Autosomal Recessive Congenital Ichthyosis, Congenital Ichthyosiform Erythroderma, Epidermolytic Ichthyosis, Ichthyosis, Lamellar Ichthyosis, Netherton Syndrome
Conditions
Brief summary
The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation. There are no therapies based on growing understanding of what causes the disease. However, there have been recent discoveries of marked elevations in expression of interleukin-17A (IL-17A) and IL-17-related cytokines in the skin of individuals with ichthyosis, which may explain the inflammation. Investigators propose that IL-17-targeting therapeutics will safely suppress the inflammation and possibly the other features of ichthyosis, improving quality of life.
Detailed description
The ichthyoses are a group of lifelong genetic disorders which share characteristics of generalized skin thickening, scaling and underlying cutaneous inflammation. The vast majority are orphan disorders and are associated with extremely poor quality of life related to social ostracism from altered appearance, associated itchiness and discomfort, and functional limitations from the skin disease. Among the most common of these orphan disorders are autosomal recessive congenital ichthyosis (ARCI) with its phenotypic subsets of lamellar ichthyosis (ARCI-LI) and congenital ichthyosiform erythroderma (ARCI-CIE), epidermolytic ichthyosis (EI) and Netherton syndrome (NS). Therapy is time-consuming for patients or parents and is supportive, focusing on clearance of the scaling. There are no therapies based on growing understanding of what causes the disease. There have been recent discoveries of marked elevations in expression of interleukin-17A (IL-17A) and IL-17-related cytokines in the skin of individuals with ichthyosis, which may explain the inflammation. Psoriasis, another inflammatory skin disorder with redness and scaling, has now been shown to result from IL-17 pathway activation and IL-17A inhibition is the most effective therapy known to treat psoriasis. Investigators propose that IL-17-targeting therapeutics will safely suppress the inflammation and possibly the other features of ichthyosis, improving quality of life. In this long-term, open-label extension, Investigators propose to treat adults with ichthyosis and at least moderate erythema with subcutaneously administered anti-IL-17 antibody (secukinumab) and to serially assess clinical response to this therapy and its safety.
Interventions
DRUGSecukinumab
Anti IL-17A antibody
DRUGPlacebo
Sponsors
Icahn School of Medicine at Mount Sinai
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent * Subjects are at least 18 years of age or older at the time of screening * Female subjects must not be pregnant or breast-feeding * Female subjects of child-bearing potential with a negative urine pregnancy test and using at least one form of contraception (abstinence allowed) * Subjects must have a confirmed diagnosis of ARCI (divided phenotypically into ARCI-LI or ARCI-CIE), EI or NS (by genotype or willingness to be genotyped) * Subjects must be clinically judged to be immunocompetent. * Subjects will have no allergy to secukinumab or components of the product. * Subjects will have normal baseline laboratory testing (CMP, CBC, HIV negative, hepatitis B, C negative, QuantiFERON®-TB gold negative) * Subjects must have an erythema score of at least 18 on IASI and an IASI-E score of 12 (at least moderate severity of erythema) at baseline
Exclusion criteria
* Subjects who are unable to give informed consent or assent. * Subjects without a confirmed diagnosis ARCI, EI, or NS. * Subjects who have a known allergy to secukinumab. * Female subjects who are pregnant, considering becoming pregnant, or will breastfeed. * Subjects who have prior biologic use targeting IL-17A/IL-17 receptor A or IL-12/IL-23 or who have prior use of TNF-alpha blockers. * Subjects who have used a systemic retinoid within one month prior to initiation. * Subjects who have used topical retinoids or keratolytics within one week prior to initiation. * Subjects who have used emollient on the area to be biopsied in the previous 24 hours
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction at Week 16 in the Ichthyosis Area Severity Index (IASI) | 16 Weeks | Primary Efficacy Endpoint. The IASI score was modelled after the Eczema Area and Severity Index (EASI) and Psoriasis Area and Severity Index (PASI), commonly used in clinical trials for atopic dermatitis and psoriasis, respectively. This scale measures erythema and scaling and has a range of 0-48 (sum of a max score of 24 for erythema and 24 for scaling). A higher score means worse clinical severity. Mean difference IASI total score at Baseline was compared to IASI total score at Week 16. |
| Total Number of Bacterial or Fungal Mucocutaneous Infections Through Week 16 | 16 weeks of secukinumab/placebo double blind followed by 32 week open label treatment | Primary Safety Endpoint |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Secukinumab Secukinumab 300mg (liquid formation) administered subcutaneously weekly for 5 weeks then monthly until end of trial
Secukinumab: Anti IL-17A antibody | 11 |
| Placebo Placebo (sterile saline) 2ml administered subcutaneously weekly for 5 weeks then monthly until end of trial
Placebo | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Secukinumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 11.7 | 35.5 years STANDARD_DEVIATION 12.7 | 34.7 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 8 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ichthyosis Area Severity Index (IASI) | 33.7 units on a scale STANDARD_DEVIATION 6.5 | 36.2 units on a scale STANDARD_DEVIATION 4.7 | 34.8 units on a scale STANDARD_DEVIATION 5.9 |
| Ichthyosis Subtype CIE | 3 Participants | 2 Participants | 5 Participants |
| Ichthyosis Subtype EI | 2 Participants | 2 Participants | 4 Participants |
| Ichthyosis Subtype LI | 4 Participants | 2 Participants | 6 Participants |
| Ichthyosis Subtype NS | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
| Site Mount Sinai | 4 Participants | 2 Participants | 6 Participants |
| Site Northwestern | 7 Participants | 7 Participants | 14 Participants |
| Weight | 69.9 kilograms STANDARD_DEVIATION 13.5 | 75.5 kilograms STANDARD_DEVIATION 30.4 | 72.4 kilograms STANDARD_DEVIATION 22 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 9 | 0 / 18 |
| other Total, other adverse events | 3 / 11 | 2 / 9 | 6 / 18 |
| serious Total, serious adverse events | 1 / 11 | 0 / 9 | 1 / 18 |
Outcome results
Primary
Reduction at Week 16 in the Ichthyosis Area Severity Index (IASI)
Primary Efficacy Endpoint. The IASI score was modelled after the Eczema Area and Severity Index (EASI) and Psoriasis Area and Severity Index (PASI), commonly used in clinical trials for atopic dermatitis and psoriasis, respectively. This scale measures erythema and scaling and has a range of 0-48 (sum of a max score of 24 for erythema and 24 for scaling). A higher score means worse clinical severity. Mean difference IASI total score at Baseline was compared to IASI total score at Week 16.
Time frame: 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Secukinumab | Reduction at Week 16 in the Ichthyosis Area Severity Index (IASI) | 2.4 units on a scale |
| Placebo | Reduction at Week 16 in the Ichthyosis Area Severity Index (IASI) | 4.3 units on a scale |
Primary
Total Number of Bacterial or Fungal Mucocutaneous Infections Through Week 16
Primary Safety Endpoint
Time frame: 16 weeks of secukinumab/placebo double blind followed by 32 week open label treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Total Number of Bacterial or Fungal Mucocutaneous Infections Through Week 16 | 5 infections |
| Placebo | Total Number of Bacterial or Fungal Mucocutaneous Infections Through Week 16 | 5 infections |
| Open Label | Total Number of Bacterial or Fungal Mucocutaneous Infections Through Week 16 | 10 infections |