Topical Everolimus in Patients With Tuberous Sclerosis Complex (EVEROST)

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.

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.

Study Overview

• Status: Withdrawn
• Conditions: Facial Angiofibromas
• Intervention / Treatment: Drug: Everolimus; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Bron, France
    • Hôpital Femme Mère Enfant

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / 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.).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Alice PHAN, MD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): December 1, 2020
• Primary Completion (ANTICIPATED): December 1, 2023
• Study Completion (ANTICIPATED): December 1, 2024

Study Registration Dates

• First Submitted: August 4, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (ESTIMATE): August 9, 2016

Study Record Updates

• Last Update Posted (ACTUAL): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: m-TOR inhibitor; dose-escalation study; Tuberous sclerosis complex (TSC); topical everolimus; seamless design
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neoplasms, Vascular Tissue; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Sclerosis; Tuberous Sclerosis; Angiofibroma; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: 69HCL16_0062; 2018-002531-18 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No