Sleep Quality, Multiple Sclerosis, Insomnia
Conditions
Keywords
Cannabidiol, Sleep, MS, Insomnia
Brief summary
Evaluating the effect of 300 mg purified cannabidiol (CBD) on sleep quality in patients with multiple sclerosis (MS).
Detailed description
The investigators conducted a series of 16 aggregated randomized, placebo-controlled N-of-1 trials to investigate the effect of purified cannabidiol (CBD) oil on nocturnal sleep quality in patients with multiple sclerosis. Each participant completed four treatment periods: two with CBD (300 mg daily) and two with placebo. The primary outcome is the insomnia severity index (ISI). Secondary outcomes included a sleep-wake diary and scores on the Checklist Individual Strength Fatigue subscale (CIS-F), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS).
Interventions
DRUGCannabidiol Oil
This study aims to compare the efficacy of CBD oil with a placebo to manage nocturnal sleep quality in MS patients.
Sponsors
Wageningen University
Nationaal MS Fonds
Rijnstate Hospital
Sleep Medicine Centre Kempenhaeghe
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
It is a double blinded trial in which neither the participants nor the researcher knows when a participant receives cannabidiol or placebo.
Intervention model description
A series of 16 N-of-1 trials; each N-of-1 trial will consist of a double crossover performed in a single patient. Within a crossover, the interventions with either CBD or placebo are randomised and double blinded. After a run-in period of 2 weeks, there will be 4 treatment periods of 3 weeks, separated from each other by a washout of 1 week.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of MS confirmed by a neurologist, based on the revised 2010 or 2017 McDonalds criteria * Relapsing-remitting or primary or secondary progressive MS * Expanded Disability Status Scale (EDSS) score \<7.5 * No relapse for at least 6 months before the screening visit * No changes in immunomodulating therapy stable * For at least 3 months before the screening visit; no changes in use of other medications used for chronic conditions for at least 6 weeks before the screening visit (e.g. anti-depressant drugs, antidiabetics) * Age minimally 18 years at the time of screening * Body Mass Index (BMI) \< 35.0 kg/m2 at the moment of screening * Elevated levels of transaminases (ALAT, ASAT) until twice the Upper Limit of Normal (2x ULN) are allowed, as elevation of these levels is a common finding in MS patients * No plans to (be involved in) getting pregnant during the trial * No breast feeding during the trial * A complaint of chronic impairment of sleep quality, leading to a diagnosis of insomnia by an MS neurologist and an experienced somnologist. In this context, insomnia is defined as difficulties initiating and/or maintaining sleep or too early awakenings, despite adequate opportunity and circumstances for sleep, resulting in some form of daytime impairment. Causes include psychophysiological insomnia, insomnia due to mental disorders like depression, and insomnia secondary to other MS-related symptoms like spasticity, pain or nocturnal voidings. * Diagnosis will be based on fulfilment of the ICDS-3 criteria of insomnia and an ISI score of minimally 15 (threshold for clinical insomnia). * Continuation of pharmacological treatments will be at the discretion of the study physicians. * Willing and able to refrain from new, sleep-facilitating pharmacological treatments until the end of the treatment phase of the study * Willing and able not to use any other cannabis product until completion of the study * Willing and able not to use any supplement that could promote sleep (e.g. L-tryptophan, * valerian, melatonin) during the treatment phase of the study. * Continuation of non-pharmacological treatments will be at the discretion of the study physicians. * Willing and able to refrain from new, sleep-facilitating nonpharmaceutical interventions until the end of the treatment phase of the study. Lifestyle should be kept as stable as possible. * Willing and able to give informed consent * Willing and able to fill in a daily digital diary during the treatment phase, to send this to the study nurse or research assistant once a week, and to be contacted by the research assistant minimally twice a week during the treatment phase of the study * Willing and able to use the Neurokeys app (thus mobile phone) daily * Willing to have blood sampled at the screening visit and have another * two blood draws during the treatment phase of the study * Willing and able not to drive a car or operate machinery within 8 hours after intake of the investigational product until the end of the treatment phase of the study * Willing and able not to do evening/night shift work and not to cross time zones until the completion of the study * Willing and able to refrain from excessive use of excessive use of caffeine (\> 1 cup of coffee or 1 serving of energy drink) and alcohol (\> 1 serving) in the evening, 6 hours before going to bed * Willing and able to refrain from (products of) grapefruit, Seville oranges (used in marmalade), limes and pomelos during the treatment phase of the study * Willing and able to refrain from experimenting with timing and type of diet, and beverages during the treatment phase of the study. A participant's dietary intake pattern should be kept as stable as possible during the treatment phase as there are numerous dietary components other than furanocoumarins that may influence CBD bioavailability
Exclusion criteria
* Circadian rhythm sleep-wake disorders, sleep related breathing disorders (such as moderate to severe obstructive sleep apnea, central breathing disorders during sleep, or sleep-related stridor that require prompt specific treatment), current delayed sleep phase syndrome where wake up time is regularly later than 8.00 a.m., or a sleep problem fulfilling the ICSD3 criteria of parasomnias * Good response to initial treatment for the assessed sleep disorder * Use of a benzodiazepine or other sleep medication, unless the patient has tapered off the sleep medication before the moment of inclusion * Liver disease or blood levels of transaminases (ALAT, ASAT) above 3x ULN, as long term administration of high doses of CBD may affect (although reversible) liver function * History of severe psychiatric comorbidity * Increased risk of suicidal thoughts or behaviour * History of drug or alcohol abuse * Known or suspected hypersensitivity to cannabinoids or to excipients of the formulation of the investigational product - almond oil * History of use with CBD oil prepared by pharmacy Clinical Cannabis Care * Structural or recreational use of a cannabinoid product \< 2 months before screening * Whether the use of any of the following medications is a reason for exclusion will be at the discretion of the study physicians and delivery pharmacist. * drugs with risk of liver injury; the decision of exclusion will be made in consultation with the MS neurologists and the pharmacist that provides the CBD product. * drugs with risk of interaction with CBD. Data on the potential drug-CBD interactions below are based on mechanistic and clinical studies: * drugs of which their biotransformation is primarily dependent on the cytochrome P450 enzymes CYP2C19 and CYP3A * drugs that are inducers or inhibitors of enzymes of which CBD is a substrate: CYP2C19, CYP3A4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insomnia Severity Index (ISI) | The ISI was administered at baseline and at the end of every treatment block, measuring perceived severity of insomnia over the last two weeks (weeks 2,5,9,13,17) | The ISI is a validated tool to assess insomnia and sensitive to treatment response. The ISI is composed of seven items, each with a 5-point rating scale ranging between and to 4 (no to severe problem). Higher scores indicate worse outcomes. A total score between 0-7, 8-14, 15-21, and 22-28 is explained as no, sub threshold, moderate, and severe insomnia, respectively. A change in ISI score of 5 is considered as a clinical improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sleep diary - total sleep time | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Total sleep time in minutes, higher scores indicate better outcomes |
| Epworth Sleepiness Scale (ESS) | At the end of every two weeks in each of 4 treatment periods (weeks 1, 2, 4, 5, 8, 9, 12, 13, 16, 17) | The ESS assesses excessive daytime sleepiness and consists of 8 items, each scored on a 0-3 point scale. Higher scores indicate worse outcomes. Score categories include 1-10, 11-14, 15-17, 18-24: no, mild, moderate, severe sleepiness, respectively. |
| Fatigue Severity Scale (FSS) | At the end of every two weeks in each of 4 treatment periods (weeks 1, 2, 4, 5, 8, 9, 12, 13, 16, 17) | Measures symptoms of fatigue using a 9-item scale scored from 1 to 7. Higher scores indicate worse outcomes. |
| Checklist Individual Strength Fatigue subscale (CIS-F) | At the end of every two weeks in each of 4 treatment periods (weeks 1, 2, 4, 5, 8, 9, 12, 13, 16, 17) | Indicator of fatigue and related behavioral aspects, containing 20 statements with a 7-point Likert scale over four categories: subjective fatigue, concentration, motivation, and activity. Higher scores indicate worse outcomes. |
| Keystroke dynamics | Continuously and daily during the 18-week study period. | Outcomes of the NeuroKeys application (i.e. clusters of keystroke dynamics including typing speed and motion sensor data (accelerometer, gyroscope and ambient light). |
| Sleep diary - sleep onset latency | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | The time (minutes) it takes to fall asleep, higher scores indicate worse outcomes. |
| Sleep diary - number of awakenings | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Number of nocturnal awakenings, higher scores indicate worse outcomes |
| Sleep diary - sleep efficiency | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Sleep Efficiency (percentage)- higher scores indicate better outcomes, calculated as as the ratio of total sleep time to time in bed (multiplied by 100 to yield a percentage). |
| Sleep diary - time in bed | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Total time spent in bed (minutes). The score is interpreted in relation to total sleep time and sleep efficiency, |
| Sleep diary - wake after sleep onset | Daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Total time (minutes) spent awake after the first falling asleep until getting up to start the day. Higher scores indicate worse outcomes. |
| NRS - fatigue | Once daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Numeric Rating Scale for fatigue, measured on a 0-6 point scale. Higher scores indicate worse outcomes. |
| NRS - pain | Once daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Numeric Rating Scale for pain, measured on a 0-6 point scale. Higher scores indicate worse outcomes. |
| NRS - spasticity | Once daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Numeric Rating Scale for MS related spasticity, measured on a 0-6 point scale. Higher scores indicate worse outcomes. |
| NRS - Noctural Voiding | Once daily; from enrollment to the end of treatment at 18 weeks, with an exception of wash out periods. | Frequency of nocturnal voiding, measured on a 0-6 point scale. Higher scores indicate worse outcomes. |
Countries
Netherlands
Contacts
PRINCIPAL_INVESTIGATORRenger Witkamp, prof.dr.
Wageningen University
Outcome results
None listed