EVEROST: Topical Everolimus in Patients With Tuberous Sclerosis Complex

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02860494

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Facial Angiofibromas	Drug: Everolimus Drug: Placebo	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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.

Anticipated Study Start Date :

Dec 1, 2020

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Topical everolimus 0.1% 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 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.).
Experimental: Topical everolimus 0.5% 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 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.).
Experimental: Topical everolimus 1% 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 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.).
Placebo Comparator: Topical placebo 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 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.).

Outcome Measures

Primary Outcome Measures

Facial Angiofibroma Severity Index (FASI) [6 months]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 2 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.