Clonazepam in patients with ARID1B-related intellectual disability

INTERVENTION: Part A (open‐label study) • Clonazepam (Rivotril) droplets for oral use, solution 2.5 mg/ml, dissolved in lemonade. Dose: 0.5 mg or 1 mg, both administered to 50% of subjects. Part B (randomised cross‐over study) • Active medication. Clonazepam (Rivotril) droplets for oral use, solution 2.5 mg/ml, dissolved in lemonade, tea or juice. • Placebo: dissolved in lemonade, tea or juice Study drug or placebo during part B will be administered to the subjects as follows: ‐ Day 1‐3: Starting dose is 0.005 mg/kg, twice daily (ma X0.5 mg, twice daily) ‐ Day 4‐6: 0.01 mg/kg, twice daily (ma X0.5 mg, twice daily) ‐ Day 7‐22: 0.015 mg/kg, twice daily (ma X0.5 mg, twice daily) At the end of the study period, clonazepam will be tapered by decreasing the daily dose by 0.01 mg/kg/day every three days. The randomization code was generated by a study‐independent statistician on‐site. The randomization code was unblinded/broken and made available for data analysis only after study closure. The randomization code was kept strictly confidential. Sealed individual randomization codes, per subject and per treatment, were placed in a sealed envelope containing the labelled 'emergency decoding envelopes' and kept in a safe cabinet on‐site. CONDITION: ARID1B‐related intellectual disability ; Mental and Behavioural Disorders SECONDARY OUTCOME: There are no secondary outcome measures INCLUSION CRITERIA: Part A: healthy volunteers 1. Healthy male or female volunteers aged 18‐30 years. 2. Informed consent provided by volunteer. Part B: ARID1B patients. 1. Informed consent provided by both parents, or the legal guardian prior to any study mandated procedure. 2. Known mutation in ARID1B. 3. Assent provided by the participant. 4. Aged 6 years or older. PRIMARY OUTCOME: ; 1. Pharmacokinetic endpoints; Part A: serum and saliva at baseline, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h and 48h post‐dose. Part B: saliva only at baseline, 4.5h n 5h post‐dose on Day 1 and Day 22 for study periods 1 en 2.; 1.1. The maximum serum concentration, Cmax; 1.2. The time to reach maximum serum concentration, tmax; 1.3. The terminal disposition rate constant (?z) with the respective half‐life, t½; 1.4. The area under the serum concentration‐time curve from zero to infinity, AUC0‐inf; 1.5. The area under the serum concentration‐time curve from zero to t of the last measured; 1.6. concentration above the limit of quantification, AUC0‐last; 1.7. Clearance, Cl; 1.8. Volume of distribution, Vz; ; 2. Trial@home endpoints (Part B) performed at home from Day 1‐Day 22 for study periods 1 and 2: Continuous physical activity, heart rate and sleep monitoring, as well as twice‐weekly finger tapping, adaptive tracking and animal fluency.; 2.1. Physical activity (daily); 2.2. Sleep (duration, %light sleep, amount of times woken up) (daily); 2.3. Heart rate (daily); 2.4. Daily symptom scores (daily); 2.5. Tapping frequency, adaptive tracking, animal fluency (twice‐weekly); ; 3. Pharmacodynamic endpoints (Part B) at baseline, 1h, 3h, 5h post‐dose on Day 1 and Day 22 for study periods 1 en 2.; 3.1. NeuroCart; 3.2. Adaptive Tracking; 3.3. Animal fluency test; 3.4. Body Sway; 3.5. Saccadic Eye Movements; 3.6. Smooth Pursuit Eye Movements; 3.7. Tapping frequency; ; 4. Questionnaires (Part B) at baseline at Day 1 and Day 22 for study periods 1 en 2.; 4.1. ABC questionnaire (parents, teacher); 4.2. Clinician’s Global Impression of improvement (CGI‐I); ; 5. Tolerability / safety endpoints; 5.1. Adverse events at dosing, 1h, 3h and 5h post‐dose, evaluation by phone at Day 3 and Day 6 and when needed.; 5.2. Vital signs measurements at baseline; 5.3. General physical examination findings on indication during the study;