ARID1B-related intellectual disability Mental and Behavioural Disorders
Conditions
Interventions
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 cro
Sponsors
Centre for Human Drug Research
Eligibility
Sex/Gender
All
Inclusion criteria
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.
Exclusion criteria
Exclusion criteria: Part A: healthy volunteers 1. Disorder that could interfere with saliva production. 2. Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication. 3. Treatment with another investigational drug within 3 months prior to screening or more than 4 times a year. 4. History or clinical evidence of any disease and/or existence of a surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug. 5. History of severe respiratory problems or severe liver- or renal insufficiency. 6. Other medical or psychosocial condition or history making the participant unsuitable for participation. 7. History or clinical evidence of alcoholism within the 3-year period prior to screening (i.e. regular use of more than 21 units of alcohol/week). 8. Clinically significant findings on physical examination. 9. Medications with a strong influence on CYP3A4 metabolism. 10. Clinically meaningful blood loss (including blood donation), or a transfusion of any blood product within 12 weeks before screening. Part B: ARID1B patients. 1. Clear indication of not wanting to participate during the study. 2. Use of benzodiazepines or any other medication or drug with the potential to influence study related endpoints in the investigator’s opinion (including e.g. CYP3A4-related drugs). 3. Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication. 4. History of severe respiratory problems or severe liver- or renal insufficiency. 5. Other medical or psychosocial condition or history making the participant unsuitable for participation as determined by the treating physician or general practitioner.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| There are no secondary outcome measures | — |
Countries
Netherlands
Contacts
Public ContactCecile Berends
Outcome results
None listed