Study to Assess Safety and Efficacy of Fingolimod in Children With Rett Syndrome (FINGORETT)
Primary Purpose
Rett's Syndrome
Status
Completed
Phase
Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
fingolimod (FTY720)
Sponsored by
About this trial
This is an interventional treatment trial for Rett's Syndrome focused on measuring Rett Syndrome (Mecp2 positive), Fingolimod (FTY 720), BDNF, Brain Atrophy
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
Sites / Locations
- Department of Neuropediatrics - University Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Rett syndrome, fingolimod (FTY720)
Arm Description
0.5 or 0.25mg Fingolimod daily
Outcomes
Primary Outcome Measures
Levels of Brain derived neurotrophic factor (BDNF) in blood and cerebrospinal fluid before and under treatment
Secondary Outcome Measures
Full Information
NCT ID
NCT02061137
First Posted
August 27, 2013
Last Updated
June 14, 2018
Sponsor
University Hospital, Basel, Switzerland
Collaborators
Novartis
1. Study Identification
Unique Protocol Identification Number
NCT02061137
Brief Title
Study to Assess Safety and Efficacy of Fingolimod in Children With Rett Syndrome
Acronym
FINGORETT
Official Title
A Phase 1 Clinical Study to Assess Safety and Efficacy of Oral Fingolimod (FTY720) in Children With Rett Syndrome.
Study Type
Interventional
2. Study Status
Record Verification Date
June 2018
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
April 2018 (Actual)
Study Completion Date
April 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Basel, Switzerland
Collaborators
Novartis
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rett's Syndrome
Keywords
Rett Syndrome (Mecp2 positive), Fingolimod (FTY 720), BDNF, Brain Atrophy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Rett syndrome, fingolimod (FTY720)
Arm Type
Experimental
Arm Description
0.5 or 0.25mg Fingolimod daily
Intervention Type
Drug
Intervention Name(s)
fingolimod (FTY720)
Other Intervention Name(s)
gilenya, fingolimod, FTY720
Intervention Description
0.5 or 0.25 mg fingolimod orally daily for each of 6 patients with rett syndrome for 12 months
Primary Outcome Measure Information:
Title
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ludwig Kappos, Prof.
Organizational Affiliation
Department of Neurology - University Hospital Basel - Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neuropediatrics - University Children's Hospital
City
Basel
ZIP/Postal Code
4056
Country
Switzerland
12. IPD Sharing Statement
Citations:
PubMed Identifier
33407685
Citation
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.
Results Reference
derived
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Study to Assess Safety and Efficacy of Fingolimod in Children With Rett Syndrome
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