Neural Biomarkers in Fragile X Syndrome

Connecta Therapeutics, S.L.20 enrolled

Overview

The purpose of this non-interventional test /re-test study is to assess neural biomarkers in adult subjects with Fragile X syndrome compared to those measured in a population of typically developing adults

This study consists of a screening period and two cross sectional evaluations assessed in one month interval (test/re-test), first on the Visit 1 (Basal) and the other on the Visit 2 (end-of-study visit, EOS).

Study Type

OBSERVATIONAL

Enrollment

Conditions

Fragile X Syndrome (FXS)Neurotypical Adults

Interventions

AnyOTHER

Any

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Demographics common to all subjects: * Male or female subjects. * Age ≥ 18 and ≤ 55 years. * Weight ≥ 50 kg and ≤ 100 kg. * Body mass index (BMI) ≥ 18.5 and ≤ 30. Subjects with Fragile X syndrome Inclusion Criteria: * Clinical and molecular diagnosis of Fragile X syndrome (\> 200 CGG repeats in the promoter region of the FMR1 gene). * Legal representative understands and accepts the study procedures. If only one parent signs, he/she should confirm that the other parent does not object to the patient's participation in the research project. * Subject assenting and/or willing to participate. * Signed informed consent by a legal representative before any study-mandated procedure. * Subject is independently mobile and has sufficient vision and hearing to participate in study evaluations. They must be able to be understood most of the time and must not use other forms of communication, signs, symbol boards or devices as their primary form of communication. * Subjects must have a parent, or other reliable caregiver, who agrees to accompany the subject to all study visits, provide information about the subject as required by the protocol, and ensure compliance with study tests. * Subjects are expected to complete all procedures scheduled during the study visits. Subjects with Fragile X syndrome Exclusion Criteria: * Personal history of infantile spasms/convulsions/epilepsy, severe head trauma or CNS infections (e.g. meningitis), with the exception of infantile febrile seizures. * Subjects with a current diagnosis including severe autism spectrum disorder or any primary psychiatric diagnosis according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-DSM-5). Diagnoses that are secondary, such as attention deficit hyperactivity disorder, depressive disorders and conduct disorders are allowed as long as they are considered to not interfere with study conduct and are stable during the 3 months before inclusion. Related allowed treatments must be on stable dosing for the last 3 months. * Substance use disorder according to the DSM-5 criteria. * Epileptiform abnormalities (excluding isolated sharp waves and beyond those expected for age). * Any life-threatening disease. * Any other clinically relevant concomitant disease or condition or finding at screening that in the judgment of the investigator could interfere with, the treatment thereof might interfere with, the conduct of the study and related procedures and/or might bias the study results interpretation, or could jeopardize the subject's safety. * Any clinically significant findings in physical examination including vital signs. * Neuroleptic or antidepressant (ISRS) drugs within 3 months before inclusion, except for sertraline at a maximum 100 mg/day, and stable for the last 3 months before inclusion. * Any prescription or over-the-counter drug (except occasional use of paracetamol) in the last 2 weeks before screening. * Patient included in a clinical study with drugs in the last three months prior to inclusion. Typically Developing Subjects Inclusion Criteria: * Abstinence for any drug abuse 72 hours prior to the screening visit and the observation days, except for nicotine (24 hours). * Able to read Spanish and/or Catalan and to adhere to the study requirements. * Signed informed consent prior to any study-mandated procedure. Typically Developing Subjects Exclusion Criteria: * Life-time clinically significant cardiovascular, renal, pulmonary, hepatic, onco-haematological, endocrine, gastrointestinal, mental or neurological disease. * Any other clinically relevant concomitant disease or condition or finding at screening that in the judgment of the investigator could interfere with, the treatment thereof might interfere with, the conduct of the study and related procedures and/or might bias the study results interpretation, or could jeopardize the subject's safety. * Any clinically significant findings in physical examination including vital signs. * Neuroleptic drugs within 3 months prior to inclusion. * Any prescription or over-the-counter drug (except occasional use of paracetamol) in the last 2 weeks before screening. * Patient included in a clinical study with drugs in the last three months before inclusion. * Personal history of infantile spasms/convulsions/epilepsy, severe head trauma or CNS infections (e.g. meningitis), except for infantile febrile seizures. * Subjects with a current diagnosis including autism spectrum disorder or any primary psychiatric diagnosis according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-DSM-5). Diagnoses that are secondary, such as attention deficit hyperactivity disorder, depressive disorders and conduct disorders are allowed as long as they are considered to not interfere with study conduct and are stable during the 3 months before inclusion. Related allowed treatments must be on stable dosing for the last 3 months. * Substance use disorder according to the DSM-5 criteria except for mild alcohol use disorder and/or mild or moderate nicotine use disorder. * Positive urine test for drugs of abuse or alcohol breath test at screening. * Epileptiform abnormalities (excluding isolated sharp waves and beyond those expected for age). * Any life-threatening disease.

Locations (2)

Hospital del Mar Research Institute (HMRI)

Barcelona, Barcelona, Spain

Consorci Corporació Sanitaria Parc Taulí. Institut Investigació i Innovació Parc Taulí (I3PT)

Sabadell, Barcelona, Spain

Outcomes

Primary Outcomes

Cognitive profile of FXS patients compared to neurotypical subjects using the NIH-TCB-ID Toolbox

The NIH-Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB-ID) provides a reliable, validated and standardized measure (composite scores) that can be used as efficacy endpoints in clinical studies in patients with neurodevelopmental disorders from 3 to 85 years old. The Fluid Cognition composite score of the NIH Toolbox cognitive battery combines the scores of five tests assessing the following cognitive domains: i) Cognitive flexibility, ii) Inhibitory control and visual attention, iii) Episodic memory, iv) Processing speed and v) Working memory.

Time frame: Day 1 and Day 28 (± 3 days)

Neural oscillations using Electroencephalography (EEG)

Multichannel EEG will be recorded using a mobile wireless helmet for high precision EEG monitoring. In total, 20 EEG channels will be used to capture brainwave activity. The EEG test contains three well differentiated sections: auditory oddball, resting-state (eyes open and eyes closed) and auditory steady-state response (ASSR). Before starting the auditory oddball, the subject will conduct a training section (40 seconds) to present the type of sounds and to check that they have understood the task by practicing it.

Time frame: Day 1

Point of gaze using eye tracking

Eye tracking technology will be used to record X and Y coordinates of eye position and pupil diameter. Stimuli will consist on 60 coloured photographs of adult human faces (equal numbers of males and females; different races and ethnicities), each face exhibiting a calm, happy, or fearful expression, and 60 scrambled versions of the face images. Testing will be conducted in a quiet room with the lights turned off. Each trial will start with presentation of a scrambled face image for 1 s followed immediately by its matched face image for 3 s. An inter-trial interval (ITI) containing a uniform grey screen will be shown for 0.5, 1, or 2 s, randomly determined. The order of face presentation will be pseudorandomized and each eye tracking session will last approximately 6 min.

Time frame: Day 1 and Day 28 (± 3 days)

Behavior troubles of the FXS patients compared to neurotypical subjects using the Aberrant Behavior Checklist (ABC)

Data from ClinicalTrials.gov

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Standardized rating scale used for assessing problematic behavior of individuals with developmental disabilities. The questionnaire explores problem behaviors across 5 domains: Irritability (15 items), Lethargy/Socially Withdrawal (16 items), Stereotypy Behavior (7 items), Hyperactivity/Noncompliance (16 items), Inappropriate Speech (4 items). Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). For the present study the total score for each of the 5 domains or subscales will be calculated and used for the analyses, as a good measure of the psychiatric symptom and behavioral disturbance profile. In all cases, higher scores in the mentioned subscales and total score indicated a greater presence and severity of behavioral problems: Agitation \[0-45\]; Lethargy/Social Withdrawal \[0-48\]; Stereotypic Behavior \[0-21\]; Hyperactivity/Noncompliance \[0-48\] and Inappropriate Speech \[0-12\].

Time frame: ≤ 1 month prior to Day 1

Adaptative functioning using the Vineland Adaptive Behaviour Scale (VABS-3)

The Vineland Adaptative Behaviour Scale 3 (VABS-3) is a psychometric instrument used in child and adolescent clinical psychology for the assessment of individuals with different types of developmental delays, regarding an adaptive level of functioning by standardized interview of the person or their caregiver through their activities of daily living such as walking, talking, getting dressed, going to school, preparing a meal, etc. Three domains explore communication, socialization and daily living, which correspond to the 3 domains of adaptive functioning recognized by the American Association on Intellectual and Developmental Disabilities.

Time frame: ≤ 1 month prior to Day 1

Clinician-rated global functioning using the Clinical Global Impression (CGI)

The Clinical Global Impression Scale (CGI) comprises two companion one-item measures evaluating the following: 1. Severity of Psychopathology (Clinical Global Impression-Severity (CGI-S) Scale): establishes the baseline illness status and rates illness severity on a 7-point scale \[range 0 to 7\]: 1 for not at all ill; 2 for borderline illness; 3 for mild illness; 4 for moderately ill; 5 for very ill; 6 for severely ill; 7 among the most severe patients; and 2. Change from the Initiation of Treatment (Clinical Global Impression-Improvement (CGI-I) Scale): rates how much the subject's illness has improved or worsened relative to the baseline state (CGI-S) on a 7-point scale \[range -7 to 7\]: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse.

Time frame: ≤ 1 month prior to Day 1 and Day 28 (± 3 days)

Stress biomarkers of the FXS patients compared to neurotypical subjects measured by cortisol concentrations in hair (occipital area)

Hair cortisol analysis characterizes chronic stress as a risk factor for chronic illness progression and is known as a biomarker of the effectiveness of stress reduction interventions. Approximately 3 cm of occipital hair will be collected at the Screening visit for the determination of cortisol concentrations \[range 2.5 - 97.5 pg/mg\].

Time frame: ≤ 1 month prior to Day 1

Biorhythm characteristics of FXS patients compared to neurotypical subjects determining vitamin D (25-Hydroxy) concentrations in serum

Vitamin D concentrations are also useful due to lack of sunlight exposure is the primary reason for the worldwide epidemic of vitamin D deficiency. The lack of sunlight exposure is involved in serotonin and melatonin production. Venous blood samples will be collected by individual venepuncture or via an indwelling catheter to measure vitamin D (25-Hydroxy) concentrations in serum \[25 - 150 ng/mL\].

Time frame: Day 1 and Day 28 (± 3 days)

Biorhythm characteristics of FXS patients compared to neurotypical subjects determining 24h urine cortisol concentrations

The activation of the Hypothalamic Pituitary Adrenal (HPA) axis leads to the synthesis and release of cortisol, a glucocorticoid hormone that peaks in the early morning hours. 24-hour urine samples will be collected before Visit 1 and Visit 2 for the determination of cortisol concentrations \[range 11.5 - 102.0 µg/24h\].

Time frame: Day 1 and Day 28 (± 3 days)

Biorhythm characteristics of FXS patients compared to neurotypical subjects using sleep diaries

Sleep schedule will be assessed by using sleep diaries to record the quality and quantity of sleep. A sleep diary allows recording when the subject goes to bed, when the subject wakes up during the night and when the subject wakes up in the morning. This will help to understand the sleep pattern and how much sleep the subject gets. It will also show how often the subject has interrupted sleep.