 9. Had end-stage renal disease, i.e., an estimated glomerular filtration rate \<15 mL/min, unless receiving renal replacement therapy. 10. Had a serum alanine aminotransferase or aspartate aminotransferase concentration \>5 x the upper limit of normal (ULN), or a serum total bilirubin concentration \>2 x the ULN and a serum direct (conjugated) bilirubin concentration \>1.5 x the ULN, as reported by the central safety laboratory, unless, in the judgment of the investigator, the abnormality(ies) was/were related to the subject's AdV infection/disease. 11. Had ongoing Grade 3 or higher diarrhea, unless, in the judgment of the investigator, the diarrhea was related to the subject's underlying AdV infection/disease. 12. Had Stage 3 or higher graft versus host disease (GVHD) of the intestine (GI-GVHD or any other GI disease that would have, in the judgment of the investigator, precluded the subject from taking or absorbing oral medication (e.g., clinically active Crohn's disease, ischemic colitis, moderate or severe ulcerative colitis, small bowel resection, ileus, or any condition expected to require abdominal surgery during the course of study participation). 13. Had any other condition, including abnormal laboratory values, that would have, in the judgment of the investigator, put the subject at increased risk by participating in the study, or would have interfered with the conduct or planned analyses of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-Cause Mortality | 60 days | The primary efficacy endpoint was the evaluation of the effect of brincidofovir (BCV) on all-cause mortality when used for the treatment of disseminated adenovirus (AdV) disease in all hematopoietic cell transplant (HCT) recipients. The primary endpoint associated with this objective was all-cause mortality through Day 60. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Reduction in Adenovirus Viremia | Assessed 13 weeks (through 7 days post-last BCV dose); during treatment up to 12 weeks reported | A secondary endpoint was the evaluation of virologic response (plasma adenovirus \[AdV\] DNA viremia) to brincidofovir treatment. Blood (plasma) was collected at screening, before dosing on Day 1 (to establish baseline), and at each subsequent assessment during the treatment and post-treatment phases for the analysis of AdV DNA viremia. All samples collected for analysis of AdV were analyzed by the designated central virology laboratory using proprietary real-time quantitative polymerase chain reaction (qPCR) assays. AdV in plasma were analyzed using the 7500 AdV qPCR Test, where the standardized assay plasma ranged from 190 copies/mL to 1 X 10\^10 copies/mL. A positive or detectable result referred to the measurement of AdV DNA at concentrations ≥190 copies/mL, a result below the lower limit of detection (LLOQ) (i.e., not detected) was imputed as 1 copy/mL, and a result below the lower limit of quantitation but detected will be imputed at 1 unit less than LLOQ (e.g., 189 copies/mL). |
| Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Baseline to 12 weeks | A secondary endpoint was the evaluation of virologic response (plasma adenovirus \[AdV\] DNA viremia) to brincidofovir treatment. Blood (plasma) was collected at screening, before dosing on Day 1 (to establish baseline), and at each subsequent assessment during the treatment and post-treatment phases for the analysis of AdV DNA viremia. All samples collected for analysis of AdV were analyzed by the designated central virology laboratory using proprietary real-time quantitative polymerase chain reaction (qPCR) assays. AdV in plasma were analyzed using the 7500 AdV qPCR Test, where the standardized assay plasma ranged from 190 copies/mL to 1 X 10\^10 copies/mL. A positive or detectable result referred to the measurement of AdV DNA at concentrations ≥190 copies/mL, a result below the lower limit of detection (LLOQ) (i.e., not detected) was imputed as 1 copy/mL, and a result below the lower limit of quantitation but detected will be imputed at 1 unit less than LLOQ (e.g., 189 copies/mL). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Allogeneic hematopoietic cell transplant recipients at risk of progression to disseminated adenovirus (AdV) disease (i.e., subjects with either asymptomatic AdV infection or localized adenovirus disease) and who weighed ≤120 kg.
Subjects who weighed \<50 kg received 2 mg/kg (not-to-exceed 100 mg) brincidofovir (BCV) twice weekly, administered orally as the appropriate volume of 10-mg/mL liquid suspension.
Subjects who weighed ≥50 kg received BCV 100 mg twice weekly, administered orally as one 100-mg tablet (or the appropriate volume of 10-mg/mL liquid suspension if unable to swallow solid medicine). | 65 |
| Cohort B Allogeneic hematopoietic cell transplant recipients with disseminated adenovirus disease who weigh ≤120 kg.
Subjects who weighed \<50 kg received 2 mg/kg brincidofovir (BCV; not to exceed 100 mg) twice weekly, administered orally as the appropriate volume of 10-mg/mL liquid suspension.
Subjects who weighed ≥50 kg received 100 mg BCV twice weekly, administered orally as one 100 mg tablet (or the appropriate volume of 10-mg/mL liquid suspension if unable to swallow solid medicine). | 93 |
| Cohort C Allogeneic hematopoietic cell transplant recipients who weighed \>120 kg and all other immunocompromised subjects with disseminated adenovirus (AdV) disease or subjects who were at risk of progression to disseminated AdV disease, as well as non-immunocompromised subjects with disseminated AdV disease.
Subjects who weighed \<50 kg received 2 mg/kg (not to exceed 100 mg) brincidofovir (BCV) twice weekly, administered orally as the appropriate volume of 10-mg/mL liquid suspension.
Subjects who weighed ≥50 kg received 100 mg BCV twice weekly, administered orally as one 100-mg tablet (or the appropriate volume of 10-mg/mL liquid suspension if unable to swallow solid medicine). | 43 |
| Total | 201 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Cohort C | Total |
|---|---|---|---|---|
| Age, Continuous | 19 years STANDARD_DEVIATION 17.4 | 20 years STANDARD_DEVIATION 23.1 | 17 years STANDARD_DEVIATION 21.9 | 19 years STANDARD_DEVIATION 21.1 |
| Sex: Female, Male Female | 26 Participants | 30 Participants | 16 Participants | 72 Participants |
| Sex: Female, Male Male | 39 Participants | 63 Participants | 27 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 127 / 130 | 71 / 71 |
| serious Total, serious adverse events | 93 / 130 | 58 / 71 |
Outcome results
Primary
Number of Participants With All-Cause Mortality
The primary efficacy endpoint was the evaluation of the effect of brincidofovir (BCV) on all-cause mortality when used for the treatment of disseminated adenovirus (AdV) disease in all hematopoietic cell transplant (HCT) recipients. The primary endpoint associated with this objective was all-cause mortality through Day 60.
Time frame: 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With All-Cause Mortality | 9 Participants |
| Cohort B | Number of Participants With All-Cause Mortality | 27 Participants |
| Cohort C | Number of Participants With All-Cause Mortality | 8 Participants |
Secondary
Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline
A secondary endpoint was the evaluation of virologic response (plasma adenovirus \[AdV\] DNA viremia) to brincidofovir treatment. Blood (plasma) was collected at screening, before dosing on Day 1 (to establish baseline), and at each subsequent assessment during the treatment and post-treatment phases for the analysis of AdV DNA viremia. All samples collected for analysis of AdV were analyzed by the designated central virology laboratory using proprietary real-time quantitative polymerase chain reaction (qPCR) assays. AdV in plasma were analyzed using the 7500 AdV qPCR Test, where the standardized assay plasma ranged from 190 copies/mL to 1 X 10\^10 copies/mL. A positive or detectable result referred to the measurement of AdV DNA at concentrations ≥190 copies/mL, a result below the lower limit of detection (LLOQ) (i.e., not detected) was imputed as 1 copy/mL, and a result below the lower limit of quantitation but detected will be imputed at 1 unit less than LLOQ (e.g., 189 copies/mL).
Time frame: Baseline to 12 weeks
Population: Subjects who had adenovirus viremia at baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Minimum on-treatment value log10 copies/mL change from baseline | -2.67 log10 copies/mL | Standard Deviation 1.559 |
| Cohort A | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Last on-treatment value log10 copies/mL change from baseline | -2.06 log10 copies/mL | Standard Deviation 1.898 |
| Cohort B | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Last on-treatment value log10 copies/mL change from baseline | -2.61 log10 copies/mL | Standard Deviation 2.338 |
| Cohort B | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Minimum on-treatment value log10 copies/mL change from baseline | -3.27 log10 copies/mL | Standard Deviation 2.163 |
| Cohort C | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Last on-treatment value log10 copies/mL change from baseline | -2.87 log10 copies/mL | Standard Deviation 2.291 |
| Cohort C | Mean Minimum On-treatment Value log10 Copies/mL Change From Baseline | Minimum on-treatment value log10 copies/mL change from baseline | -3.11 log10 copies/mL | Standard Deviation 2.127 |
Secondary
Number of Participants With Reduction in Adenovirus Viremia
A secondary endpoint was the evaluation of virologic response (plasma adenovirus \[AdV\] DNA viremia) to brincidofovir treatment. Blood (plasma) was collected at screening, before dosing on Day 1 (to establish baseline), and at each subsequent assessment during the treatment and post-treatment phases for the analysis of AdV DNA viremia. All samples collected for analysis of AdV were analyzed by the designated central virology laboratory using proprietary real-time quantitative polymerase chain reaction (qPCR) assays. AdV in plasma were analyzed using the 7500 AdV qPCR Test, where the standardized assay plasma ranged from 190 copies/mL to 1 X 10\^10 copies/mL. A positive or detectable result referred to the measurement of AdV DNA at concentrations ≥190 copies/mL, a result below the lower limit of detection (LLOQ) (i.e., not detected) was imputed as 1 copy/mL, and a result below the lower limit of quantitation but detected will be imputed at 1 unit less than LLOQ (e.g., 189 copies/mL).
Time frame: Assessed 13 weeks (through 7 days post-last BCV dose); during treatment up to 12 weeks reported
Population: Subjects with AdV viremia at baseline in the Intention-to-Treat Analysis Set. The Intention-to-Treat Analysis Set included all subjects who received at least 1 dose of BCV.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at any time on-treatment | 30 Participants |
| Cohort A | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at last on-treatment value | 25 Participants |
| Cohort B | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at any time on-treatment | 52 Participants |
| Cohort B | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at last on-treatment value | 41 Participants |
| Cohort C | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at any time on-treatment | 17 Participants |
| Cohort C | Number of Participants With Reduction in Adenovirus Viremia | Undetectable AdV viremia at last on-treatment value | 16 Participants |