|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Skin and Connective Tissue Diseases [C17]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective of the phase II study is to identify the most appropriate dose of topical everolimus in terms of efficacy and safety and in the phase III, to demonstrate its superiority versus placebo for treatment of FA in patients with TSC after 6 months of treatment.
|Secondary objectives of the trial
|1. To evaluate the efficacy of topical everolimus versus placebo by: Clinical assessment of FA (composite score); Blinded assessment of the redness using Reactiv’IP system; Assessment of the FA size reduction with topical everolimus versus placebo; Assessment of FA global improvement from patient’s and dermatologist’s perspectives; Improvement of quality of life of patients.
2. To correlate the results of the primary endpoint with the results of the clinical assessment of FA.
3. To evaluate safety of topical everolimus: Local tolerance of topical everolimus; Systemic safety of topical everolimus.
|Trial contains a sub-study
|Principal inclusion criteria
| Male and female subjects > 2 years old.
Subjects meeting the criteria for a definite or possible diagnosis of TSC
Subjects with at least 3 FA, diagnosed by a dermatologist
Women of child-bearing potential with a negative blood pregnancy test at the inclusion.
Subjects or their parents or legal guardians must provide written informed consent prior to participation in the study
Subjects covered by French national health insurance
|Principal exclusion criteria
| Systemic treatment by sirolimus, everolimus, or any other immunosuppressive drug, within 6 months pre inclusion.
Use of topical tacrolimus or sirolimus on the face, within 6 months pre inclusion.
Destructive treatment (laser therapy, surgery, cryotherapy) of facial angiofibroma, within 6 months pre inclusion.
Current concomitant use of topical treatments that could affect facial erythema (e.g. bromonidine)
Known internal organ involvement requiring systemic mTOR inhibitor in the next 6 months
Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
Known chronic infectious disease
Known hypersensitivity to mTOR inhibitor
Neutropenia < 1000/mm3
Thrombopenia < 75,000/mm3
Chronic renal insufficiency (estimated Glomerular Filtration Rate < 60 mls/min)
Chronic liver disease (SGOT or SGPT > 3 times upper normal limit)
Breast feeding or pregnant women, or women of childbearing potential without any effective method of contraception during treatment and up to 12 weeks after treatment discontinuation.
Subjects who, in the Investigator’s opinion, are unable or unwilling to comply with the protocol.
|E.5 End points
|Primary end point(s)
|The primary endpoint is the mean reduction of the validated and published score for assessment of angiofibromas, the Facial Angiofibroma Severity Index (FASI) after 6 months of treatment.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|- Efficacy assessments
a. Clinical assessment of FA: Mean reduction of a composite clinical score (0-12) for FA.
b. Blinded assessment of the redness and extension using Reactiv’IP system.
c. FA size (in millimetres) of the 3 largest targeted FA papules.
d. Global improvement of FA on a 7-point Likert scale
i. Dermatologist’s global assessment of efficacy
ii. Patient or parents self-assessment
e. Dermatological quality of life of patients, self-assessment using 2 validated dermatological surveys, both available in French:
i. DLQI (Dermatology Life Quality Index) for adults
ii. CDLQI (Children's Dermatology Life Quality Index) for children
2. Correlation of the results of FASI blindly assessed and the clinical assessment of FA
3. Safety of topical everolimus
a. Local tolerance of the topical formulation applied:
i. Patient self-assessment: composite scores of 5 items (stinging, burning, itching, dryness, and scaling), each item consists of 3 states: 0=absent, 1=mild, 2=moderate and 3=severe.
ii. The physicians will assess dryness and scaling scores.
b. Safety of the topical formulation applied:
i. Quantification of blood levels of topical everolimus.
ii. Laboratory assessments (creatinine, serum electrolytes including Na, K, Cl, CO2, Ca, Total protein and Urea, liver enzymes, total cholesterol, triglycerides, glucose, complete blood count).
iii. Adverse events and serious adverse events
|Timepoint(s) of evaluation of this end point
|Day-21, 1, month 1,month 2, month 3, month 4, month 5 et month 6
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days