Dominant Dystrophic Epidermolysis Bullosa, Dystrophic Epidermolysis Bullosa, Recessive Dystrophic Epidermolysis Bullosa
Conditions
Keywords
DEB
Brief summary
To determine whether administration of topical B-VEC improves wound healing as compared to placebo, and to evaluate durability, repeat dosing (Primary Endpoint) and further obtain safety and tolerability data.
Detailed description
Thirty-one (31) participants with DEB, aged 6 months or older at time of consent were enrolled for this Phase III study. The trial duration for each subject was about 6 months, with administration occurring once weekly. A Safety Follow-up Visit occurring 30 days from the date of final treatment with the Investigational Product also occurred. Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. In addition to the primary target wound pair(s), additional wounds (secondary wounds) were selected to be treated with B-VEC. Throughout the study, participants complete questionnaires, had images captured of their study wounds, underwent physical exams, had vital signs and safety labs monitored.
Interventions
BIOLOGICALTopical Beremagene Geperpavec
Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein
OTHERPlacebo
Matching masked inactive topical gel
Sponsors
Krystal Biotech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
An intra-subject parallel study. Primary wounds are randomized within each subject, such that one wound receives B-VEC and the other wound receives placebo. Secondary wounds are selected to receive B-VEC only.
Eligibility
Sex/Gender
ALL
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject or legally appointed and authorized representative must have read, understood and signed an Institutional Review Board/Ethics Committee (IRB/EC) approved Informed Consent or Assent Form and must be able to and willing to follow study procedures and instructions. 2. Age ≥ 6 months and older at the time of Informed Consent. 3. Clinical diagnosis of the Dystrophic Epidermolysis Bullosa. 4. Confirmation of DEB diagnosis (either DDEB or RDEB) by genetic testing including COL7A1. 5. Two (2) cutaneous wounds meeting the following criteria: 1. Location: similar in size, located in similar anatomical regions, and have similar appearance 2. Appearance: clean with adequate granulation tissue, excellent vascularization, and do not appear infected. 6. Subjects and caregivers who, in the opinion of the Investigator, are able to understand the study, co-operate with the study procedures and are willing to return to the clinic for all the required follow-up visits. 7. Male or Female of childbearing potential must use a reliable birth control method throughout the duration of the study and for three (3) months post last dose of B-VEC. 8. Negative pregnancy test at Visit 1 (Week 1), if applicable.
Exclusion criteria
1. Medical instability limiting ability to travel to the Investigative Center. 2. Diseases or conditions that could interfere with the assessment of safety and efficacy of the study treatment and compliance of the subject with study visits/procedures, as determined by the Investigator. 3. Current evidence or a history of squamous cell carcinoma in the area that will undergo treatment. 4. Subjects actively receiving chemotherapy or immunotherapy at Visit 1 (Week 1). 5. Active drug or alcohol addiction as determined by the Investigator. 6. Hypersensitivity to local anesthesia (lidocaine/prilocaine cream). 7. Participation in an interventional clinical trial within the past three (3) months (not including BVEC administration). 8. Receipt of a skin graft in the past three (3) months. 9. Pregnant or nursing women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26 | 26 weeks post-baseline | The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 22 and Week 24, or * Complete wound healing on Week 24 and Week 26. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12 | 12 weeks post-baseline | The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 8 and Week 10, or * Complete wound healing on Week 10 and Week 12. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers). |
| Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | 26 weeks post-baseline | Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | All Participants (Topical Beremagene Geperpavec (B-VEC), and Placebo) |
|---|---|
| Age, Continuous | 17.2 years STANDARD_DEVIATION 10.7 |
| Age, Customized > 12 and <= 18 years | 9 Participants |
| Age, Customized <= 12 years | 10 Participants |
| Age, Customized > 18 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Primary Wound Area(cm^2) B-VEC | 14.354 cm^2 STANDARD_DEVIATION 12.693 |
| Primary Wound Area(cm^2) Placebo | 15.565 cm^2 STANDARD_DEVIATION 12.1315 |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants |
| Race (NIH/OMB) Asian | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 31 |
| other Total, other adverse events | 17 / 31 |
| serious Total, serious adverse events | 3 / 31 |
Outcome results
Primary
Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26
The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 22 and Week 24, or * Complete wound healing on Week 24 and Week 26. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
Time frame: 26 weeks post-baseline
Population: The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B-VEC | Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26 | 20.9 number of wounds with complete healing |
| Placebo | Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26 | 6.7 number of wounds with complete healing |
Comparison: The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.p-value: 0.0019295% CI: [23.6, 68]McNemar
Secondary
Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.
Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.
Time frame: 26 weeks post-baseline
Population: The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not. For pain severity, only subjects ages 6 and above were evaluated (n=27). The analyses were based on observed data where missing data were not imputed, therefore the numbers of available data for analyses could be less than the total.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| B-VEC | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 22 | -0.88 score on a scale of 0 to 10 | Standard Deviation 2.346 |
| B-VEC | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 24 | -0.64 score on a scale of 0 to 10 | Standard Deviation 2.325 |
| B-VEC | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 26 | -0.63 score on a scale of 0 to 10 | Standard Deviation 2.123 |
| Placebo | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 22 | -0.71 score on a scale of 0 to 10 | Standard Deviation 2.476 |
| Placebo | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 24 | -0.08 score on a scale of 0 to 10 | Standard Deviation 2.548 |
| Placebo | Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26. | Week 26 | -0.38 score on a scale of 0 to 10 | Standard Deviation 2.871 |
Secondary
Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12
The primary wound was defined as a responder wound that met either of the following conditions: * Complete wound healing on Week 8 and Week 10, or * Complete wound healing on Week 10 and Week 12. For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
Time frame: 12 weeks post-baseline
Population: The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B-VEC | Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12 | 21.9 number of wounds with complete healing |
| Placebo | Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12 | 6.1 number of wounds with complete healing |
Comparison: The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.p-value: 0.0004795% CI: [29.3, 72.6]McNemar