* To test the hypothesis that clonazepam administration has acute beneficial effects compared to placebo on body sway, adaptive tracking, smooth eye pursuit, tapping frequency and the animal fluency test.* To test the hypothesis that multiple-doses…
ID
Source
Brief title
Condition
- Mental impairment disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic endpoints
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, t*
* 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)
Tolerability / safety endpoints
* Adverse events
* Vital signs measurements
* General physical examination findings
Secondary outcome
NA
Background summary
Clonazepam is a registered and safe drug which is being used for the treatment
of epilepsy. Preclinical experiments show that clonazepam rescues some of the
preclinical phenotypes in ARID1B +/- mice. There is currently no treatment for
ARID1B-related intellectual disability. The aim of this study is to assess the
efficacy and safety of clonazepam in patients with ARID1B-related intellectual
disability.
Study objective
* To test the hypothesis that clonazepam administration has acute beneficial
effects compared to placebo on body sway, adaptive tracking, smooth eye
pursuit, tapping frequency and the animal fluency test.
* 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 explore the feasibility of using saliva PK to predict plasma PK
* 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.
Study design
Part A. Open label study in 20 healthy volunteers where pharmacokinetics of
clonazepam will be measured in paired plasma and saliva samples.
Part B. Two-way cross over, placebo-controlled randomized study in patients
with ARID1B-related intellectual disability. Each period will be 22 days and
periods will be separated by a three-week washout. Patients will be monitored
in the clinic for 5 hours for safety, PK, and biomarker effects on day 1 and 22
in both periods. Between those days, patients remain at home and fill in
questionnaires and wear digital technologies.
Intervention
Clonazepam and placebo
Study burden and risks
Potential benefit consists of improvement of behaviour and/or cognitive
function. The burden consist of potential experience of side effects of
clonazepam, and the burden of the non-invasive study procedures. The study is
group related since treatment effects on ARID1B-related intellectual disability
can only be assessed by treating patients with this disease.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Part A, correlation blood-saliva PK.
* Healthy male or female volunteers aged 18-30 years
* 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
Exclusion criteria
Part A, healthy volunteers
* 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
* Clinically meaningful blood loss (including blood donation), or a transfusion
of any blood product within 12 weeks before screening.
* 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003558-98-NL |
| CCMO | NL71395.056.19 |
| OMON | NL-OMON29120 |