Biomarkers in Rett Syndrome

Rett Syndrome Clinical Trial

— BIRS  

Official title:

BIRS (Biomarkers in Rett Syndrome): a Long-term Observational Multicenter Study of the Natural History of Rett Syndrome to Define New Clinical and Instrumental Biomarkers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06346444
• Other study ID #: 2.780.113
• Status: Recruiting
• Start date: August 3, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: March 2024
• Source: IRCCS Fondazione Stella Maris
• Contact: Roberta Battini
• Phone: 050886282
• Email: rbattini[@]fsm.unipi.it
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Rett syndrome (RTT) is an X-linked genetic disorder that causes severe neurological development disorder. In its classic form, it seems to affect almost exclusively females with an incidence of up to one in 10,000 females. Patients affected by Rett Syndrome can present a wide range of symptoms, in different combinations and of varying intensity, such as slowed growth of head circumference, abnormalities in walking and balance, loss of functional use of the hands often replaced by repetitive and stereotyped hand movements like "hand washing", loss of communicative-relational skills including expressive language, epilepsy, breathing abnormalities, and osteo-muscular alterations. In light of the growing potential of clinical therapies, identification and early diagnosis are considered essential. Many disease modification strategies have been achieved through translational research studies and clinical trials that have allowed the recognition of the most effective therapeutic and clinical interventions to date.

This study arises from the need to advance in the understanding of the pathogenesis of RTT through a multicentric collaboration in order to (a) identify early biomarkers of RTT (b) delve into the alterations of interconnectivity, crucial for understanding the loss of motor functions and language through systematic collection of anamnestic, genetic, and clinical-instrumental data. The aim is to provide a valuable contribution to the study of the clinical phenotype of Rett and the identification of early interventions.

Description:

The study aims to collect and analyze clinical-instrumental data from patients affected by Rett Syndrome through a prolonged monitoring program aimed at identifying disease biomarkers.

The study is a prospective observational type, with multicentric enrollment (IRCCS Stella Maris, AOU Meyer, Versilia Hospital Regional Reference Center for Rett Syndrome-USL Toscana Nord-Ovest), non-profit. New diagnosis patients and patients already included in the databases of each center will be enrolled. The cohort observational study will be completed, where possible, by a case-control study that involves the enrollment of siblings of the proband included in the study cohort.

Data regarding the registration of brain electrical activity through EEG of both the cohort and the patients' siblings, and acquisitions through Eye Tracker of the patients only, will be analyzed by Dr. Daniela Tropea's study group at Trinity College Dublin (Genetic Neuropsychiatry and Neuroscience Institute).

The study is expected to start immediately after the approval of the protocol by this Ethics Committee.

The study is expected to last four years. The study involves the enrollment of every case of Rett syndrome in the developmental age attending one of the Italian centers and an annual follow-up with clinical and instrumental controls provided by a dedicated path.

Sample Size The sample size has been estimated according to the syndrome's prevalence in the general population and based on the number of retrospective patient samples affected by Rett Syndrome.

The study plans to enroll approximately 100 patients consecutively, according to a pre-established schedule that includes observations and evaluations provided by the protocol.

FOLLOW-UP PROCEDURE The follow-up of each patient will be carried out annually through clinical monitoring and instrumental application of what is listed in the primary endpoint except for the brain MRI, whose repetition if necessary will be agreed upon based on the evolution of the clinical picture.

DEFINITION OF STUDY CONCLUSION The end of the monitoring of patients is expected upon reaching the age of 18 years.

DATA MANAGEMENT For each recruited patient, after deliberation through informed consent, data contained within the clinical record will be collected. At recruitment, data related to diagnosis, gestational age at birth, auxological parameters at birth, Apgar score, main clinical anamnestic data related to the perinatal period, and outcome of neuroimaging assessments carried out (for example, brain MRI, transfontanellar cerebral ultrasound) will be acquired and recorded in a specific database.

To protect privacy, each patient will be assigned a numeric code, therefore the database will not contain any demographic data, and access will be protected by a password and limited to personnel involved in the study only. The database will be progressively implemented with the outcomes of the assessments, acquired systematically, according to the correspondence code of the individual subject. The EEG video recording data will be accessible from the clinical documentation and coded systematically. The EEG data and the acquisitions through Eye Tracker obtained in the Italian enrollment centers will be analyzed at Trinity College Dublin in an anonymous manner through identification by numeric code and only after signed consent from the parents.

DATA CONSERVATION The data managers and the measures of anonymization will be the responsibility of the main experimenters of the study. All data will be stored in secure places and on password-protected files, at the patient's home institute.

ETHICAL CONSIDERATIONS The study conforms to the ethical principles recognized for clinical experimentation, to the principles of good clinical practice.

The protocol has been submitted for approval to the ethical committee and/or competent authority.

ACQUISITION OF INFORMED CONSENT AND DATA PROCESSING At the time of the direct interview with the families, a detailed explanation will be provided orally and a written informative note (which will remain with the parents). The importance of the study and the data used for the purposes of our study will also be explained, specifying the request for release for the compilation of the database, however under an identification code.

The paper documents related to informed consent will be handed over to the family so that they can be read and understood in their entirety and retrieved following a subsequent interview in which the parents can ask clarifying questions and definitively confirm their consent to the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 31, 2024
• Est. primary completion date: February 20, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 0 Years to 18 Years

Eligibility

Inclusion Criteria:

• All subjects aged between 0 and 18 years with Rett Syndrome, classic (mutation of the MECP2 gene) and Rett variants (CDKL5, FOXG1 mutations, and other MECP2 mutations), genetically confirmed:

• newly diagnosed

• previously diagnosed if possessing data recorded and stored in the enrollment centers' records;

• upon written informed consent from the parents.

• Siblings of the probands of any age who will undergo EEG registration will also be enrolled.

Exclusion Criteria:

• Patients with Rett Syndrome presenting a compromise in the general health status to such an extent that it makes it impossible to apply the clinical-instrumental evaluation and monitoring tools used for the study.

Related Conditions & MeSH terms

• Rett Syndrome
• Syndrome

Intervention

Other:
• Diagnostic test and behavioral
Questionnaires (CGI, RSBQ) and Outcome measurements (Neuroscope, EEG, Brain MRI, Bone densitometry, X-ray of thoracic and lumbosacral spine Blood biomarkers-RNA, proteins, other metabolites-)

Locations

Country	Name	City	State
Ireland	Trinity College Institute of Neuroscience, Lloyd Building, D2	Dublin
Italy	IRCCS Fondazione Stella Maris	Calambrone	Pisa
Italy	AOU Meyer	Firenze
Italy	Ospedale Versilia Centro di Riferimento	Lido Di Camaiore	Lucca

Sponsors (4)

Lead Sponsor	Collaborator
IRCCS Fondazione Stella Maris	Azienda USL Toscana Nord Ovest, Meyer Children's Hospital IRCCS, University of Dublin, Trinity College

Countries where clinical trial is conducted

Ireland,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Age at diagnosis		every year for four years
Primary	Mutation in MECP2	Number of different single variant	every year for four years
Primary	Neuroscope alterations	NeuroScope is an advanced viewer for neurophysiological and behavioral data: it can display local field potentials (LFPs), neuronal spikes and behavioral events.	every year for four years
Primary	Electroencephalogram (EEG) alterations		every year for four years
Primary	Brain magnetic resonance imaging (MRI) alteration		every year for four years
Primary	Bone densitometry alterations		every year for four years
Primary	Thoracic radiographic alterations		every year for four years
Primary	Lumbosacral spine radiographic alterations		every year for four years
Primary	Clinical Global Impression (CGI) scale	The CGI scale has two components-the CGI-Severity, which rates illness severity of ill (Score from 1 to 7, where 1 is normal and 7 severely ill) , and the CGI-Improvement, which rates change from the initiation (baseline) of observation (Score from 1 to 7, where 1 is very much improved since the initiation of observation and 7 is very much worse since the initiation of observation)	every year for four years
Primary	The Rett Syndrome Behavioural Questionnaire (RSBQ)	The Rett Syndrome Behaviour Questionnaire (RSBQ) assesses the severity of neurobehavioral problems from the perspective of the caregiver. The RSBQ consists of 45 items of which 38 items are grouped into 8 domains/subscales that reflect the core features (General Mood; Breathing Problems; Hand Behaviors; Repetitive Face Movements; Body Rocking and Expressionless Face; Nighttime Behaviors; Fear/Anxiety; and Walking/Standing) and 7 items are grouped into a subscales classed as "uncategorized" but contribute to the overall total score. Each item is rated on a Likert scale as 0 (behavior "not true"), 1 (behavior "somewhat or sometimes true") or 2 (behavior "often true"), with the total score ranging from 0 to 90 (higher scores indicate increased severity)	every year for four years
Secondary	Alterations of neurovisual functions		every year for four years
Secondary	Possibility of applying alternative forms of communication to verbal communication	Possibility of applying alternative forms of communication to verbal communication (in patients presenting with the absence of expressive language) through the application of the EYE TRACKER device (Tobii Dyanvox) that uses near-infrared lighting in combination with high-definition cameras to project light into the eye and record the direction reflected by the cornea	every year for four years