Sirolimus in Cutaneous Sarcoidosis

Study Overview
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Brief Summary
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Sarcoidosis is a multisystemic disease of unknown etiology characterized by the presence of epithelioid granulomas without caseous necrosis in the organs involved. Sarcoidosis cutaneous lesions can be severe. There is no recommendation for the treatment of cutaneous sarcoidosis. A recent study highlights the potential efficacy of mTOR inhibitors in the treatment of sarcoidosis granulomas. The hypothesis is that sirolimus could be effective for sarcoidosis treatment, especially for cutaneous lesions. The main objective of this study is to evaluate sirolimus efficacy on cutaneous sarcoidosis of the face. The main evaluation criteria is the percentage of patients with a significant clinical response (relative decrease in facial SASI ≥ 25%) at week 16 of treatment.

Official Title
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Cutaneous Sarcoidosis With Moderate to Severe Involvement of the Face : Multicenter Open-label Study of Oral Sirolimus Efficacy and Tolerance

Conditions
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Sarcoidosis, Cutaneous Sarcoidosis

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old <75 years old (men and women) Cutaneous sarcoidosis of the face (diagnosed according to the following criteria : compatible clinical appearance showing erythemato-purple, brownish or yellowish macules or papules or nodules and compatible histological appearance with a facial or extra facial skin biopsy confirming the diagnosis of sarcoidosis showing epithelioid and giganto-cellular granuloma without caseous necrosis) moderate to severe defined by: Facial SASI Score (Sarcoidosis Area and Severity Index) ≥ 2 and PGA (Physician's Global Assessment,0 to 10 scale) ≥ 5 Health insurance plan coverage Patients who never had a systemic treatment or who had at least one classical systemic treatment failure for sarcoidosis treatment For women of childbearing age (unless post-menopausal or sterile), pregnancy test with βHCG negative. Effective contraception should be used during sirolimus treatment and for 12 weeks after stopping sirolimus Patients who have signed a written consent Exclusion Criteria: Severe hepatic failure (Cytolysis (ALAT)> 3N and / or Cholestase (PAL)> 3N) Allergy or intolerance to sirolimus or at one of its excipients Allergy to peanut or soybeans Patient with a pulmonary or hepatic graft General corticotherapy or immunosuppressive treatment (methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, ciclosporin) in the month before the inclusion Intra-lesional corticotherapy for less than 3 months Biotherapy (anti-TNFa, anti-IL12/23, anti-IL17A) within 3 months preceding the inclusion Thalidomide or other -imide treatment for less than 3 months Cyclins treatment for less than 1 month Topical corticosteroids or topical tacrolimus for less than 1 week Sarcoidosis involvement of at least one organ requiring systemic treatment other than sirolimus (oral corticosteroid or systemic immunosuppressive treatment) Cholesterolemia> 300 mg/ dl or triglyceridemia> 400 mg/dl Administration of strong CYP3A4 inhibitors or inducers such as rifampicin, ketoconazole, voriconazole, telithromycin , diltiazem, verapamil, erythromycin, clarythromycin, ciclosporin Pregnancy or breastfeeding Active infection including tuberculosis disease Non-controlled arterial hypertension (TAS> 150 mmHg and / or TAD> 100 mmHg) Patient under guardianship or curatorship, patients deprived of freedom, under safeguarding of justice, receiving psychiatric care, under the constraint, admitted in a health or social institution for purposes other than those of research Patient with cancer (except cutaneous basal cell carcinoma or in situ cervical cancer) Risk of patient bad compliance Grapefruit or grapefruit juice consumption during the treatment duration Patients with fructose intolerance, galactose intolerance, glucose-galactose malabsorption, insufficiency in sucrase-isomaltase or Lapp lactase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus Arm<br>Sirolimus, tablets 2 mg/day with dose adjustment of 1 to 3 mg/day for residual concentrations between 4 and 10 ng/mL 1 dose daily for 16 weeks | Drug: Sirolimus<br>* Sirolimus, tablets 2 mg/day with dose adjustment of 1 to 3 mg/day for residual concentrations between 4 and 10 ng/mL 1 dose daily for 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with a significant clinical response | Significant clinical response will be defined as a relative decrease in facial SASI ≥ 25% compared to baseline. Facial SASI score evaluates 4 features for each of 4 facial quadrants and the nose: erythema, induration, and desquamation, each ranging from 0 (none) to 4 (very severe), and an area score ranging from 0 (0%) to 6 (90-100%). The maximal range of modified Facial SASI scores is 0 to 72. | at week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with a good clinical response | A good clinical response will be defined as a relative decrease of facial SASI ≥ 50%. Facial SASI score evaluates 4 features for each of 4 facial quadrants and the nose: erythema, induration, and desquamation, each ranging from 0 (none) to 4 (very severe), and an area score ranging from 0 (0%) to 6 (90-100%). The maximal range of modified Facial SASI scores is 0 to 72. | at week 16 | 
| Percentage of patients with complete clinical response | Complete clinical response will be defined as facial SASI = 0. Facial SASI score evaluates 4 features for each of 4 facial quadrants and the nose: erythema, induration, and desquamation, each ranging from 0 (none) to 4 (very severe), and an area score ranging from 0 (0%) to 6 (90-100%). The maximal range of modified Facial SASI scores is 0 to 72. | at week 16 | 
| Percentage of patients with an improvement of their quality of dermatological life | An improvement will be defined as a decrease of Dermatology Life Quality Index (DLQI) questionnaire> 25%. DLQI goes from 0 to 30. A lower score indicated a good quality of Life, and a higher score a worse quality of life. | at week 16 | 
| Comparison of face facial photographs with good brightness compared to baseline | Qualitative clinical aspects of skin sarcoidosis lesions will be compared between baseline and Week 16, as an illustrative proof in addition to quantitative skin score assessment (Facial SASI) | at week 16 | 
| Sarcoidosis activity score evaluated for other organs evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) | Sarcoidosis activity for all organs will be evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) (from 0 (normal) to 6(severe impairment)) | at week 16 | 
| Sarcoidosis activity score evaluated for other organs evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) | Sarcoidosis activity for all organs will be evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) (from 0 (normal) to 6(severe impairment)) | at 12 months | 
| Sarcoidosis activity score evaluated for other organs using Score Sarcoidosis disease activity index (SDAI score) | Sarcoidosis activity for all organs will be evaluted using Score Sarcoidosis disease activity index (SDAI score) : it goes from 0 to 167 (the higher the score, the greater the disease activity). | at 16 weeks | 
| Sarcoidosis activity score evaluated for other organs using Score Sarcoidosis disease activity index (SDAI score) | Sarcoidosis activity for all organs will be evaluted using Score Sarcoidosis disease activity index (SDAI score) : it goes from 0 to 167 (the higher the score, the greater the disease activity). | at 12 months | 
| Pulmonary Sarcoidosis activity | Pulmonary Sarcoidosis activity will be assessed using Abbreviated CT score to quantify disease activity in pulmonary sarcoidosis (aCTAS score) to assess pulmonary involvement. It goes from 0 to 4 (the higher the score, the greater the pulmonary disease activity). | at week 16 | 
| Pulmonary Sarcoidosis activity | Pulmonary Sarcoidosis activity will be assessed using Abbreviated CT score to quantify disease activity in pulmonary sarcoidosis (aCTAS score) to assess pulmonary involvement. It goes from 0 to 4 (the higher the score, the greater the pulmonary disease activity). | at 12 months | 
| Pulmonary sarcoidosis functionnal evaluation assessed using Functional respiratory explorations by vital capacity | Pulmonary sarcoidosis functionnal evaluation will be assessed using Functional respiratory explorations by vital capacity | at week 16 | 
| Pulmonary sarcoidosis functionnal evaluation assessed using Functional respiratory explorations by vital capacity | Pulmonary sarcoidosis functionnal evaluation will be assessed using Functional respiratory explorations by vital capacity | at 12 months | 
| Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter | Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters) | at week 16 | 
| Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter | Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters) | at 12 months | 
| Percentage of patients with adverse events |  | up to 16 weeks | 
| Evaluate CD68, phospho-mTOR and phospho-p70S6K expression on skin biopsies | Immunohistochemical assessment will be assessed using optical microscopy | at 16 weeks | 
| Transcriptomic analysis of skin | It will be assessed using microarray (Affymetrix) | at 16 weeks | 
| Circulating monocytes | It will be assessed using microarray (Affymetrix) | at 16 weeks | 
| Percentage of patients with a complete or near-complete response based on PGA (PGA = 0 or 1) of the skin. |  | at 16 weeks |