Efficacy and Safety of Orally Administered DS107 in Adult Patients With Moderate to Severe Atopic Dermatitis

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to compare the efficacy and safety of orally administered DS107 (2g) versus placebo in the treatment of moderate to severe Atopic Dermatitis (AD). Oral DS107/Placebo capsules will be administered for 16 weeks. The study will enrol approximately 220 subjects.

Detailed Description
-----------------
This study involves a comparison of 2g DS107 with placebo, administered orally once daily for a total of 16 weeks. Patients will be randomized to one of the two treatment arms in a 1:1 ratio. The primary endpoint will be the vIGA (Validated Investigator's Global Assessment) and EASI (Eczema Area and Severity Index). Other endpoints include vIGA, EASI, SCORAD, BSA (Body Surface Area) and NRS (Numeric Rating Scale).

Official Title
-----------------
A Randomised, Double-blind, Placebo-controlled, Study to Assess the Efficacy and Safety of Orally Administered DS107 in Adult Patients With Moderate to Severe Atopic Dermatitis

Conditions
-----------------
Atopic Dermatitis

Intervention / Treatment
-----------------
* Drug: DS107
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with a clinically confirmed diagnosis of active AD according to the American Academy of Dermatology Consensus Criteria that had been present for at least 6 months before the screening visit. Patients with moderate to severe AD at baseline as defined by a Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-ADTM) score of 3 Or 4 at baseline. Patients with an Eczema Area and Severity Index (EASI) score of ≥16 at screening and baseline. Patients with AD covering a minimum 10% of the Body Surface Area (BSA) at baseline. Patients with a worst itch Numeric Rating Scale (NRS) score in a day of ≥4 (on 11-point NRS) at the screening and baseline visits. Patients whose pre-study clinical laboratory findings did not interfere with their participation in the study, in the opinion of the investigator. Patients who were able and willing to stop all current treatments for AD throughout the study (except for allowed emollients). Patients who were on a stable dose of a bland emollient for at least 7 days prior to baseline. Male or female patients aged 18 years and older on the day of signing the informed consent form (ICF). Female patients and male patients with female partners of child bearing potential had to use highly effective birth control methods or have a sterilised partner for the duration of the study. Recent history (within 6 months before the screening visit) of inadequate response to treatment with topical medications or for whom topical treatments were otherwise medically inadvisable (e.g. because of important side effects or safety risks). Patients who were able to communicate well with the investigator, to understand and comply with the requirements of the study, and understand and sign the written informed consent prior to initiation of any study specific activities or procedures. Exclusion Criteria: Patients with other skin conditions that might interfere with AD diagnosis and/or evaluation (such as psoriasis or current active viral, bacterial and fungal topical skin infections) as assessed by the investigator. Patients who had used systemic treatments that could affect AD less than 4 weeks prior to Baseline Visit (Day 0), e.g. retinoids, methotrexate, cyclosporine, hydroxycarbamide (hydroxyurea), azathioprine and oral/injectable corticosteroids. Intranasal corticosteroids and inhaled corticosteroids for stable medical conditions were allowed. Patients with previous exposure to DS107. Patients who had used any topical medicated treatment for AD (except for emollients) two weeks prior to start of treatment/Baseline (Day 0) including but not limited to, topical corticosteroids, calcineurin inhibitors, tars, bleach, antimicrobials and bleach baths. Patients who used emollients containing urea, ceramides or hyaluronic acid less than 12 weeks prior to Baseline (Day 0). Patients who have had excessive sun exposure, have used tanning booths or other ultraviolet (UV) light sources four weeks prior to Baseline (Day 0) and/or were planning a trip to a sunny climate or to use tanning booths or other UV sources between screening and follow-up visits. Patients who had a history of hypersensitivity to any substance in DS107 or placebo capsules. Patients who had a history of hypersensitivity to soy beans or soy lecithin. Patients who had a white cell count or differential white cell count outside of the normal reference range at screening. Patients who had any clinically significant controlled or uncontrolled medical condition or laboratory abnormality that would, in the opinion of the investigator, put the patient at undue risk or interfere with interpretation of study results. Patients who had a clinically significant impairment of renal or hepatic function. Patients with significant uncontrolled cardiovascular, neurologic, malignant, psychiatric, respiratory or hypertensive disease, as well as uncontrolled diabetes and fluoride arthritis or any other illness that, in the opinion of the investigator, was likely to interfere with completion of the study. Patients with active infectious diseases (e.g. hepatitis B, hepatitis C or advanced disease secondary to infection with human immunodeficiency virus). Patients with a history of clinically significant drug or alcohol abuse in the opinion of the investigator in the last year prior to Baseline (Day 0). Patients who had participated in any other clinical study with an investigational drug within 3 months before the first day of administration of study treatment. Patients who have had treatment with biologics as follows: Any cell-depleting agents including but not limited to rituximab: within 6 months before the screening visit, or until lymphocyte count returned to normal, whichever was longer. b. Other biologics influencing cell proliferation: within 6 months before the screening visit. c. Dupilumab or other monoclonal antibodies within 5 half-lives (if known) or 16 weeks prior to baseline visit, whichever was longer. Patients who were pregnant, planning pregnancy, breastfeeding and/or were unwilling to use adequate contraception (as specified in Inclusion Criterion 10) during the trial. Patients, in the opinion of the investigator, not suitable to participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2g Oral DS107<br>2g DS107 (4 DS107 capsules) administered once-daily for 16 weeks | Drug: DS107<br>* DS107 Capsule<br>* Other names: DS107 500mg DGLA Capsules/DS107 500mg Placebo Capsules;|
| Placebo Comparator: Placebo<br>Placebo (4 placebo capsules) orally administered once-daily for 16 weeks | Drug: Placebo<br>* Placebo capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving a Validated Investigator Global Assessment Scale for Atopic Dermatitis Score of 0 or 1 and a Decrease of at Least 2 Points in vIGA-ADTM in Treated Population Compared to Placebo Population From Baseline at Week 16. | Proportion of patients achieving a Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-ADTM) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points in vIGA-ADTM in treated population compared to placebo population from Baseline at Week 16 using GLMM.The vIGA-ADTM scale awards a score of 0-4 based on a 5-point severity scale from clear to severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). The scale uses clinical characteristics of erythema, infiltration, papulation and oozing/crusting as scoring guidelines for the overall severity assessment. | 16 Weeks | 
| Proportion of Patients Achieving EASI-75 in Treated Population Compared to Placebo Population at Week 16. | Proportion of patients achieving EASI-75 (≥75% improvement from Baseline) in treated population compared to placebo population at Week 16 using GLMM. | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving a vIGA-ADTM Score of 0 or 1 and a Decrease of at Least 2 Points in vIGA-ADTM in Treated Population Compared to Placebo Population From Baseline to Week 4, 8, 12, 18 and 20. | Proportion of patients achieving a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-ADTM) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points in vIGA-ADTM in treated population compared to placebo population from baseline to Week 4, 8, 12, 18 and 20 and the change in proportion of patients from Week 16 to Week 18 and 20. The vIGA-ADTM scale awards a score of 0-4 based on a 5-point severity scale from clear to severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). The scale uses clinical characteristics of erythema, infiltration, papulation and oozing/crusting as scoring guidelines for the overall severity assessment. | Baseline, Week 4, Week 8, Week 12, Week 18 and Week 20. | 
| Proportion of Patients Achieving EASI-75 (≥75% Improvement From Baseline) in Treated Population Compared to Placebo Population at Weeks 4, 8, 12, 18 and 20 | Proportion of Patients Achieving EASI-75 (≥75% Improvement in Eczema Area and Severity Index from Baseline) in Treated Population Compared to Placebo Population at Weeks 4, 8, 12, 18 and 20 EASI quantifies the severity of a patient's AD based on both lesion severity and the percent of BSA affected. The EASI is a composite score ranging from 0-72 that takes into account the degree of erythema, induration/papulation, excoriation, and lichenification (each scored from 0 to 3 separately, half points are permitted) for each of four body regions, with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. | Baseline, Week 4, Week 8, Week 12, Week 18 and Week 20. | 
| Change From Baseline in Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-ADTM) Score in Treated Population Compared to Placebo Population to Weeks 4, 8, 12, 16, 18 and 20. | The Validated Global Investigator Assessment scale for Atopic Dermatitis (vIGA-AD) scale awards a score of 0-4 based on a 5-point severity scale from clear to severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease). The scale uses clinical characteristics of erythema, infiltration, papulation and oozing/crusting as scoring guidelines for the overall severity assessment. A decrease in Validated Global Investigator Assessment scale indicates a positive outcome for the participant. | 20 Weeks | 
| Change From Baseline in EASI in Treated Population Compared to Placebo Population to Weeks 4, 8, 12, 16, 18 and 20. | Change from Baseline in Eczema Area and Severity Index (EASI) in treated population compared to placebo population to Weeks 4, 8, 12, 16, 18 and 20. EASI quantifies the severity of a patient's atopic dermatitis (AD) based on both lesion severity and the percent of body surface area (BSA) affected. The EASI is a composite score ranging from 0 (no lesion severity) to 72 (severe lesions) that takes into account the degree of erythema, induration/papulation, excoriation, and lichenification (each scored from 0 to 3 separately, half points are permitted) for each of four body regions, with adjustment for the percent of Body Surface Area (BSA) involved for each body region and for the proportion of the body region to the whole body. The severity of each sign is assessed using a 4-point scale (half points are permitted): 0 = none 1 = mild 2 = moderate 3 = severe A decrease in EASI indicates a positive outcome for the participant. | Week 20 | 
| Change From Baseline in Worst Itch NRS in Treated Population Compared to Placebo Population to Week 4, 8, 12, 16, 18. | Change from Baseline in worst itch Numeric Rating Scale (NRS) in treated population compared to placebo population to Week 4, 8, 12, 16 and 18. Severity of pruritus related to atopic dermatitis (AD) was self-assessed by patients daily using the NRS. Patients were asked to estimate the intensity of pruritus at its worst over the previous 24 hours. The Pruritus NRS is a single-question assessment tool that was used to assess the patient's worst itch as a result of AD in the previous 24 hours. Patients will score their pruritus due to AD on a scale of 0 - 10, with 0 indicating no itch and 10 indicating the worst itch imaginable. Patients will complete the rating scale daily starting at screening through to the last study visit. A decrease in worst itch NRS indicates a positive outcome for the participant. | Week 18 | 
| Proportion of Patients Achieving a Decrease of at Least 3 Points in Worst Itch NRS in Treated Population Compared to Placebo Population From Baseline to Week 4, 8, 12, 16, 18 and 20. | Proportion of Patients Achieving a Decrease of at Least 3 Points in Worst Itch Numeric Rating Scale (NRS) in Treated Population Compared to Placebo Population From Baseline to Week 4, 8, 12, 16, 18 and 20. The Pruritus NRS is a single-question assessment tool that will be used to assess the patient's worst itch as a result of AD in the previous 24 hours. Patients score their pruritus due to AD on a scale of 0 - 10, with 0 (no itch) and 10 (worst itch imaginable). Patients will complete the rating scale daily starting at screening through to the last study visit. | Week 20 | 
| Proportion of Patients Achieving a Decrease of at Least 4 Points in Worst Itch NRS in Treated Population Compared to Placebo Population From Baseline to Week 4, 8, 12, 16, 18 and 20, | Proportion of patients achieving a decrease of at least 4 points in worst itch Numeric Rating Scale (NRS) in treated population compared to placebo population from baseline to Week 4, 8, 12, 16, 18 and 20. Severity of pruritus related to atopic dermatitis (AD) was self-assessed by patients daily using the NRS. Patients were asked to estimate the intensity of pruritus at its worst over the previous 24 hours. The Pruritus NRS is a single-question assessment tool that is used to assess the patient's worst itch as a result of AD in the previous 24 hours. Patients will score their pruritus due to AD on a scale of 0 - 10, with 0 indicating no itch and 10 indicating the worst itch imaginable. Patients completed the rating scale daily starting at screening through to the last study visit. A decrease in worst itch NRS indicates a positive outcome for the participant. | Week 20 | 
| Proportion of Patients Achieving EASI-50 (≥50% Improvement From Baseline) in Treated Population Compared to Placebo Population at Week 4, 8, 12, 16, 18 and 20. | Proportion of Patients Achieving EASI-50 (≥50% Improvement in Eczema Area and Severity Index From Baseline) in Treated Population Compared to Placebo Population at Week 4, 8, 12, 16, 18 and 20. The EASI is a composite score ranging from 0-72 that takes into account the degree of erythema, induration/papulation, excoriation, and lichenification (each scored from 0 to 3 separately, half points are permitted) for each of four body regions, with adjustment for the percent of Body Surface Area (BSA) involved for each body region and for the proportion of the body region to the whole body. The severity of each sign is assessed using a 4-point scale (half points are permitted): 0 = none 1 = mild 2 = moderate 3 = severe A decrease in EASI indicates a positive outcome for the participant. | Week 20 | 
| Change From Baseline in the Body Surface Area Affected by AD in Treated Population Compared to Placebo Population to Weeks 4, 8, 12, 16, 18. | Change from Baseline in the Body Surface Area (BSA) affected by AD in treated population compared to placebo population to Weeks 4, 8, 12, 16, 18. | Week 18 | 
| Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score in Treated Population Compared to Placebo Population to Weeks 4, 8, 12, 16, 18. | The SCORing Atopic Dermatitis (SCORAD) grading system was developed by the European Task Force on Atopic Dermatitis and has been a standard tool to assess atopic dermatitis (AD) severity in clinical studies. Six items (erythema, edema/papulation, oozing/crusts, excoriation, lichenification, and dryness) will be selected to evaluate the AD severity. The intensity of each item is graded using a 4-point scale: 0 = No symptoms 1 = Mild 2 = Moderate 3 = Severe The overall body surface area (BSA) affected by AD is evaluated (from 0 to 100%) and included in the SCORAD scores. Loss of sleep and pruritus will be evaluated by patients on a visual analog scale (0-10). | 18 Weeks | 
| Incidence of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs). | Incidence of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Safety Analysis Set. | 20 Weeks |