ARID1B-related intellectual disability
Conditions
Interventions
Trade Name: Rivotril
Product Name: Rivotril
Pharmaceutical Form: Oral drops
INN or Proposed INN: CLONAZEPAM
CAS Number: 1622-61-3
Concentration unit: mg milligram(s)
Concentration type: up to
Concentr
Sponsors
Centre for Human Drug Research
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Part A, saliva PK. • Healthy male or female volunteers • Informed consent provided by volunteer Part B, ARID1B patients. • Informed consent provided by both parents, or the legal guardian prior to any study mandated procedure. • Known mutation in ARID1B • Assent provided by the participant. • Aged 6 years or older Are the trial subjects under 18? yes Number of subjects for this age range: 20 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Part A • Disorder that could interfere with saliva production. • Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication. • Treatment with another investigational drug within 3 months prior to screening or more than 4 times a year. • 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. • History of severe respiratory problems or severe liver- or renal insufficiency. • Other medical or psychosocial history making the participant unsuitable for participation as determined by the treating paediatrician. • 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). • Clinically significant findings on physical examination. • Medications with a strong influence on CYP3A4 metabolism • Subjects with a BMI > 30 and/or cardiovascular, respiratory or immune system disorders Part B, ARID1B patients. • Clear indication of not wanting to participate during the study • 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). • Known hypersensitivity to clonazepam, other benzodiazepines or other excipients of the study medication. • History of severe respiratory problems or severe liver- or renal insufficiency. • Other medical or psychosocial history making the participant unsuitable for participation as determined by the treating paediatrician.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To test the hypothesis that clonazepam administration has acute beneficial effects compared to placebo on neurocognitive tests. • To test the hypothesis that multiple-doses clonazepam has beneficial effects compared to placebo on behaviour and cognitive function in ARID1B patients as measured by the ABC, and CGI-I scale. • Assess safety and tolerability of clonazepam in ARID1B patients. • To assess the potential of at-home neurocognitive tests for the evaluation of treatment effects in children with neurodevelopmental disorders. • To assess and compare the difference in predictive capability between linear and nonlinear (NONMEM) regression of the saliva:plasma relationship. ;Secondary Objective: Assess safety and tolerability of clonazepam in ARID1B patients. ;Primary end point(s): Part A: serum and saliva. Part B: saliva only. • The maximum serum concentration, Cmax • The time to reach maximum serum concentration, tmax • The terminal disposition rate constant (?z) with the respective half-life, t½ • The area under the serum concentration-time curve from zero to infinity, AUC0-inf • The area under the serum concentration-time curve from zero to t of the last measured concentration above the limit of quantification, AUC0-last • Clearance, Cl • Volume of distribution, Vz Trial@home endpoints • Physical activity • Sleep (duration, %light sleep, amount of times woken up) • Heart rate • Daily symptom scores • Tapping frequency, adaptive tracking, animal fluency (twice-weekly ) Pharmacodynamic endpoints • NeuroCart o Adaptive Tracking o Animal fluency test o Body Sway o Saccadic Eye Movements o Smooth Pursuit Eye Movements o Tapping frequency • Questionnaires o ABC questionnaire (parents, teacher) o Clinician’s Global Impression of improvement (CGI-I) ;Timepoint(s) of evaluation of this end point: baseline to EoS | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Tolerability / safety endpoints • Adverse events • Vital signs measurements • General physical examination findings (only performed when clinically indicated) ;Timepoint(s) of evaluation of this end point: from baseline to EoS | — |
Countries
Netherlands
Contacts
Public ContactRob Zuiker
Centre for Human Drug Research
Outcome results
None listed