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Sirolimus in Cutaneous Sarcoidosis (SIRIUS)

Primary Purpose

Sarcoidosis, Cutaneous Sarcoidosis

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Sirolimus

About this trial

This is an interventional treatment trial for Sarcoidosis

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sirolimus Arm

Arm Description

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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)

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))

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))

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).

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).

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).

Pulmonary Sarcoidosis activity

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

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

Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter

Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters)

Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter

Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters)

Percentage of patients with adverse events

Evaluate CD68, phospho-mTOR and phospho-p70S6K expression on skin biopsies

Immunohistochemical assessment will be assessed using optical microscopy

Transcriptomic analysis of skin

It will be assessed using microarray (Affymetrix)

Circulating monocytes

It will be assessed using microarray (Affymetrix)

Percentage of patients with a complete or near-complete response based on PGA (PGA = 0 or 1) of the skin.

Full Information

NCT ID

NCT05458492

First Posted

October 11, 2021

Last Updated

July 12, 2022

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT05458492

Brief Title

Sirolimus in Cutaneous Sarcoidosis

Acronym

SIRIUS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

July 2022 (Anticipated)

Primary Completion Date

May 2024 (Anticipated)

Study Completion Date

May 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sarcoidosis, Cutaneous Sarcoidosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sirolimus Arm

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Intervention Description

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

Primary Outcome Measure Information:

Title

Percentage of patients with a significant clinical response

Description

Time Frame

at week 16

Secondary Outcome Measure Information:

Title

Percentage of patients with a good clinical response

Description

Time Frame

at week 16

Title

Percentage of patients with complete clinical response

Description

Time Frame

at week 16

Title

Percentage of patients with an improvement of their quality of dermatological life

Description

Time Frame

at week 16

Title

Comparison of face facial photographs with good brightness compared to baseline

Description

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)

Time Frame

at week 16

Title

Sarcoidosis activity score evaluated for other organs evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST)

Description

Sarcoidosis activity for all organs will be evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) (from 0 (normal) to 6(severe impairment))

Time Frame

at week 16

Title

Sarcoidosis activity score evaluated for other organs evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST)

Description

Sarcoidosis activity for all organs will be evaluted using Extra-Pulmonary Physician Organ Severity Tool (ePOST) (from 0 (normal) to 6(severe impairment))

Time Frame

at 12 months

Title

Sarcoidosis activity score evaluated for other organs using Score Sarcoidosis disease activity index (SDAI score)

Description

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).

Time Frame

at 16 weeks

Title

Sarcoidosis activity score evaluated for other organs using Score Sarcoidosis disease activity index (SDAI score)

Description

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).

Time Frame

at 12 months

Title

Pulmonary Sarcoidosis activity

Description

Time Frame

at week 16

Title

Pulmonary Sarcoidosis activity

Description

Time Frame

at 12 months

Title

Pulmonary sarcoidosis functionnal evaluation assessed using Functional respiratory explorations by vital capacity

Description

Pulmonary sarcoidosis functionnal evaluation will be assessed using Functional respiratory explorations by vital capacity

Time Frame

at week 16

Title

Pulmonary sarcoidosis functionnal evaluation assessed using Functional respiratory explorations by vital capacity

Description

Pulmonary sarcoidosis functionnal evaluation will be assessed using Functional respiratory explorations by vital capacity

Time Frame

at 12 months

Title

Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter

Description

Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters)

Time Frame

at week 16

Title

Pulmonary sarcoidosis functionnal evaluation assessed by walking perimeter

Description

Pulmonary sarcoidosis functionnal evaluation will be assessed by walking perimeter (in meters)

Time Frame

at 12 months

Title

Percentage of patients with adverse events

Time Frame

up to 16 weeks

Title

Evaluate CD68, phospho-mTOR and phospho-p70S6K expression on skin biopsies

Description

Immunohistochemical assessment will be assessed using optical microscopy

Time Frame

at 16 weeks

Title

Transcriptomic analysis of skin

Description

It will be assessed using microarray (Affymetrix)

Time Frame

at 16 weeks

Title

Circulating monocytes

Description

It will be assessed using microarray (Affymetrix)

Time Frame

at 16 weeks

Title

Percentage of patients with a complete or near-complete response based on PGA (PGA = 0 or 1) of the skin.

Time Frame

at 16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jean-David Bouaziz, Pr

Phone

+331 42 49 43 91

jean-david.bouaziz@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Matthieu Resche-Rigon

Phone

+33142499742

matthieu.resche-rigon@u-paris.fr

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Sirolimus in Cutaneous Sarcoidosis

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