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

• ClinicalTrials.gov Identifier: NCT03614221
• Recruitment Status: Recruiting
• First Posted: August 3, 2018
• Last Update Posted: August 29, 2019
• Sponsor: Chang Gung Memorial Hospital
• Collaborator: Ministry of Science and Technology, Taiwan
• Information provided by (Responsible Party): Chang Gung Memorial Hospital

Study Description

Brief Summary:

The aims of this study are:

1. Compare the efficacy of Lindioil ointment and Protopic® ointment in treating atopic dermatitis.
2. Compare the safety of Lindioil ointment and Protopic® ointment in treating atopic dermatitis.
3. Compare the time to relapse after ceasing of treatment of Lindioil ointment and Protopic® ointment.
4. Compare the change of skin microbiome before and after Lindioil ointment and Protopic® ointment treatment.

Condition or disease	Intervention/treatment	Phase
Atopic Dermatitis	Drug: Lindioil ointment; Drug: Protopic ointment 0.1%	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 3, 2019
• Estimated Primary Completion Date: July 31, 2021
• Estimated Study Completion Date: July 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lindioil; 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 terminate participation in this trial.	Drug: Lindioil ointment; 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.; Other Name: Indigo naturalis oil extract ointment; Drug: Protopic ointment 0.1%; 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.; Other Name: Tacrolimus ointment 0.1%
Active Comparator: Protopic; 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 terminate participation in this trial.	Drug: Lindioil ointment; 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.; Other Name: Indigo naturalis oil extract ointment; Drug: Protopic ointment 0.1%; 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.; Other Name: Tacrolimus ointment 0.1%

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   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.

Secondary Outcome Measures :

1. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   It is defined as at least 50%, 75%, and 90% reduction in EASI score compare to the baseline.
2. 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. [ Time Frame: 6-week, 12-week (the end of the second 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.
3. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   BSA is total body surface area affected by atopic dermatitis, ranging from 0% (none) to 100% (total body surface affected).
4. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   Length of relapse free days after ceasing treatment
5. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   Numeric Rating Scale for pruritus (NRS) is a tool to evaluate itching intensity from 0 (no itch) to 10 (most imaginable itch)
6. 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. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   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.
7. 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. [ Time Frame: 6-week, 12-week (the end of the second 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).
8. The participants' preference of using Lindioil ointment and Protopic® ointment treatment. [ Time Frame: 13 weeks (the end of the second treatment period) ]
   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.
9. The change of skin microbiome before and after Lindioil ointment and Protopic® ointment treatment. [ Time Frame: 6-week, 12-week (the end of the second treatment period) ]
   Skin swabs of lesion and non-lesion will be obtained from patient before and after study treatment to analyze skin microbiome.

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Between 16 and 65 years old, female or male.
2. Chronic or sub-acute atopic dermatitis fulfilling the United Kingdom (UK) diagnostic criteria of atopic dermatitis.
3. Atopic dermatitis involving 3-40% of BSA at screening and baseline.
4. An IGA score of 2 (mild) to 4 (severe) at screening and baseline.
5. Not supposed to or unwilling to use corticosteroids.
6. Female patients of child-bearing age agree to use effective birth control measures approved by the investigator.
7. Agree to avoid natural and artificial sunlight over-exposure during the study.
8. Willing to comply with study protocol and agree to sign an informed consent form

Exclusion Criteria:

1. Acute atopic dermatitis or concurrence of viral or bacterial infection on dermatitis lesion(s).
2. A history of topical or systematic hypersensitivity to indigo naturalis, tacrolimus, or the excipient(s) in the ointment(s).

3. 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.

4. Having used topical therapy (e.g. corticosteroids) for dermatitis within 4 days before the first application of the study medication.
5. Having a significant concurrent disease such as severe uncontrolled chronic disease (e.g., hypertension, diabetes mellitus, metabolic arthritis, hyperthyroidism), psychiatric disease, cancer or AIDS.
6. 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.
7. Women who are lactating, pregnant or planning to be pregnant during the study.

Contacts and Locations

Contacts

Contact: Yin-Ku Lin, MD., PhD.; 886-2-24313131 ext 2127; lin1266@cgmh.org.tw

Locations

Taiwan

Taipei Chang Gung Memorial Hospital; Recruiting

Taipei, Taiwan, 10507

Contact: Yin-Ku Lin, MD., PhD. 886-2-24311311 ext 2127 lin1266@cgmh.org.tw

Principal Investigator: Yin-Ku Lin, MD., PhD.

Sub-Investigator: Chun-Bing Chen, MD.

Sub-Investigator: Chin-Yi Yang, MD.

Sub-Investigator: Chun-Wei Lu, MD.

Sub-Investigator: Wen-Hung Chung, MD., PhD.

Sub-Investigator: Chih-Yung Chiu, MD., PhD

Sub-Investigator: Shih-Chi Su, PhD.

Sub-Investigator: Lai-Chu See, PhD.

Sub-Investigator: I-Hsin Shih, MD.

Sub-Investigator: Min-Hui Chi, MD.

Sub-Investigator: Jennifer Wu, MD.

Linkou Chang Gung Memorial Hospital; Recruiting

Taoyuan, Taiwan, 33305

Contact: Yin-Ku Lin, MD., PhD 886-2-241-3131 ext 2127 lin1266@cgmh.org.tw

Principal Investigator: Yin-Ku Lin, MD., PhD

Sub-Investigator: Chun-Bing Chen, MD.

Sub-Investigator: Chin-Yi Yang, MD.

Sub-Investigator: Chun-Wei Lu, MD.

Sub-Investigator: Wen-Hung Chung, MD., PhD

Sub-Investigator: Chih-Yung Chu, MD., PhD

Sub-Investigator: Shih-Chi Su, PhD.

Sub-Investigator: Lai-Chu See, PhD.

Sub-Investigator: I-Hsin Shih, MD.

Sub-Investigator: Min-Hui Chi, MD.

Sub-Investigator: Jennifer Wu, MD.

Sponsors and Collaborators

Chang Gung Memorial Hospital

Ministry of Science and Technology, Taiwan

Investigators

• Principal Investigator: Yin-Ku Lin, MD., PhD.; Chang Gung Memorial Hospital

More Information

Publications:

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Lan CC, Kao YH, Huang SM, Yu HS, Chen GS. FK506 independently upregulates transforming growth factor beta and downregulates inducible nitric oxide synthase in cultured human keratinocytes: possible mechanisms of how tacrolimus ointment interacts with atopic skin. Br J Dermatol. 2004 Sep;151(3):679-84.

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Lin YK, Chang YC, Hui RC, See LC, Chang CJ, Yang CH, Huang YH. A Chinese Herb, Indigo Naturalis, Extracted in Oil (Lindioil) Used Topically to Treat Psoriatic Nails: A Randomized Clinical Trial. JAMA Dermatol. 2015 Jun;151(6):672-4. doi: 10.1001/jamadermatol.2014.5460.

Lin YK, See LC, Huang YH, Chang YC, Tsou TC, Lin TY, Lin NL. Efficacy and safety of Indigo naturalis extract in oil (Lindioil) in treating nail psoriasis: a randomized, observer-blind, vehicle-controlled trial. Phytomedicine. 2014 Jun 15;21(7):1015-20. doi: 10.1016/j.phymed.2014.02.013. Epub 2014 Mar 26.

Lin YK, See LC, Huang YH, Chi CC, Hui RC. Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: a randomized, double-blind, dosage-controlled trial. Br J Dermatol. 2018 Jan;178(1):124-131. doi: 10.1111/bjd.15894. Epub 2017 Dec 14.

Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol. 1999 May;1(1):60-7.

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Sethi G, Ahn KS, Sandur SK, Lin X, Chaturvedi MM, Aggarwal BB. Indirubin enhances tumor necrosis factor-induced apoptosis through modulation of nuclear factor-kappa B signaling pathway. J Biol Chem. 2006 Aug 18;281(33):23425-35. Epub 2006 Jun 19.

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Lin YK, Chen HW, Leu YL, Yang YL, Fang Y, Su Pang JH, Hwang TL. Indigo naturalis upregulates claudin-1 expression in human keratinocytes and psoriatic lesions. J Ethnopharmacol. 2013 Jan 30;145(2):614-20. doi: 10.1016/j.jep.2012.11.044. Epub 2012 Dec 7. Erratum in: J Ethnopharmacol. 2013 May 20;147(2):546. Su Pang, Jong-Hwei [added].

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• Responsible Party: Chang Gung Memorial Hospital
• ClinicalTrials.gov Identifier: NCT03614221 History of Changes
• Other Study ID Numbers: MOST107-2320-B-182A-002 -MY3
• First Posted: August 3, 2018
• Last Update Posted: August 29, 2019
• Last Verified: June 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Chang Gung Memorial Hospital:

Atopic Dermatitis; Indigo naturalis; Tacrolimus

Additional relevant MeSH terms:

Dermatitis, Atopic; Dermatitis; Eczema; Skin Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action