Cytomegalovirus Infection
Conditions
Keywords
Allogeneic stem cell transplant, CMV seropositive (R+), transplant
Brief summary
This was a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study of brincidofovir (BCV) administered orally once or twice weekly for up to 11 weeks. Dosing was initiated immediately following engraftment (between Days 14-30 post-transplant) to prevent/control cytomegalovirus (CMV) infection or prevent disease in R+ hematopoietic stem cell transplant (HCT) recipients.
Detailed description
This was to be a 2-part study. Part 1 was a randomized, double-blind, placebo-controlled, dose-escalation study of multiple doses of oral brincidofovir (BCV) in R+ hematopoietic stem cell transplant (HCT) recipients. In Part 2, one of the dose levels administered in Part 1 was to be tested against placebo to evaluate the statistical significance of BCV as a therapy for preventing progression of cytomegalovirus (CMV) infection or preventing CMV disease. The first 3 dose-escalating cohorts in Part 1 were to include 32 subjects within each cohort (24 randomized to receive oral BCV and 8 randomized to receive placebo in a 3:1 ratio) for a total of 96 planned subjects. Following completion of the first 3 cohorts and subsequent safety review of the data, up to an additional 3 cohorts of 32 subjects each could have been enrolled. Two additional cohorts (labeled Cohort 4 and Cohort 4A) beyond the initial 3 cohorts were actually enrolled in Part 1 of the study. Following the safety and antiviral activity analyses of the 5 cohorts in Part 1 and the number of subjects enrolled in each of those cohorts, Part 2 of the study was not conducted.
Interventions
DRUGBrincidofovir
Subjects received their first dose of study drug of brincidofovir (BCV) within 30 (+5) days post-transplant and were treated through Week 13 post-transplant.
DRUGPlacebo
Subjects received their first dose of study drug within 30 (+5) days post-transplant and were treated through Week 13 post-transplant. Matching placebo administered for each cohort.
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For inclusion into the study, all prospective subjects were required to fulfill all of the following criteria (as applicable): 1. Were aged ≥18 years. Males must have been able and willing to use adequate contraceptive methods throughout the treatment and follow-up phases of the study. 2. Were cytomegalovirus (CMV) seropositive before allogeneic hematopoietic stem cell transplantation (HCT) (i.e., R+ subjects). 3. Were less than 30 days post qualifying transplant. 4. Had evidence of engraftment before randomization and receiving their first dose of study drug. 5. Were able to ingest and absorb oral medication (in the judgment of the investigator and based on lack of significant gastrointestinal \[GI\] events). 6. Were willing and able to understand and provide written informed consent. 7. To the best of his or her knowledge, were willing and able to participate in all required study activities for the duration of the study.
Exclusion criteria
Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant CMV Infection | Randomization to Week 8 post-treatment (~19 weeks) | The primary efficacy endpoint was a binomial outcome of failure to prevent cytomegalovirus (CMV) infection defined as CMV DNAemia \>200 copies/mL obtained at the time of the last treatment with study drug or diagnosis of CMV disease at some point during the treatment phase. |
Countries
United States
Participant flow
Recruitment details
Note: While a total of 239 subjects were enrolled, 1 center was excluded from analysis due to concerns about investigator/site compliance with the study protocol. This center had enrolled 9 subjects: 5 subjects who received brincidofovir (BCV) in Cohort 1, 2 subjects who received placebo in Cohort 1, and 2 subjects who received BCV in Cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 BCV 40 mg brincidofovir (BCV) administered once weekly (QW) | 25 |
| Cohort 1 Placebo Placebo administered once weekly (QW) | 8 |
| Cohort 2 BCV 100 mg brincidofovir (BCV) administered once weekly (QW) | 27 |
| Cohort 2 Placebo Placebo administered once weekly (QW) | 10 |
| Cohort 3 BCV 200 mg brincidofovir (BCV) administered once weekly (QW) | 39 |
| Cohort 3 Placebo Placebo administered once weekly (QW) | 14 |
| Cohort 4 BCV 200 mg brincidofovir (BCV) administered twice weekly (BIW)
Note: This dose was reduced to 200 mg BCV once weekly for ongoing subjects in this cohort following the recommendation of the Data and Safety Monitoring Board. No new subjects were enrolled into this cohort following the decision to reduce the dose. | 30 |
| Cohort 4 Placebo Placebo administered twice weekly (BIW) | 10 |
| Cohort 4a BCV 100 mg brincidofovir (BCV) administered twice weekly (BIW) | 50 |
| Cohort 4a Placebo Placebo administered twice weekly (BIW) | 17 |
| Total | 230 |
Baseline characteristics
| Characteristic | Cohort 1 BCV | Cohort 1 Placebo | Cohort 2 BCV | Cohort 2 Placebo | Cohort 3 BCV | Cohort 3 Placebo | Cohort 4 BCV | Cohort 4 Placebo | Cohort 4a BCV | Cohort 4a Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 10.02 | 56.8 years STANDARD_DEVIATION 10.12 | 51.7 years STANDARD_DEVIATION 10.13 | 53.5 years STANDARD_DEVIATION 11.08 | 49.5 years STANDARD_DEVIATION 12.75 | 47.9 years STANDARD_DEVIATION 14.05 | 50.4 years STANDARD_DEVIATION 11.47 | 52.2 years STANDARD_DEVIATION 14.76 | 48.8 years STANDARD_DEVIATION 12.74 | 46.1 years STANDARD_DEVIATION 12.14 | 50.7 years STANDARD_DEVIATION 12.12 |
| Sex: Female, Male Female | 10 Participants | 1 Participants | 10 Participants | 5 Participants | 17 Participants | 9 Participants | 12 Participants | 3 Participants | 24 Participants | 7 Participants | 98 Participants |
| Sex: Female, Male Male | 15 Participants | 7 Participants | 17 Participants | 5 Participants | 22 Participants | 5 Participants | 18 Participants | 7 Participants | 26 Participants | 10 Participants | 132 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 25 | 8 / 8 | 27 / 27 | 9 / 10 | 39 / 39 | 14 / 14 | 30 / 30 | 10 / 10 | 50 / 50 | 17 / 17 |
| serious Total, serious adverse events | 12 / 25 | 4 / 8 | 10 / 27 | 6 / 10 | 19 / 39 | 6 / 14 | 21 / 30 | 3 / 10 | 30 / 50 | 8 / 17 |
Outcome results
Primary
Number of Participants With Clinically Significant CMV Infection
The primary efficacy endpoint was a binomial outcome of failure to prevent cytomegalovirus (CMV) infection defined as CMV DNAemia \>200 copies/mL obtained at the time of the last treatment with study drug or diagnosis of CMV disease at some point during the treatment phase.
Time frame: Randomization to Week 8 post-treatment (~19 weeks)
Population: Modified Intent-to-Treat Population, which included all randomized subjects who took at least 1 dose of study treatment and who had at least 1 efficacy evaluation following baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 BCV | Number of Participants With Clinically Significant CMV Infection | 13 Participants |
| Cohort 1 Placebo | Number of Participants With Clinically Significant CMV Infection | 4 Participants |
| Cohort 2 BCV | Number of Participants With Clinically Significant CMV Infection | 6 Participants |
| Cohort 2 Placebo | Number of Participants With Clinically Significant CMV Infection | 4 Participants |
| Cohort 3 BCV | Number of Participants With Clinically Significant CMV Infection | 12 Participants |
| Cohort 3 Placebo | Number of Participants With Clinically Significant CMV Infection | 4 Participants |
| Cohort 4 BCV | Number of Participants With Clinically Significant CMV Infection | 7 Participants |
| Cohort 4 Placebo | Number of Participants With Clinically Significant CMV Infection | 3 Participants |
| Cohort 4a BCV | Number of Participants With Clinically Significant CMV Infection | 5 Participants |
| Cohort 4a Placebo | Number of Participants With Clinically Significant CMV Infection | 7 Participants |