Comparison of Lindioil (Indigo Naturalis Oil Extract) Ointment to Protopic® Ointment 0.1% in Treating Atopic Dermatitis

Study Overview
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Brief Summary
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The aims of this study are: Compare the efficacy of Lindioil ointment and Protopic® ointment in treating atopic dermatitis. Compare the safety of Lindioil ointment and Protopic® ointment in treating atopic dermatitis. Compare the time to relapse after ceasing of treatment of Lindioil ointment and Protopic® ointment. Compare the change of skin microbiome before and after Lindioil ointment and Protopic® ointment treatment.

Detailed Description
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Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by itchiness. Topical corticosteroids are typically used to treat AD. However, many patients have concerns about the safety of long-term use, and seek alternative therapies such as traditional Chinese medicine (TCM). In TCM, indigo naturalis has been used to treat various infectious and inflammatory skin diseases for hundreds of years. The investigate also found that the results of indigo naturalis ointment treatment in other trial were comparable to the results of calcineurin inhibitor (such as Tacrolimus) treatment, and would like to verify this assertion. The aim of this study is to compare the efficacy of Lindioil ointment with that of Protopic® (Tacrolimus ointment 0.1%) in treating AD.

Official Title
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Comparison of the Efficacy and Safety of Lindioil (Indigo Naturalis Oil Extract) Ointment to Protopic® (Tacrolimus 0.1%) Ointment in Treating Atopic Dermatitis: A Randomized, Evaluator-blind, Crossover, Active-Controlled Trial

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Lindioil ointment
* Drug: Protopic ointment 0.1%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 16 and 65 years old, female or male. Chronic or sub-acute atopic dermatitis fulfilling the United Kingdom (UK) diagnostic criteria of atopic dermatitis. Atopic dermatitis involving 3-40% of BSA at screening and baseline. An IGA score of 2 (mild) to 4 (severe) at screening and baseline. Not supposed to or unwilling to use corticosteroids. Female patients of child-bearing age agree to use effective birth control measures approved by the investigator. Agree to avoid natural and artificial sunlight over-exposure during the study. Willing to comply with study protocol and agree to sign an informed consent form Exclusion Criteria: Acute atopic dermatitis or concurrence of viral or bacterial infection on dermatitis lesion(s). A history of topical or systematic hypersensitivity to indigo naturalis, tacrolimus, or the excipient(s) in the ointment(s). Having received systemic therapy (e.g. immunosuppressive agents) within 14 days, or phototherapy (e.g. ultraviolet B (UVB), psoralen and ultraviolet A (PUVA)) within 42 days before the first application of the study medication. Having used topical therapy (e.g. corticosteroids) for dermatitis within 4 days before the first application of the study medication. Having a significant concurrent disease such as severe uncontrolled chronic disease (e.g., hypertension, diabetes mellitus, metabolic arthritis, hyperthyroidism), psychiatric disease, cancer or AIDS. Having significant abnormal liver or renal function (Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) >3 x upper limit of normal (ULN), creatinine >2.0 mg/dl) or clinically significant abnormal hematological lab result, according to investigator's judgment, on the safety lab test to be performed within 30 days before the baseline visit. Women who are lactating, pregnant or planning to be pregnant during the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lindioil<br>Lindioil ointment is applied twice daily for 6 weeks, followed by a washout period of 4 days to 8 weeks depending on the results of the first treatment period and the amount of time it takes the participant to relapse to IGA ≥ 2 and less than 1-point of change from baseline1ST IGA. If relapse to IGA ≥ 2 and less than 1-point of change from baseline1ST IGA is achieved, the patient is using Protopic ointment 0.1% twice daily for another 6 weeks. If the criteria for entering the 2nd treatment are not achievable after 8-week of ceasing 1st treatment, the subject will be followed up for another 6 weeks to the end of the study | Drug: Lindioil ointment<br>* Each gram contains 200µg of indirubin. Apply 0.5 g of ointment per 10 cm x 10 cm of affected skin areas twice daily for 6 weeks.<br>* Other names: Indigo naturalis oil extract ointment;Drug: Protopic ointment 0.1%<br>* Each gram contains (w/w) 0.1% of tacrolimus. Apply 0.1 g of ointment per 10 cm x 10 cm of affected skin areas twice daily for 6 weeks.<br>* Other names: Tacrolimus ointment 0.1%;|
| Active Comparator: Protopic<br>Protopic ointment 0.1% is applied twice daily for 6 weeks, followed by a washout period of 4 days to 8 weeks depending on the results of the first treatment period and the amount of time it takes the participant to relapse to IGA ≥ 2 and less than 1-point of change from baseline1ST IGA. If relapse to IGA ≥ 2 and less than 1-point of change from baseline1ST IGA is achieved, the patient is using Lindioil ointment twice daily for another 6 weeks. If the criteria for entering the 2nd treatment are not achievable after 8-week of ceasing 1st treatment, the subject will be followed up for another 6 weeks to the end of the study | Drug: Lindioil ointment<br>* Each gram contains 200µg of indirubin. Apply 0.5 g of ointment per 10 cm x 10 cm of affected skin areas twice daily for 6 weeks.<br>* Other names: Indigo naturalis oil extract ointment;Drug: Protopic ointment 0.1%<br>* Each gram contains (w/w) 0.1% of tacrolimus. Apply 0.1 g of ointment per 10 cm x 10 cm of affected skin areas twice daily for 6 weeks.<br>* Other names: Tacrolimus ointment 0.1%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean percentage change from baseline to the end of week 6 of Eczema Area Severity Index (EASI) scores (range 0-72), for each of the two 6-week treatment periods. | The Eczema Area and Severity Index (EASI) is used to measure the disease severity of erythema, infiltration/papulation, excoriation, and lichenification each on a scale of 0 to 3 (none to severe) as well as the percentage of disease area on a scale of 0 to 6 for the 4 body regions: head ⁄ neck, upper limbs, trunk and lower limbs. Each body region score is calculated by multiplying the disease severity score by the disease area score and by the multiplier, 0.1 for head/neck, 0.2 for upper limbs, 0.3 for trunk, and 0.4 for lower limbs. The scores are summed to give the total EASI score, ranging from 0 to a maximum 72. | 6-week, 12-week (the end of the second treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who have achieved a 50%, 75% and 90% improvement in EASI scores (EASI-50, EASI-75 and EASI-90, respectively) at the end of week 6 of each treatment period. | It is defined as at least 50%, 75%, and 90% reduction in EASI score compare to the baseline. | 6-week, 12-week (the end of the second treatment period) | 
| Proportion of participants with an Investigator's Global Assessment (IGA, 0-5) score of 0 (clear) or 1 (almost clear) at the end of week 6 of each treatment period. | Investigator's Global Assessment (IGA) is a 6-points scale ranging from 0 (cleared) to 5 (Very severe) for evaluation of the severity of atopic dermatitis. | 6-week, 12-week (the end of the second treatment period) | 
| The mean percentage change from baseline to the end of week 6 of the Body Surface Area (BSA, range 0%-100%) affected by AD, for each of the two 6-week treatment periods. | BSA is total body surface area affected by atopic dermatitis, ranging from 0% (none) to 100% (total body surface affected). | 6-week, 12-week (the end of the second treatment period) | 
| Number of days until relapse to IGA ≥ 2, after ceasing treatment, for subjects who achieved IGA 0 or 1 at the end of week 6 of each treatment period. | Length of relapse free days after ceasing treatment | 6-week, 12-week (the end of the second treatment period) | 
| The change from baseline to the end of week 6 of Numeric Rating Scale for pruritus (NRS, 0-10), for each of the two 6-week treatment periods. | Numeric Rating Scale for pruritus (NRS) is a tool to evaluate itching intensity from 0 (no itch) to 10 (most imaginable itch) | 6-week, 12-week (the end of the second treatment period) | 
| The change from baseline to the end of week 6 of Dermatology Life Quality Index (DLQI) for each of the two 6-week treatment periods. | The DLQI is a self-administered 10-item questionnaire, ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired. | 6-week, 12-week (the end of the second treatment period) | 
| Proportion of participants with a Subject's Global Assessment (SGA, 0-6) score of 0 (much better) or 1 (better) at the end of week 6 of each treatment period. | Subject's Global Assessment (SGA) is a self-evaluated the change from baseline of their AD condition as 'much better' (0), 'better' (1) , 'slightly better' (2), 'same' (3), 'slightly worse' (4), 'worse' (5) or 'much worse' (6). | 6-week, 12-week (the end of the second treatment period) | 
| The participants' preference of using Lindioil ointment and Protopic® ointment treatment. | Patients who completed the second treatment period will answer which ointment with better efficacy, which with more adverse events, and the adverse event bothering them most. | 13 weeks (the end of the second treatment period) | 
| The change of skin microbiome before and after Lindioil ointment and Protopic® ointment treatment. | Skin swabs of lesion and non-lesion will be obtained from patient before and after study treatment to analyze skin microbiome. | 6-week, 12-week (the end of the second treatment period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atopic Dermatitis, Indigo naturalis, Tacrolimus