Evaluation of Cannabidiol on Sleep Quality in Multiple Sclerosis Patients with Insomnia: A Randomized, Placebo-Controlled N-of-1 Trial Series

Trial ID: 2024-518280-35-00
Protocol: NL83212.091.22
Sponsor: Wageningen Research Stichting

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Diseases & Conditions

Insomnia

Objectives

The primary objective of the CanISleepinMS Study is to investigate the effect of **cannabidiol (CBD)** on sleep quality in patients with multiple sclerosis who experience impaired sleep. This is clinically relevant as sleep disturbances are a common issue in multiple sclerosis, impacting patients' quality of life and potentially exacerbating other symptoms. By evaluating the efficacy of CBD, the study aims to provide insights into potential therapeutic options for improving sleep quality in this patient population.

Participants

The clinical trial investigating the effect of CBD on patients with **multiple sclerosis** (MS) and impaired sleep quality involves a study population that includes both male and female participants. The age range of the participants is not specified, but the minimum age for inclusion is 18 years. Participants are required to have a confirmed diagnosis of MS, as well as a diagnosis of insomnia due to chronic impairment of sleep quality. The trial does not involve a vulnerable population. Participants must maintain a stable lifestyle, including diet and physical activity, and refrain from using new sleep-facilitating treatments or certain dietary components that could affect CBD bioavailability. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed to evaluate the effect of **cannabidiol** (CBD) on sleep quality in patients with multiple sclerosis (MS) who experience insomnia. This study is structured as a series of 15 randomized, placebo-controlled N-of-1 trials, ensuring a robust and scientifically sound methodology. The trial is double-blind, meaning neither the participants nor the researchers know who is receiving the active treatment or the placebo, which helps to eliminate bias. The trial is expected to commence recruitment on June 4, 2024, and conclude by August 1, 2025, with each participant involved for a maximum treatment period of three months.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of MS, a complaint of chronic sleep impairment, and an Expanded Disability Status Scale (EDSS) score of less than 7.5. During this visit, blood samples will be collected, and participants will be briefed on the study requirements, including the use of the Neurokeys app and maintaining a stable lifestyle. Follow-up visits will occur throughout the treatment phase, during which participants will continue to provide data via a daily digital diary and undergo additional blood draws. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

Participants are expected to adhere to specific conditions, such as refraining from new sleep-facilitating treatments, cannabis products, and certain dietary components that may affect CBD bioavailability. Any deviation from these conditions, significant adverse events, or withdrawal of consent may lead to early termination from the study. The primary endpoint of the trial is the Insomnia Severity Index (ISI) questionnaire, while secondary endpoints include sleep-related outcomes recorded in a diary, such as Sleep Onset Latency (SOL) and Total Sleep Time (TST), as well as non-sleep outcomes like nocturnal voiding and adverse events. The trial is conducted under the authorization of the relevant regulatory bodies, ensuring compliance with ethical and scientific standards.

Treatment

The clinical trial involves the administration of **Clinican CBD 10% oil**, an investigational medication formulated as an **oromucosal solution**. The active substance in this formulation is **cannabidiol** (CBD), a chemical compound. The solution is administered via the **oral route**. The maximum daily dose is 300 mg, with a total maximum dose of 300 mg over the treatment period. The treatment period is limited to a maximum of 3 days. The product is not a paediatric formulation and is classified under the sponsor product code "CLINICAN CBD 10% OIL". The product is manufactured by Wageningen Research Stichting and is authorized under the marketing authorization number NL/H21/2026847.

In addition to the experimental treatment, the study utilizes an **investigational placebo**. The placebo is used to maintain the integrity of the double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is not specified in terms of pharmaceutical form, active substance, or route of administration, and it is not a paediatric formulation. The placebo is also authorized under the marketing authorization number NL/H21/2026847.

A **run-in placebo** is also employed in the study. Similar to the investigational placebo, the run-in placebo lacks specific details regarding its pharmaceutical form, active substance, or route of administration. It serves as a control measure to establish baseline conditions before the administration of the active investigational product. The run-in placebo is not a paediatric formulation and shares the same marketing authorization number, NL/H21/2026847.

Efficacy

Efficacy in the clinical trial titled "The CanISleepinMS Study: Effect of cannabidiol (CBD) on sleep quality in patients with multiple sclerosis" will be assessed using both primary and secondary endpoints. The primary endpoint is the Insomnia Severity Index (ISI) questionnaire, which will evaluate the severity of insomnia symptoms in participants. Secondary endpoints include a diary with sleep-related outcomes such as Sleep Onset Latency (SOL), number of awakenings (NA), Wake time After Sleep Onset (WASO), Total Sleep Time (TST), and Sleep Efficiency (SE). Additionally, daily recorded non-sleep outcomes will be assessed, including the number of nocturnal voiding events and any potentially occurring adverse events (AEs). The Neurokeys app will also be utilized, along with the administration of the ESS, FSS, and CIS-F questionnaires.

Inclusion and Exclusion Criteria

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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. BMI is used as a proxy for a participant’s fat content; as CBD accumulates in fatty tissue, a higher fat content may prolong the elimination half-life of CBD
Elevated levels of transaminases (ALT, AST) 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
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 non-pharmaceutical 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. These citrus fruits contain furanocoumarins which irreversibly inhibit CYP3A4 enzymes. Sweet oranges as navel or Valencia do not inhibit CYP3A4 activity
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

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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 (ALT, AST) 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 Clinical Cannabis Care pharmacy
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: 1) Drugs of which their biotransformation is primarily dependent on the cytochrome P450 enzymes CYP2C19 and CYP3A 2) Drugs that are inducers or inhibitors of enzymes of which CBD is a substrate: CYP2C19, CYP3A4.