Topical Everolimus in Patients With Tuberous Sclerosis Complex

Study Overview
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Brief Summary
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Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder characterized by the development of hamartomas in several organs (e.g. brain, heart, kidney, liver, lung), and skin in more than 90% of cases. Facial angiofibromas (FA), present in about 80% of patients, are a stigmatizing hallmark of the disease. Everolimus could be a candidate for use as a topical formulation to treat FA. This adaptive seamless Phase II/III study primary objective is to determine the dose of topical everolimus for treatment of FA and evaluate the efficacy and safety of topical everolimus versus placebo in patients with angiofibromas.

Official Title
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Topical Everolimus Versus Placebo for the Treatment of Facial Angiofibromas in Patients With Tuberous Sclerosis Complex. A Phase II/III, Multicentre, Randomized, Double-blind, Placebo-controlled Study of 3 Doses of Topical Everolimus.

Conditions
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Facial Angiofibromas

Intervention / Treatment
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* Drug: Everolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over the age of 2 years With definite or possible diagnosis of TSC With at least 3 FA, diagnosed by a dermatologist Patients (or parents or legal guardians) who have provided written informed consent prior to participation in the study Willing and able to comply with study requirements With negative blood pregnancy test at the screening visit and using effective contraceptive methods for women of childbearing potential, up to 12 weeks after treatment discontinuation Covered by national health insurance Exclusion Criteria: Systemic treatment by sirolimus, everolimus, or any other immunosuppressive drug, during the previous 6 months Use of topical tacrolimus or sirolimus on the face, during the previous 6 months Destructive treatment (laser therapy, surgery, cryotherapy) of facial angiofibromas during the previous 6 months Concomitant use of topical treatments that could affect facial erythema (e.g. Brimonidine) 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) Uncontrolled dyslipidaemia Uncontrolled diabetes Brest feeding or pregnant women, or women on childbearing age 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.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 2 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical everolimus 0.1%<br>Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.). | Drug: Everolimus<br>* Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.).<br>|
| Experimental: Topical everolimus 0.5%<br>Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.). | Drug: Everolimus<br>* Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.).<br>|
| Experimental: Topical everolimus 1%<br>Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.). | Drug: Everolimus<br>* Everolimus topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months. Dose regimens will be identical, regardless of the dose-strength of the topical formulation. The topical formulation will be applied onto areas of the face affected by FA by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.).<br>|
| Placebo Comparator: Topical placebo<br>Topical placebo will be identical to the everolimus topical formulation. Topical placebo will be applied to the affected areas, once daily, in the evening, for 6 months by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.). | Drug: Placebo<br>* Placebo topical formulation will be applied to the affected areas, once daily, in the evening, for 6 months, by the patient or the patient's parents/legal guardians, while observing standardised precautions (avoiding the eyes, washing the hands after application, etc.).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Facial Angiofibroma Severity Index (FASI) | The FASI is a composite score summing the scores for erythema (0-3), size (0-3) and extension of FA (2:<50% of the cheek surface; 3:>50% of the cheek surface). The FASI will be centrally-measured on patient's face photographs by an independent and blinded adjudication committee of 2 dermatologists, with third-dermatologist review for disagreements. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FA size | FA size (in millimetres) of the 3 largest targeted FA papules previously identified by the investigator | 6 months | 
| Dermatologist's global assessment of efficacy | using 7-point Likert scale | 6 months | 
| Patient or parents self-assessment | using 7-point Likert scale | 6 months | 
| Local tolerance of the topically applied formulation using patient self-assessment |  | 6 months | 
| blood levels of topically applied everolimus |  | 6 months | 
| dryness score | assessed by physicians | 6 months | 
| scaling scores | assessed by physicians | 6 months | 
| Dermatological quality of life | using DLQI (Dermatology Life Quality Index) for adults, CDLQI (Children's Dermatology Life Quality Index) for children | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberous sclerosis complex (TSC), topical everolimus, seamless design, dose-escalation study, m-TOR inhibitor