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

• ClinicalTrials.gov Identifier: NCT02061137
• Recruitment Status: Completed
• First Posted: February 12, 2014
• Last Update Posted: June 15, 2018
• Sponsor: University Hospital, Basel, Switzerland
• Collaborator: Novartis
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Rett's Syndrome	Drug: fingolimod (FTY720)	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Clinical Study to Assess Safety and Efficacy of Oral Fingolimod (FTY720) in Children With Rett Syndrome.
• Study Start Date: August 2013
• Actual Primary Completion Date: April 2018
• Actual Study Completion Date: April 2018

Arms and Interventions

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 Name: gilenya, fingolimod, FTY720

Outcome Measures

Primary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Switzerland

Department of Neuropediatrics - University Children's Hospital

Basel, Switzerland, 4056

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Novartis

Investigators

• Principal Investigator: Ludwig Kappos, Prof.; Department of Neurology - University Hospital Basel - Switzerland

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT02061137
• Other Study ID Numbers: CFTY720D2201T
• First Posted: February 12, 2014
• Last Update Posted: June 15, 2018
• Last Verified: June 2018

Keywords provided by University Hospital, Basel, Switzerland:

Rett Syndrome (Mecp2 positive); Fingolimod (FTY 720); BDNF; Brain Atrophy

Additional relevant MeSH terms:

Rett Syndrome; Syndrome; Disease; Pathologic Processes; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Fingolimod Hydrochloride; Sphingosine 1 Phosphate Receptor Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs