Clonazepam in patients with ARID1B-related intellectual disability
| ISRCTN | ISRCTN11225608 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11225608 |
| EudraCT/CTIS number | 2019-003558-98 |
| Secondary identifying numbers | CHDR1939 |
- Submission date
- 06/09/2022
- Registration date
- 07/09/2022
- Last edited
- 02/01/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
Background and study aims
Intellectual disability (ID) is one of the most frequent neurodevelopmental disorders and affects up to 2-3% of the population. Mutations in ARID1B are found to be the most frequent cause of ID, explaining about 1% of the patients. Besides non-specific ID, ARID1B mutations have been identified in a high proportion (>50%) of patients with a clinical diagnosis of Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. Although there are no good estimates of incidence and prevalence, ~50 patients with ARID1B mutations are currently known in the LUMC’s expertise center. Worldwide the largest group of described patients consists of 143. Except for supporting therapies such as physiotherapy and speech therapy, no treatment options are available for ARID1B patients.
Clonazepam (Rivotril) is a well-known and safe drug used to treat epilepsy in children and adults and occasionally for behavioral problems. Studies in laboratory animals indicate that clonazepam may be effective in the condition ARID1B-related intellectual disability. Plasma sampling is not desirable in the ARID1B patient population, therefore we will first establish the relations between clonazepam plasma concentrations and saliva in healthy volunteers in Part A. Such correlation was previously established for diazepam.
The study will continue with Part B, a two-way crossover study evaluating the effects of clonazepam in patients with ARID1B-related intellectual disability. We will do this by conducting a number of questionnaires and performing neurological tests after the use of clonazepam.
Who can participate?
Part A: 20 Healthy male or female volunteers
Part B: 20 ARID1B patients.
What does the study involve?
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.
What are the benefits and risks of participating?
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.
Where is the study run from?
Centre for Human Drug Research (The Netherlands)
When is the study starting and how long is it expected to run for?
February 2020 to June 2022
Who is funding the study?
CHDR and ZonMW (The Netherlands)
Who is the main contact?
R. (Rob) Zuiker, MD, PhD, Principal Investigator, clintrials@chdr.nl
Contact information
Public
Zernikedreef 8
Leiden
2333 CL
Netherlands
| Phone | +31 71 5246 400 |
|---|---|
| clintrials@chdr.nl |
Study information
| Study design | Open-label study followed by a two-way cross over placebo-controlled randomized study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet. |
| Scientific title | Randomized, double-blind, placebo-controlled, two way crossover, single centre study evaluating the acute and chronic effect of clonazepam on cognitive tests and patient-reported outcome measures in patients with ARID1B-related intellectual disability |
| Study acronym | CARE study |
| Study objectives | Clonazepam administration has acute beneficial effects on neurocognitive tests and multiple-doses clonazepam has beneficial effects on behaviour and cognitive function in ARID1B patients as measured by the ABC and CGI-I scale. |
| Ethics approval(s) | Approved 10/02/2020, Stichting Beoordeling Ethiek Biomedisch Onderzoek (stichting BEBO, Dr. Nassaulaan 109401 HK ASSEN, The Netherlands; +31592405871; info@stbebo.nl), ref: NL71395.056.19 |
| Health condition(s) or problem(s) studied | 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 (max 0.5 mg, twice daily) - Day 4-6: 0.01 mg/kg, twice daily (max 0.5 mg, twice daily) - Day 7-22: 0.015 mg/kg, twice daily (max 0.5 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. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Clonazepam |
| Primary outcome measure | 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 (λz) 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 outcome measures | There are no secondary outcome measures |
| Overall study start date | 10/02/2020 |
| Completion date | 03/06/2022 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Mixed |
| Lower age limit | 6 Years |
| Upper age limit | 30 Years |
| Sex | Both |
| Target number of participants | 40 |
| Total final enrolment | 36 |
| Key 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. |
| Key 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. |
| Date of first enrolment | 10/02/2022 |
| Date of final enrolment | 03/05/2022 |
Locations
Countries of recruitment
- Netherlands
Study participating centre
Leiden
2333CL
Netherlands
Sponsor information
Research organisation
Zernikedreef 8
Leiden
2333 CL
Netherlands
| Phone | +31 71 5246 400 |
|---|---|
| clintrials@chdr.nl | |
| Website | https://chdr.nl/ |
"ROR" |
https://ror.org/044hshx49 |
Funders
Funder type
Research organisation
No information available
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- Netherlands Organisation for Health Research and Development
- Location
- Netherlands
Results and Publications
| Intention to publish date | 03/06/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in publicly available repository |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a publically available repository. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Other files | Adverse Events Listing | 04/08/2022 | 30/01/2023 | No | No |
| Other files | Demographics and Baseline Characteristics | 04/08/2022 | 30/01/2023 | No | No |
| Other files | Statistical appendix ABC data | 18/01/2023 | 30/01/2023 | No | No |
| Other files | Statistical appendix CGI data | 18/01/2023 | 30/01/2023 | No | No |
| Other files | Statistical appendix Drug concentration data | 19/10/2022 | 30/01/2023 | No | No |
| Other files | Statistical appendix Drug concentration data individual subjects | 05/10/2022 | 30/01/2023 | No | No |
| Other files | Study Participants and Safety Data | 04/08/2022 | 30/01/2023 | No | No |
| Other files | Subject Disposition | 04/08/2022 | 30/01/2023 | No | No |
| Protocol file | version 6 | 21/01/2022 | 30/01/2023 | No | No |
| Results article | 01/05/2022 | 30/01/2023 | Yes | No | |
| Dataset | Excel | 24/02/2023 | 27/02/2023 | No | No |
| Other files | Analysis of pharmacodynamic parameters | 16/12/2022 | 11/09/2023 | No | No |
| Results article | 31/12/2024 | 02/01/2025 | Yes | No |
Additional files
- 42330 Protocol_V6_21Jan2022.pdf
- 42330 Demographics and Baseline Characteristics CHDR1939B_FSR_L_Demographics_04Aug2022.pdf
- Demographics and Baseline Characteristics
- 42330 Subject Disposition CHDR1939B_FSR_L_Disposition_04Aug2022.pdf
- Subject Disposition
- 42330 Study Participants and Safety Data CHDR1939B_FSR_Summary_04Aug2022.pdf
- Study Participants and Safety Data
- 42330 Adverse Events Listing CHDR1939B_FSR_L_AES_04Aug2022.pdf
- Adverse Events Listing
- 42330 Statistical appendix Drug concentration data CHDR1939B_FPK 19Oct2022.pdf
- Statistical appendix Drug concentration data
- 42330 Statistical appendix Drug concentration data individual subjects CHDR1939_FPK_05Oct2022.pdf
- Statistical appendix Drug concentration data individual subjects
- 42330 Statistical appendix CGI data CHDR1939-B_FPD_18Jan2023.pdf
- Statistical appendix CGI data
- 42330 Statistical appendix ABC data CHDR1939-B_FPD_18Jan2023.pdf
- Statistical appendix ABC data
- ISRCTN11225608 raw data.xlsx
- Excel
- 42330 Statistical appendix Analysis of pharmacodynamic parameters 16Dec2022.pdf
- Analysis of pharmacodynamic parameters
Editorial Notes
02/01/2025: Publication reference added.
11/09/2023: Another file of statistical analysis was added.
27/02/2023: The dataset was uploaded as an additional file.
30/01/2023: The following changes were made to the trial record:
1. The participant level data sharing statement was added.
2. Uploaded protocol (not peer-reviewed) as an additional file.
3. Publication reference added.
4. Other files of statistical analysis were added.
07/09/2022: Trial's existence confirmed by Stichting Beoordeling Ethiek Biomedisch Onderzoek
