Study to Assess Safety and Efficacy of Fingolimod in Children With Rett Syndrome (FINGORETT)

A Phase 1 Clinical Study to Assess Safety and Efficacy of Oral Fingolimod (FTY720) in Children With Rett Syndrome.

The Trial Objective is to assess safety and efficacy of oral fingolimod (FTY720) in children older than 6 years with Rett Syndrome. So far there is no established treatment for children with Rett Syndrome. Therefore a positive result in terms of safety and first indications of efficacy would path the way to a phase II clinical study with more patients to further test the hypothesis that fingolimod treatment may slow down the regression of motor and language skills.

Study Overview

• Status: Completed
• Conditions: Rett's Syndrome
• Intervention / Treatment: Drug: fingolimod (FTY720)

Detailed Description

Rett syndrome is a neurodevelopmental disorder characterized by normal early psychomotor development followed by the loss of psychomotor and acquired purposeful hand skills and the onset of stereotyped movement of the hands and gait disturbance. The gene was discovered in 1999 and the disease was found to be caused by a mutation of the methyl-CpGbinding protein 2 (MeCP2). However, in many ways this clinically peculiar condition remains a mystery, with no clear correlations between the gene mutation and abnormal biological markers, neuropathology and/or unique clinical symptoms and signs.

Rett syndrome is an X-linked (Xq28) dominant postnatal severe neurodevelopmental disorder which is the second most common cause for genetic mental retardation in girls and the first pervasive disorder with a known genetic basis. Its incidence is between 1/10,000-15000 live births. The classical variant is characterized by apparently normal development for the first 6-18 months accompanied usually with early deceleration of head growth, followed by period of regression of motor and language skills, hand stereotypes, seizures, autonomic dysfunction and other neurological and related symptoms.

Repeated observations and experiments of the mouse models in several laboratories led to the appreciation of the role of BDNF in the disease pathophysiology. BDNF is a neurotrophic factor playing a major role in neurogenesis, neuronal survival, differentiation, and maturation during early development as well as in synaptic function and plasticity throughout life. Abnormalities in BDNF homeostasis are believed to contribute to the neurological phenotype and pathophysiology in part of the symptoms in methyl-CpG binding protein 2(Mecp2) null mice that show progressive deficits in its expression during the symptomatic stage.

FTY720 (Gilenya) is an orally active modulator of four of the five sphingosine-1 phosphate(S1P) receptors. FTY720 acts as 'super agonist' on the S1P receptor on thymocytes and lymphocytes, inducing uncoupling/internalization of that receptor.

A local study group (Yves-Alain Barde) found that FTY720 increases the levels of brain derived neurotrophic factor and improves symptoms of mice lacking MeCP2. In addition the volume of the striatum seemed to be higher (4 week old mice were treated in 4 days intervals with 0.1mg/kg body weight intraperitoneally).

Based on these results we intend to perform a phase I clinical,study to assess safety and efficacy of oral fingolimod (FTY720) in children with Rett Syndrome. Children will be included if being older than 6 years of age, fulfilling diagnostic criteria of Rett Syndrome in clinical Stages II -IV and having parents that do agree.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4056
    • Department of Neuropediatrics - University Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children fulfilling diagnostic criteria (2001, Hagberg B et al. Eur. J. Paediatr. Neurol. 2002) of Rett Syndrome
• Stages II -IV Hagberg/ Witt-Engerström (Hagberg B, Witt-Engerström I. Am J Med Genet 1986, Hagberg B. Ment Retard Dev Disabil Res Rev 2002)
• Patients older than 6 years old (have had their 6th birthday)
• Written informed consent of parents/ of legal guardian
• Negative testing for pregnancy
• Positive confirmation of a MECP2 mutation

Exclusion Criteria:

• Any uncertainty about diagnosis of Rett Syndrome
• Patients younger than 6 years old (have not yet had their 6thbirthday)
• Additional associated neurological diseases such as a brain malformation
• Patient <15kg body weight at timepoint of screening
• Patients with negative varicella-zoster virus immunoglobulin G (IgG) antibodies
• Pregnancy or breastfeeding for girls in childbearing potential age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rett syndrome, fingolimod (FTY720); 0.5 or 0.25mg Fingolimod daily	Drug: fingolimod (FTY720); 0.5 or 0.25 mg fingolimod orally daily for each of 6 patients with rett syndrome for 12 months; Other Names: gilenya, fingolimod, FTY720

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Levels of Brain derived neurotrophic factor (BDNF) in blood and cerebrospinal fluid before and under treatment	change of BDNF measured at Baseline, at first dose, at 6 and at 12 months after start of treatment.

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Novartis
• Investigators: Principal Investigator: Ludwig Kappos, Prof., Department of Neurology - University Hospital Basel - Switzerland

Publications and helpful links

General Publications

• Naegelin Y, Kuhle J, Schadelin S, Datta AN, Magon S, Amann M, Barro C, Ramelli GP, Heesom K, Barde YA, Weber P, Kappos L. Fingolimod in children with Rett syndrome: the FINGORETT study. Orphanet J Rare Dis. 2021 Jan 6;16(1):19. doi: 10.1186/s13023-020-01655-7.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): April 1, 2018
• Study Completion (Actual): April 1, 2018

Study Registration Dates

• First Submitted: August 27, 2013
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): June 15, 2018
• Last Update Submitted That Met QC Criteria: June 14, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: BDNF; Brain Atrophy; Rett Syndrome (Mecp2 positive); Fingolimod (FTY 720)
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Syndrome; Rett Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Sphingosine 1 Phosphate Receptor Modulators; Fingolimod Hydrochloride
• Other Study ID Numbers: CFTY720D2201T