Congenital Ichthyosis
Conditions
Brief summary
The purpose of this study is to investigate the efficacy and safety of two concentrations of topically applied ointment formulation of isotretinoin called TMB-001 (0.05% and 0.1% isotretinoin) in subjects 9 years of age and older for the treatment of congenital ichthyosis (CI), including recessive X-linked ichthyosis (RXLI) and autosomal recessive congenital ichthyosis-lamellar ichthyosis (ARCI-LI) subtypes. Funding Source FDA-OOPD
Detailed description
This is a randomized, parallel, double-blind, vehicle-controlled study to evaluate the safety and efficacy of two concentrations of topical TMB-001 for the treatment of CI in subjects with either the ARCI-LI or RXLI subtypes. The duration of treatment will be 12 weeks. Each subject will participate in the study for up to 24 weeks (including up to a 90-day Screening period). Eleven study centers from United States of America and Australia participated in this global study. Each subject participated in the study for up to 24 weeks (including up to a 90-day Screening period). Eligible subjects were randomized (1:1:1) to one of 3 treatment groups: 1. TMB-001, 0.05%, twice daily (bid) 2. TMB-001, 0.1%, bid 3. Vehicle Ointment (Control), 0%, bid Subjects were evaluated on a monthly basis for safety and efficacy results over the 12- week treatment period. Efficacy was determined in 2 ways: 1. VIIS (or Visual Index of Ichthyosis Severity) "treatment success" (VIIS-50) was defined as ≥ 50% reduction from Baseline for VIIS scaling score for the sum of the scores for 'VIIS body areas' that had a Baseline score ≥ 3). The proportion of subjects achieving VIIS-50 at Visit 6 at Week 12 relative to Baseline was the primary efficacy endpoint and time point used to compare the two active treatments to vehicle. 2. The proportion of subjects achieving IGA (Investigator Global Assessment) treatment success will be the key secondary endpoint. For this endpoint, the IGA score was established as "treatment success" or "treatment failure" where "treatment success" is defined as at least a 2-grade decrease in severity score (for example, severe or score of 4 at baseline to mild or score of 2 at Visit 6) relative to Baseline at Visit 6 at week 12. The safety analyses conducted were extent of exposure, changes in physical examinations and vital signs, blood and urine testing including urine pregnancy testing as indicated, local skin reactions (including burning/stinging, redness, erosions, and swelling) and other adverse events.
Interventions
DRUGIsotretinoin
Topical Isotretinoin ointment
OTHERVehicle
Topical Vehicle Ointment
Sponsors
LEO Pharma
Timber Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
A Randomized, Parallel, Double-Blind, Vehicle-Controlled Study
Eligibility
Sex/Gender
ALL
Age
9 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is male or female, 9 years of age or older at Visit 2 (Baseline) * Subject has provided written informed consent * Females of child bearing potential must be surgically sterile or agree to 2 forms of birth control * Subject has clinical diagnosis of Congenital Ichthyosis with genetic confirmation of subtype * Subject has between 10% and 90% total BSA affected by Congenital Ichthyosis * Subject has at least 2 VIIS assessment areas with a scaling score of 3 or greater
Exclusion criteria
* Subject has inflammatory skin diseases unrelated to ichthyosis * Subject has used other prohibited topical treatments in the assessment areas within certain days from baseline * Subject has used systemic retinoids within12 weeks of baseline * Subject has untreated secondary infections * Subject has lesions suspicious for skin cancer or untreated skin cancers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement | 12 weeks | Number of subjects with Visual Index for Ichthyosis Severity (VIIS) treatment success, defined as 50% or greater decreased in VIIS scaling score |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment | 12 weeks | Number of subjects with Investigator Global Assessment decrease in disease severity by at least 2 grades |
| Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12 | 12 weeks | Mean numeric Change from baseline in Itch-Numeric Rating Scale (I-NRS) at Week 12 for entire population. I-NRS is an 11-point visual analogue scale scored based upon 0 being no itch and 10 being worst itch imaginable. Subjects were asked to grade their itch on such a scale at each visit where I-NRS was administered. A 4-point change from baseline is considered clinically significant |
| Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | 12 weeks | Change from Baseline in Dermatology Life Quality Index (DLQI) at Week 12 in all adult subjects. The DLQI is validated in all subjects over age 16 years and is a 10-question questionnaire which requests information on how the dermatological condition affects different aspects of their life. Each question is scored on a 0-3 scale (0=no impact, 3=major impact) for a total possible maximal score of 30. Scores over 11 in adults are considered to indicate moderate impairment of quality of life due to the skin disease. A 4-point improvement from baseline is considered clinically significant |
Countries
Australia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vehicle Ointment (Control) Topical, BID (Twice daily)
Vehicle: Topical Vehicle Ointment | 12 |
| TMB-001 Ointment, 0.05% Topical, BID ( twice daily)
Isotretinoin: Topical Isotretinoin ointment | 11 |
| TMB-001 Ointment, 0.1% Topical, BID (Twice daily)
Isotretinoin: Topical Isotretinoin ointment | 10 |
| Total | 33 |
Baseline characteristics
| Characteristic | Vehicle Ointment (Control) | Total | TMB-001 Ointment, 0.1% | TMB-001 Ointment, 0.05% |
|---|---|---|---|---|
| Age, Continuous | 36.8 years STANDARD_DEVIATION 24.6 | 34.5 years STANDARD_DEVIATION 20.7 | 34.5 years STANDARD_DEVIATION 19.7 | 31.9 years STANDARD_DEVIATION 18.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 27 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 26 Participants | 8 Participants | 8 Participants |
| Region of Enrollment Australia | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 12 participants | 32 participants | 9 participants | 11 participants |
| Sex: Female, Male Female | 4 Participants | 12 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 21 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 3 / 12 | 9 / 11 | 8 / 10 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 | 0 / 10 |
Outcome results
Primary
Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement
Number of subjects with Visual Index for Ichthyosis Severity (VIIS) treatment success, defined as 50% or greater decreased in VIIS scaling score
Time frame: 12 weeks
Population: Intention to treat analysis only on subjects who received at least one dose of study medication; one subject in TMB-001 0.1% arm was randomized but never received study medication due to COVID
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle Ointment (Control) | Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement | 4 Participants |
| TMB-001 Ointment, 0.05% | Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement | 7 Participants |
| TMB-001 Ointment, 0.1% | Number of Subjects With Reduction in Targeted Ichthyosis Severity Using the Visual Index for Ichthyosis Severity Measurement | 4 Participants |
Secondary
Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12
Change from Baseline in Dermatology Life Quality Index (DLQI) at Week 12 in all adult subjects. The DLQI is validated in all subjects over age 16 years and is a 10-question questionnaire which requests information on how the dermatological condition affects different aspects of their life. Each question is scored on a 0-3 scale (0=no impact, 3=major impact) for a total possible maximal score of 30. Scores over 11 in adults are considered to indicate moderate impairment of quality of life due to the skin disease. A 4-point improvement from baseline is considered clinically significant
Time frame: 12 weeks
Population: Intention to treat analysis based upon available data collected. Data imputation was not performed for DLQI but only for primary endpoint as above
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vehicle Ointment (Control) | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | -3.4 units on a scale | Standard Deviation 4.72 |
| TMB-001 Ointment, 0.05% | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | -3.2 units on a scale | Standard Deviation 9.28 |
| TMB-001 Ointment, 0.1% | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | -1.3 units on a scale | Standard Deviation 3.95 |
Secondary
Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12
Mean numeric Change from baseline in Itch-Numeric Rating Scale (I-NRS) at Week 12 for entire population. I-NRS is an 11-point visual analogue scale scored based upon 0 being no itch and 10 being worst itch imaginable. Subjects were asked to grade their itch on such a scale at each visit where I-NRS was administered. A 4-point change from baseline is considered clinically significant
Time frame: 12 weeks
Population: Intention to treat analysis based upon available data collected. Data imputation was not performed for I-NRS but only for primary endpoint as above
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vehicle Ointment (Control) | Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12 | -1.7 units on a scale | Standard Deviation 2.54 |
| TMB-001 Ointment, 0.05% | Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12 | -1.9 units on a scale | Standard Deviation 5.3 |
| TMB-001 Ointment, 0.1% | Change in I-NRS (Itch-Numeric Rating Scale) From Baseline at Week 12 | 1.1 units on a scale | Standard Deviation 2.64 |
Secondary
Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment
Number of subjects with Investigator Global Assessment decrease in disease severity by at least 2 grades
Time frame: 12 weeks
Population: Intention to treat analysis only on subjects who received at least one dose of study medication; one subject in TMB-001 0.1% arm was randomized but never received study medication due to COVID
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle Ointment (Control) | Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment | 1 Participants |
| TMB-001 Ointment, 0.05% | Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment | 6 Participants |
| TMB-001 Ointment, 0.1% | Number of Subjects With Reduction in Overall Ichthyosis Severity as Measured With Investigator Global Assessment | 4 Participants |