Mechanisms of Cannabidiol in Persons With MS: the Role of Sleep and Pain Phenotype

• ClinicalTrials.gov Identifier: NCT05269628
• Recruitment Status: Recruiting
• First Posted: March 8, 2022
• Last Update Posted: December 14, 2023
• Sponsor: Tiffany J. Braley, MD, MS
• Collaborator: National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): Tiffany J. Braley, MD, MS, University of Michigan

Study Description

Brief Summary:

The purpose of this research study is to compare the effects of cannabidiol (CBD), tetrahydrocannabinol (THC), or both, on sleep and pain in persons with multiple sclerosis (MS). Little is known about how CBD and/or THC may help sleep, reduce pain, or perhaps even treat pain through better sleep.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis; Sleep; Pain	Drug: Cannabidiol (CBD); Drug: Tetrahydrocannabinol (THC); Drug: Placebo CBD; Drug: Placebo THC	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 166 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Mechanisms of Cannabidiol (CBD) in Persons With Multiple Sclerosis (MS): the Role of Sleep and Pain Phenotype
• Actual Study Start Date: March 25, 2022
• Estimated Primary Completion Date: June 2026
• Estimated Study Completion Date: June 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cannabidiol (CBD); Epidiolex® doses will be 0.5 mL twice daily during the first seven days of active treatment and 1 mL twice daily (b.i.d.) for the remaining days of treatment. PLUS Placebo Tetrahydrocannabinol (TCH) capsules which contain no active ingredients. Matching placebo capsules will be taken twice per day in the same schedule and manner as active dronabinol.	Drug: Cannabidiol (CBD); Epidiolex® doses will be 0.5 mL twice daily during the first seven days of active treatment and 1 mL twice daily (b.i.d.) for the remaining treatment.; Other Name: Epidiolex®; Drug: Placebo THC; Placebo capsules will be taken twice per day in the same schedule and manner as active dronabinol.
Active Comparator: Tetrahydrocannabinol (THC); The drug dose will be 2.5 mg b.i.d. during the first seven days of active treatment, and 5 mg b.i.d. for the following days of active treatment. PLUS Placebo CBD (A matching placebo oral solution to Epidiolex® will be used that consists of all of the excipients in the active solution without the cannabidiol component). The placebo will be dosed in the same schedule and manner as active Epidiolex®.	Drug: Tetrahydrocannabinol (THC); The drug dose will be 2.5 mg b.i.d. during the first 7 days of active treatment, and 5 mg b.i.d. for the following treatment.; Other Name: Marinol®, dronabinol; Drug: Placebo CBD; Placebo solution will be taken twice per day, using the same dosing regimen as described for Epidiolex®.
Active Comparator: CBD + THC; Epidiolex® (CBD) doses will be 0.5 mL twice daily during the first seven days of active treatment and 1 mL twice daily (b.i.d.) for the remaining days of treatment. The THC dose will be 2.5 mg b.i.d. during the first seven days of active treatment, and 5 mg b.i.d. for the following days of active treatment.	Drug: Cannabidiol (CBD); Epidiolex® doses will be 0.5 mL twice daily during the first seven days of active treatment and 1 mL twice daily (b.i.d.) for the remaining treatment.; Other Name: Epidiolex®; Drug: Tetrahydrocannabinol (THC); The drug dose will be 2.5 mg b.i.d. during the first 7 days of active treatment, and 5 mg b.i.d. for the following treatment.; Other Name: Marinol®, dronabinol
Placebo Comparator: Placebo CBD + Placebo THC; Placebo CBD (A matching placebo oral solution to Epidiolex® will be used that consists of all of the excipients in the active solution without the cannabidiol component). The placebo will be dosed in the same schedule and manner as the active CBD. Placebo Tetrahydrocannabinol (TCH) capsules which contain no active ingredients. Matching placebo capsules will be taken twice per day in the same schedule and manner as active drug.	Drug: Placebo CBD; Placebo solution will be taken twice per day, using the same dosing regimen as described for Epidiolex®.; Drug: Placebo THC; Placebo capsules will be taken twice per day in the same schedule and manner as active dronabinol.

Outcome Measures

Primary Outcome Measures :

1. Mean change in sleep bout length [ Time Frame: Baseline, 12 weeks ]
   Measured with in-laboratory polysomnography, reported as average length of continuous bouts of sleep, for each sleep stage and total sleep (in minutes).
2. Change in Walsh Spectral Entropy [ Time Frame: Baseline, 12 weeks ]
   Measured with in-laboratory polysomnography, computed from EEG sleep stage data to quantify hypnogram regularity (dimensionless, values range from 0-1)
3. Change in Transition Entropy [ Time Frame: Baseline, 12 weeks ]
   Measured with in-laboratory polysomnography. Entropy measure computed from sleep stage transition matrix that quantifies hypnogram regularity (dimensionless, values range from 0-1)
4. Change of center of activity [ Time Frame: Baseline, 12 weeks ]
   Measured with in-laboratory polysomnography. Weighted mean temporal location over the night of all 30 second epochs scored as N3 and Rapid eye movement (REM) sleep
5. Change in sleep rhythmicity [ Time Frame: Baseline, 12 weeks ]
   Measured by actigraphy. Probability of being in the same sleep/wake state 24h apart
6. Change in sleep regularity [ Time Frame: Baseline, 12 weeks ]
   Measured by actigraphy in hours.
7. Change in sleep continuity and duration [ Time Frame: Baseline, 12 weeks ]
   Measured by actigraphy in minutes to obtain time in wakefulness after sleep onset (WASO) and total sleep time.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients with clinically definite MS (those who are on a disease modifying therapy must be on a stable dose without evidence of liver toxicity for at least 3 months);
2. Presence of chronic pain defined as moderate to severe pain for at least 3 months, based on a 0-10 numeric rating scale (NRS);
3. Willingness to maintain stable analgesic regimen during study period;
4. Recent serum aspartate transaminase, alanine transaminase, and bilirubin testing within 90 days of screening;

Exclusion Criteria:

1. Current shift work sleep disorder, or narcolepsy diagnosed with polysomnography and multiple sleep latency test;
2. History of MS relapse within the last 30 days prior to screening (participants will be considered eligible after the 30-day window);
3. Pain due to cancer;
4. Pregnancy or breastfeeding;
5. Current cannabinoid use (participants may be reconsidered for inclusion after 30-day washout) and/or unwillingness to abstain from cannabinoids in any form from 30 days prior to the study of the study drugs and until the last follow up phone call at the end of the study (30 - 37 days after taking the last dose of the study drug).
6. Unwillingness to use contraception from screening until the end of drug treatment
7. Current suicidal ideation (SI) with intent and/or plan; these individuals will be assessed by a study psychologist and referred for urgent mental health treatment as indicated;
8. Current severe depression as indicated by a PHQ-9 score of ≥ 17 that includes indicators of significant depressed mood (sum of items #1 and #2 ≥ 5).
9. History of mania or schizophrenia diagnosis
10. Known hypersensitivity to cannabinoids in general, or Epidiolex® or Dronabinol specifically or its excipients (e.g., sesame oil)
11. History of the following cardiovascular conditions: recent myocardial infarction or stroke (last 6 months prior to screening), unstable angina, left ventricular hypertrophy, mitral valve prolapses, severe coronary artery disease, NYHA class III or IV congestive heart failure.
12. History severe hepatic impairment (must have blood AST ≤ 2.0x ULN, ALT ≤ 2,0x ULN, and bilirubin ≤ 1.5x ULN within the last 90 days (AST, ALT, bilirubin testing will be required within 90 days of screening);
13. History of seizure disorder (recurrent, unprovoked seizures not explained by a known reversible cause) or history of certain types of head injury that could cause an increased risk of seizures;
14. History of prescription or illicit drug abuse (such as cocaine, amphetamine, methamphetamine, heroin);
15. Current risk for alcohol misuse as indicated by a score of ≥ 8 on the Alcohol Use Disorders Identification Test (AUDIT) self-report measure.
16. Current warfarin, valproate or clobazam use.
17. Current use of known moderate or strong inhibitors of CYP3A4 [topical ketoconazole, and temporary (<= 4 week) oral courses of clarithromycin, fluconazole and itraconazole will be allowed].
18. Current use of strong inducers of CYP3A4 or CYP2C19 (does not include glucocorticoids or modafinil/armodafinil, which are permitted),
19. Current use of moderate or strong inhibitors/inducers of CYP2C9, and narrow therapeutic index drugs (e.g., cyclosporine, amphotericin B).
20. Current use of known non-minor Sensitive CYP2C19 Substrates, with the exception of some proton pump inhibitors (e.g., esoprazole, omeprazole)), periodic self-limited courses of diazepam (e.g., for MRI sedation) and submaximal doses of some antidepressant class medications (e.g., citalopram, and escitalopram), which will be permitted by the discretion of the treating neurologist PI.
21. Refusal to avoid grapefruit or grapefruit products during the study treatment interval.
22. Current use of opioids (tramadol permitted).
23. Employed as a commercial driver or employed in an occupation that involves extreme heights or use of heavy machinery.
24. History of car crashes or near-crashes due to untreated sleepiness that has led to near-misses in the past 6 months.
25. Cognitive dysfunction as indicated by >=3 errors on the six-item cognitive screener
26. Expanded Disability Status Scale (EDSS) score >=8.0.
27. Blood pressure at screening above 180 mmHg systolic and/or 120 mmHg diastolic, or below 90 mmHg systolic and or 60 mmHg diastolic, or history of syncope related to orthostatic hypotension;
28. Resting heart rate at screening less than 50 bpm or greater than 100 bpm;
29. Any other treatment or medical, neurological, sleep, or psychiatric condition that, in the opinion of the investigators, could affect participant safety or eligibility.

Contacts and Locations

Contacts

Contact: David Johnson; 734-615-9650; johnsodj@umich.edu

Locations

United States, Michigan

University of Michigan; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: David Johnson 734-615-9650 johnsodj@umich.edu

Principal Investigator: Tiffany Braley

Sponsors and Collaborators

Tiffany J. Braley, MD, MS

National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Tiffany Braley; University of Michigan

More Information

• Responsible Party: Tiffany J. Braley, MD, MS, Associate Professor of Neurology, University of Michigan
• ClinicalTrials.gov Identifier: NCT05269628
• Other Study ID Numbers: HUM00190734; 1R01AT011341-01 ( U.S. NIH Grant/Contract )
• First Posted: March 8, 2022
• Last Update Posted: December 14, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tiffany J. Braley, MD, MS, University of Michigan:

Cannabidiol

Additional relevant MeSH terms:

Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Dronabinol; Cannabidiol; Anticonvulsants; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists