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RESEARCH QUESTION/RATIONALE

Mutations in ARID1B are one of the most frequent causes of intellectual disability. Preclinical research shows clonazepam treatment improves symptoms in Arid1b mice. Clonazepam is used for treatment of seizures in humans. Does clonazepam treatment positively affect ARID1B patients?

HYPOTHESIS

Clonazepam treatment restores the excitatory/inhibitory imbalance caused by reduced numbers of inhibitory interneurons which leads to improved behaviour and/or cognition in patients.

STUDY DESIGN

Randomized, double-blind, placebo-controlled, two way crossover, single centre study.

STUDY POPULATION

20 patients with ARID1B syndrome.

INTERVENTION

Clonazepam droplets 0.01 mg/kg/day divided in 2 doses. Dose will be increased every 3 days in steps of 0.01 mg/kg/day to a maximal dose of 0.03 mg/kg/day. In case of side effects, dose will be halved. After 3 days dose will be doubled, if side effects re-emerge patient will remain on maximum tolerated dose.

After the study period dose will be tapered by 0.01 mg/kg/day every 3 days.

OUTCOME MEASURES

• 6 NeuroCart tests based on our pervious study with 12 ARID1B patients (a.o. Adaptive Tracking, Animal fluency test),

• ABC questionnaire (parents, teacher), Clinician’s Global Impression of improvement (CGI-I).

SAMPLE SIZE/DATA-ANALYSIS

With 20 patients this study has an 80% power to detect a clinically meaningful 1 point difference in CGI-I, and changes in Neurocart measurements corresponding to 8-35% of the difference between ARID1B patients and controls (as previously measured).

Each parameter will be analyzed with a mixed model analysis of covariance (ANCOVA) with treatment, time, and treatment by time as fixed factors and subject, subject by treatment and subject by time as random factors and the (average) baseline measurement as covariate.

 

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