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Topical Everolimus in Patients With Tuberous Sclerosis Complex (EVEROST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02860494
Recruitment Status : Not yet recruiting
First Posted : August 9, 2016
Last Update Posted : December 19, 2019
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 96 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.
Estimated Study Start Date : December 2020
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2024


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.).




Primary Outcome Measures :
  1. Facial Angiofibroma Severity Index (FASI) [ Time Frame: 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 :
  1. FA size [ Time Frame: 6 months ]
    FA size (in millimetres) of the 3 largest targeted FA papules previously identified by the investigator

  2. Dermatologist's global assessment of efficacy [ Time Frame: 6 months ]
    using 7-point Likert scale

  3. Patient or parents self-assessment [ Time Frame: 6 months ]
    using 7-point Likert scale

  4. Local tolerance of the topically applied formulation using patient self-assessment [ Time Frame: 6 months ]
  5. blood levels of topically applied everolimus [ Time Frame: 6 months ]
  6. dryness score [ Time Frame: 6 months ]
    assessed by physicians

  7. scaling scores [ Time Frame: 6 months ]
    assessed by physicians

  8. Dermatological quality of life [ Time Frame: 6 months ]
    using DLQI (Dermatology Life Quality Index) for adults, CDLQI (Children's Dermatology Life Quality Index) for children



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Ages Eligible for Study:   up to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02860494


Contacts
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Contact: Alice PHAN, MD 4 27 85 61 26 ext +33 alice.phan01@chu-lyon.fr
Contact: Behrouz KASSAI, Pr 4 72 35 75 51 ext +33 behrouz.kassai-koupai@chu-lyon.fr

Locations
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France
Hopital Femme Mère Enfant
Bron, France
Contact: Vincent DES PORTES, Pr         
Contact: Segolene Gaillard, Project manager    (0)4 27 85 77 28 ext +33    segolene.gaillard@chu-lyon.fr   
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
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Principal Investigator: Alice PHAN, MD Hospices Civils de Lyon
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT02860494    
Other Study ID Numbers: 69HCL16_0062
2018-002531-18 ( EudraCT Number )
First Posted: August 9, 2016    Key Record Dates
Last Update Posted: December 19, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
Tuberous sclerosis complex (TSC)
topical everolimus
seamless design
dose-escalation study
m-TOR inhibitor
Additional relevant MeSH terms:
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Tuberous Sclerosis
Angiofibroma
Sclerosis
Pathologic Processes
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Everolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs