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: March 31, 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

Tracking Information

• First Submitted Date: February 13, 2022
• First Posted Date: March 8, 2022
• Last Update Posted Date: March 31, 2023
• Actual Study Start Date: March 25, 2022
• Estimated Primary Completion Date: June 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2022)

• 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).
• 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)
• 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)
• 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
• Change in sleep rhythmicity [ Time Frame: Baseline, 12 weeks ]
  Measured by actigraphy. Probability of being in the same sleep/wake state 24h apart
• Change in sleep regularity [ Time Frame: Baseline, 12 weeks ]
  Measured by actigraphy in hours.
• 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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mechanisms of Cannabidiol in Persons With MS: the Role of Sleep and Pain Phenotype
• Official Title: Mechanisms of Cannabidiol (CBD) in Persons With Multiple Sclerosis (MS): the Role of Sleep and Pain Phenotype
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Supportive Care

Condition

• Multiple Sclerosis
• Sleep
• Pain

Intervention

• 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
• 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.

Study Arms

• 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.

  Interventions:

  • Drug: Cannabidiol (CBD)
  • Drug: Placebo THC
• 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®.

  Interventions:

  • Drug: Tetrahydrocannabinol (THC)
  • Drug: Placebo CBD
• Active Comparator: CBD + THC
  Interventions:

  • Drug: Cannabidiol (CBD)
  • Drug: Tetrahydrocannabinol (THC)
• Placebo Comparator: Placebo CBD + Placebo THC
  Interventions:

  • Drug: Placebo CBD
  • Drug: Placebo THC

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 2, 2022): 166
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2026
• Estimated Primary Completion Date: June 2026 (Final data collection date for primary outcome measure)

Eligibility 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 Patient Health Questionnaire (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. Severe cardiovascular disease (examples: stroke, myocardial infarction, unstable angina, severe coronary artery disease, congestive heart failure, or severe valvular abnormalities)
12. History severe hepatic impairment (must have blood alanine aminotransferase (AST) ≤ 2.0x upper limit of normal (ULN), alanine transaminase (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 and CYP2C19 [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 Sensitive CYP2C19 Substrates, with the exception of some proton pump inhibitors (esomeprazole, omeprazole, and pantoprazole), imipramine, clomipramine, periodic self-limited courses of diazepam (e.g., for MRI sedation) and submaximal doses of some antidepressant class medications (amitriptyline, citalopram, and escitalopram), which will be permitted by the discretion of the treating neurologist principal investigator.
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 sleepiness.
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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05269628
• Other Study ID Numbers: HUM00190734; 1R01AT011341-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Tiffany J. Braley, MD, MS, University of Michigan
• Original Responsible Party: Same as current
• Current Study Sponsor: Tiffany J. Braley, MD, MS
• Original Study Sponsor: Same as current
• Collaborators: National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Tiffany Braley; University of Michigan

• PRS Account: University of Michigan
• Verification Date: March 2023