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

Brief Title

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

Official Title

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

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.
    

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 Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

Levels of Brain derived neurotrophic factor (BDNF) in blood and cerebrospinal fluid before and under treatment

Condition

Rett's Syndrome

Intervention

fingolimod (FTY720)

Study Arms / Comparison Groups

 Rett syndrome, fingolimod (FTY720)

Description:  0.5 or 0.25mg Fingolimod daily

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

6

Start Date

August 2013

Completion Date

April 2018

Primary Completion Date

April 2018

Eligibility 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
      

Gender

All

Ages

6 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Ludwig Kappos, Prof., , 

Location Countries

Switzerland

Location Countries

Switzerland

NCT ID

NCT02061137

Organization ID

CFTY720D2201T

Responsible Party

Sponsor

Study Sponsor

University Hospital, Basel, Switzerland

Collaborators

 Novartis

Study Sponsor

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

Verification Date

June 2018