Epidermolysis Bullosa
Conditions
Keywords
Amicus Therapeutics, Scioderm, Inc., Simplex, Recessive Dystrophic, Junctional non-Herlitz, Epidermolysis Bullosa, SD-101 6%, SD-101-6.0, Allantoin 6%, Zorblisa
Brief summary
The aim was to assess the efficacy and safety of SD-101-6.0 cream versus Placebo (SD-101-0.0) cream in the treatment of skin lesions in participants with Epidermolysis Bullosa. Funding Source - United States Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD).
Detailed description
This was a Phase 3, multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of SD-101-6.0 cream versus placebo (SD-101-0.0) cream on skin lesions in participants with Simplex, Recessive Dystrophic, or Junctional non-Herlitz Epidermolysis Bullosa. Epidermolysis Bullosa is a rare group of inherited disorders that typically manifest at birth as blistering and lesion formation on the skin in response to little or no apparent trauma. In this study, SD-101-6.0 cream or placebo (SD-101-0.0) cream was to be applied topically, once a day to the entire body for a period of 90 days. Participants had 1 target wound selected at baseline by the investigator. The selected target wound was required to have been present for at least 21 days. Photographic confirmation of the target wound location was collected at baseline, and the picture saved from the first visit was used to confirm location of the target wound at subsequent visits. The participant returned to the study site for Visit 2 (approximately 14 days from baseline), Visit 3 (approximately 30 days from baseline), Visit 4 (approximately 60 days from baseline), and Visit 5 (approximately 90 days from baseline) to have the target wound assessed for the level of healing. In addition, itching, pain, body surface area, target wound closure, and scarring of healed target wound were assessed at each visit. The ARANZ SilhouetteStar™ was used to measure the target wound at all visits.
Interventions
DRUGSD-101-6.0 cream
applied topically once a day for 90 days
DRUGPlacebo (SD-101-0.0) cream
applied topically once a day for 90 days
Sponsors
Amicus Therapeutics
Scioderm, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed Consent form signed by the participant or participant's legal representative; if the participant was under the age of 18 but capable of providing assent, signed assent from the participant. * Participant (or caretaker) must have been willing to comply with all protocol requirements. * Diagnosis of Simplex, Recessive Dystrophic, or Junctional non-Herlitz EB. * Participant must have had 1 target wound (size 10 to 50 cm\^2) at study entry. * Participants 1 month and older. * Target wound must have been present for at least 21 days.
Exclusion criteria
* Participants who did not meet the entry criteria outlined above. * Selected target wound did not have clinical evidence of local infection. * Use of any investigational drug within the 30 days before enrollment. * Use of immunotherapy or cytotoxic chemotherapy within the 60 days before enrollment. * Use of systemic or topical steroidal therapy within the 30 days before enrollment. (Inhaled steroids and ophthalmic drops containing steroids were allowed). * Use of systemic antibiotics within the 7 days before enrollment. * Current or former malignancy. * Arterial or venous disorder resulting in ulcerated lesions. * Pregnancy or breastfeeding during the study. (A urine pregnancy test was performed at screening and every 30 days until the final visit for female participants of childbearing potential). * Females of childbearing potential who were not abstinent and not practicing a medically acceptable method of contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time To Complete Target Wound Closure Within 3 Months | From baseline to Month 3 visit | Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. Time to target wound closure was measured from the date of the first administration of the study drug to the date of target wound closure. Participants were censored if they did not have a response within 3 months, or withdrew earlier before the confirmation of their target wound closing. This primary end point displays the mean time to complete target wound closure, analyzed using a Kaplan-Meier approach. |
| The Percentage Of Participants Experiencing Complete Closure Of Their Target Wound Within 3 Months | From baseline to Month 3 visit | Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. Participants were considered responders if they experienced complete wound closure at the Week 2 or Months 1, 2, or 3 visits. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits. This primary end point displays the percentage of participants from the ITT population who had complete target wound closure by the end of the study period (that is, 3 months). Analysis was performed on participants with post-baseline wound closure data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In BSAI Of Total Body Wound Burden At Month 3 Visit | Baseline, Month 3 visit | Total body wound burden was calculated using BSAI. A wound defined as an open area on the skin (that is, epidermal covering disrupted). BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (that is, head/neck, upper limbs, lower limbs, trunk \[includes groin\]), and multiplied by the weighting factor, then summed for all body regions. |
| Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits | From baseline to Month 1 and Month 2 visits | Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. The percentage of participants who completed target wound closure at the Month 1 and Month 2 study visits is displayed. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits. |
| Change From Baseline In Pain Score At Day 7 | Baseline, Day 7 | Change in pain assessed at Day 7 compared to baseline was measured using the Face, Legs, Activity, Cry, and Consolability (FLACC) behavioral scale for participants 1 month to 3 years of age. Each of the 5 FLACC categories was scored from 0 to 2, which resulted in a total score between 0 and 10 with 0=Relaxed and comfortable, 1 to 3=Mild discomfort, 4 to 6=Moderate pain, and 7 to 10=Severe discomfort/pain. For participants 4 years of age and older, the Wong Faces Pain Scale was used. This scale shows a series of faces ranging from a happy face at 0, which represents no hurt, to a crying face at 10, which represents hurts worst. Pain scores were categorized into 3 groups based on improvement: Improved or No Pain, Not Improved, and Missing. A pain score reduction from baseline greater than or equal to 2 points on the scale was classed as improved. |
| Change From Baseline In Itching Score At Day 7 | Baseline, Day 7 | Itching was assessed using the 5-point Itch Man Pruritus Assessment Tool. For participants up to 5 years of age, itching was assessed using caretaker's response and participants 6 years of age and older self-reported their itching assessments based on the following scores: 0=Comfortable, no itch; 1=itches a little, does not interfere with activity; 2=itches more, sometimes interferes with activity; 3=itches a lot, difficult to be still, concentrate; 4=itches most terribly, impossible to sit still or concentrate. Itching scores were categorized into 3 groups based on improvement; Improved or No Itching, Not Improved, and Missing. An itching score reduction from baseline greater than or equal to 1 point on the scale was classed as improved. |
| Change From Baseline In Body Surface Area Index (BSAI) Of Lesional Skin At Month 3 Visit | Baseline, Month 3 visit | Lesional skin was defined as areas that contained any of the following: blisters, erosions, ulcerations, scabbing, bullae, or eschars, as well as areas that were weeping, sloughing, oozing, crusted, or denuded. BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (that is, head/neck, upper limbs, trunk \[includes groin\], and lower limbs), multiplied by the weighting factor, then summed for all body regions. |
Countries
Australia, Austria, France, Germany, Israel, Italy, Lithuania, Netherlands, Poland, Serbia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Of 210 participants screened for this study, 169 participants were randomly assigned, on a 1:1 basis, to treatment with SD-101-6.0 or placebo at 31 study centers in 13 countries. The first participant was enrolled on 11 March 2015 and the last participant completed the study on 05 July 2017.
Pre-assignment details
Participants had to be \>1 month of age with a diagnosis of simplex, recessive dystrophic, or junctional non-Herlitz Epidermolysis Bullosa (EB) and a target wound with a surface area of 10 to 50 cm\^2 and ≥21 days old to be considered for participation. Participants who did not meet all inclusion/exclusion criteria were eligible for rescreening.
Participants by arm
| Arm | Count |
|---|---|
| SD-101-6.0 Cream SD-101-6.0 cream applied topically, once a day to the entire body for a period of 90 days. | 82 |
| Placebo (SD-101-0.0) Cream Placebo (SD-101-0.0) cream applied topically, once a day to the entire body for a period of 90 days. | 87 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Elective medical treatment | 1 | 0 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Returned to previous therapeutic regimen | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | SD-101-6.0 Cream | Placebo (SD-101-0.0) Cream | Total |
|---|---|---|---|
| Age, Continuous | 13.8 years STANDARD_DEVIATION 13.15 | 13.9 years STANDARD_DEVIATION 13.12 | 13.9 years STANDARD_DEVIATION 13.09 |
| EB type Junctional non-Herlitz | 15 Participants | 17 Participants | 32 Participants |
| EB type Recessive dystrophic | 57 Participants | 62 Participants | 119 Participants |
| EB type Simplex | 10 Participants | 8 Participants | 18 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Black/African American | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White/Caucasian | 69 Participants | 72 Participants | 141 Participants |
| Sex: Female, Male Female | 33 Participants | 48 Participants | 81 Participants |
| Sex: Female, Male Male | 49 Participants | 39 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 1 / 87 |
| other Total, other adverse events | 49 / 82 | 46 / 87 |
| serious Total, serious adverse events | 4 / 82 | 8 / 87 |
Outcome results
Primary
The Percentage Of Participants Experiencing Complete Closure Of Their Target Wound Within 3 Months
Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. Participants were considered responders if they experienced complete wound closure at the Week 2 or Months 1, 2, or 3 visits. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits. This primary end point displays the percentage of participants from the ITT population who had complete target wound closure by the end of the study period (that is, 3 months). Analysis was performed on participants with post-baseline wound closure data.
Time frame: From baseline to Month 3 visit
Population: ITT population with post-baseline wound closure data and whose target wound had closed within 3 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SD-101-6.0 Cream | The Percentage Of Participants Experiencing Complete Closure Of Their Target Wound Within 3 Months | 49.4 percentage of participants |
| Placebo (SD-101-0.0) Cream | The Percentage Of Participants Experiencing Complete Closure Of Their Target Wound Within 3 Months | 53.6 percentage of participants |
Comparison: Comparison between treatment groups of complete closure of target wound within 3 months was performed using a logistic regression model with multiple imputation with EB type, baseline target wound size, and baseline target wound age as covariates.p-value: 0.3995% CI: [0.365, 1.474]Regression, Logistic
Primary
Time To Complete Target Wound Closure Within 3 Months
Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. Time to target wound closure was measured from the date of the first administration of the study drug to the date of target wound closure. Participants were censored if they did not have a response within 3 months, or withdrew earlier before the confirmation of their target wound closing. This primary end point displays the mean time to complete target wound closure, analyzed using a Kaplan-Meier approach.
Time frame: From baseline to Month 3 visit
Population: ITT population with post-baseline wound closure data and whose target wound had closed within 3 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SD-101-6.0 Cream | Time To Complete Target Wound Closure Within 3 Months | 41.6 days | Standard Deviation 25.5 |
| Placebo (SD-101-0.0) Cream | Time To Complete Target Wound Closure Within 3 Months | 53.6 days | Standard Deviation 28.59 |
Comparison: Cox proportional hazards model compares treatment groups with baseline target wound size, target wound age, and EB type as covariates.p-value: 0.98595% CI: [0.651, 1.549]Cox Model Analysis
Secondary
Change From Baseline In Body Surface Area Index (BSAI) Of Lesional Skin At Month 3 Visit
Lesional skin was defined as areas that contained any of the following: blisters, erosions, ulcerations, scabbing, bullae, or eschars, as well as areas that were weeping, sloughing, oozing, crusted, or denuded. BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (that is, head/neck, upper limbs, trunk \[includes groin\], and lower limbs), multiplied by the weighting factor, then summed for all body regions.
Time frame: Baseline, Month 3 visit
Population: Analysis was performed on the ITT population. The ITT population included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SD-101-6.0 Cream | Change From Baseline In Body Surface Area Index (BSAI) Of Lesional Skin At Month 3 Visit | -4.637 Percentage change in BSAI | Standard Error 1.404 |
| Placebo (SD-101-0.0) Cream | Change From Baseline In Body Surface Area Index (BSAI) Of Lesional Skin At Month 3 Visit | -5.319 Percentage change in BSAI | Standard Error 1.354 |
Comparison: Mixed Model Repeated Measures (MMRM) Analysis. The MMRM approach (using restricted maximum likelihood \[REML\] estimation) was used on each multiply-imputed data set. The model included treatment, baseline BSAI of lesional skin, EB type, visit, and visit-treatment interaction as the fixed effects.p-value: 0.70695% CI: [-2.873, 4.238]Mixed Models Analysis
Secondary
Change From Baseline In BSAI Of Total Body Wound Burden At Month 3 Visit
Total body wound burden was calculated using BSAI. A wound defined as an open area on the skin (that is, epidermal covering disrupted). BSAI was calculated as a percentage, ranging from 0% to 100%, of affected body surface area, recorded for each defined body region (that is, head/neck, upper limbs, lower limbs, trunk \[includes groin\]), and multiplied by the weighting factor, then summed for all body regions.
Time frame: Baseline, Month 3 visit
Population: Analysis was performed on the ITT population. The ITT population included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SD-101-6.0 Cream | Change From Baseline In BSAI Of Total Body Wound Burden At Month 3 Visit | -3.050 Percentage change in BSAI | Standard Error 0.816 |
| Placebo (SD-101-0.0) Cream | Change From Baseline In BSAI Of Total Body Wound Burden At Month 3 Visit | -2.922 Percentage change in BSAI | Standard Error 0.813 |
Comparison: MMRM Analysis. The MMRM approach (using REML estimation) was used on each multiply-imputed data set. The model included treatment, baseline BSAI of lesional skin, EB type, visit, and visit-treatment interaction as the fixed effects.p-value: 0.995% CI: [-2.116, 1.861]Mixed Models Analysis
Secondary
Change From Baseline In Itching Score At Day 7
Itching was assessed using the 5-point Itch Man Pruritus Assessment Tool. For participants up to 5 years of age, itching was assessed using caretaker's response and participants 6 years of age and older self-reported their itching assessments based on the following scores: 0=Comfortable, no itch; 1=itches a little, does not interfere with activity; 2=itches more, sometimes interferes with activity; 3=itches a lot, difficult to be still, concentrate; 4=itches most terribly, impossible to sit still or concentrate. Itching scores were categorized into 3 groups based on improvement; Improved or No Itching, Not Improved, and Missing. An itching score reduction from baseline greater than or equal to 1 point on the scale was classed as improved.
Time frame: Baseline, Day 7
Population: Analysis was performed on the ITT population. The ITT population included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SD-101-6.0 Cream | Change From Baseline In Itching Score At Day 7 | -0.5 units on a scale | Standard Deviation 1.31 |
| Placebo (SD-101-0.0) Cream | Change From Baseline In Itching Score At Day 7 | -0.3 units on a scale | Standard Deviation 1.24 |
Comparison: The proportion of participants experiencing improvement in itching versus non-improvement (including missing) was compared between the 2 treatment groups for Day 7 using the logistic regression model with baseline itching score, and EB type as covariates.p-value: 0.26295% CI: [0.759, 2.752]Regression, Logistic
Secondary
Change From Baseline In Pain Score At Day 7
Change in pain assessed at Day 7 compared to baseline was measured using the Face, Legs, Activity, Cry, and Consolability (FLACC) behavioral scale for participants 1 month to 3 years of age. Each of the 5 FLACC categories was scored from 0 to 2, which resulted in a total score between 0 and 10 with 0=Relaxed and comfortable, 1 to 3=Mild discomfort, 4 to 6=Moderate pain, and 7 to 10=Severe discomfort/pain. For participants 4 years of age and older, the Wong Faces Pain Scale was used. This scale shows a series of faces ranging from a happy face at 0, which represents no hurt, to a crying face at 10, which represents hurts worst. Pain scores were categorized into 3 groups based on improvement: Improved or No Pain, Not Improved, and Missing. A pain score reduction from baseline greater than or equal to 2 points on the scale was classed as improved.
Time frame: Baseline, Day 7
Population: Analysis was performed on the ITT population. The ITT population included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SD-101-6.0 Cream | Change From Baseline In Pain Score At Day 7 | -0.3 units on a scale | Standard Deviation 2.57 |
| Placebo (SD-101-0.0) Cream | Change From Baseline In Pain Score At Day 7 | -0.6 units on a scale | Standard Deviation 3.07 |
Comparison: The proportion of participants experiencing improvement in pain versus non-improvement (including missing) was compared between the 2 treatment groups for Day 7 using the logistic regression model with baseline pain score and EB type as covariates.p-value: 0.09895% CI: [0.323, 1.1]Regression, Logistic
Secondary
Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits
Target wounds were monitored at each study visit for complete closure, defined as skin re-epithelialization without drainage. The percentage of participants who completed target wound closure at the Month 1 and Month 2 study visits is displayed. If a target wound was documented to have closed at a given visit, it was considered closed at all subsequent visits.
Time frame: From baseline to Month 1 and Month 2 visits
Population: Analysis was performed on participants from the ITT population with post-baseline wound closure data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SD-101-6.0 Cream | Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits | Month 1 | 31.6 percentage of participants |
| SD-101-6.0 Cream | Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits | Month 2 | 43.0 percentage of participants |
| Placebo (SD-101-0.0) Cream | Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits | Month 1 | 22.6 percentage of participants |
| Placebo (SD-101-0.0) Cream | Percentage Of Participants Experiencing Complete Closure Of Their Target Wound At Month 1 And Month 2 Visits | Month 2 | 42.9 percentage of participants |
Comparison: Logistic Regression Analysis at Month 1 visit. Comparison between treatment groups of complete closure of target wound within 1 month was performed using a logistic regression model with multiple imputation with EB type, baseline target wound size, and baseline target wound age as covariates.p-value: 0.21295% CI: [0.758, 3.517]Regression, Logistic
Comparison: Logistic Regression Analysis at Month 2 visit. Comparison between treatment groups of complete closure of target wound within 2 months was performed using a logistic regression model with multiple imputation with EB type, baseline target wound size, and baseline target wound age as covariates.p-value: 0.80295% CI: [0.436, 1.821]Regression, Logistic