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Cannabinoid Interactions With Central and Peripheral Pain Mechanisms in Osteoarthritis of the Knee

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04992624
Recruitment Status : Recruiting
First Posted : August 5, 2021
Last Update Posted : November 1, 2022
Sponsor:
Collaborators:
National Center for Complementary and Integrative Health (NCCIH)
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Richard Harris, University of Michigan

Brief Summary:

This clinical trial is being done to better understand how daily treatment with Tetrahydrocannabinol (THC), Cannabidiol (CBD), or the combination of CBD plus THC affects knee osteoarthritis pain and other related symptoms.

Consented participants will have a screening period and visit (up to 30 days to treatment start). If participants pass the screening phase, they will be randomly assigned to take one of the investigational study drugs. For this study, participants will not know when or if they are taking CBD, THC, THC plus CBD, and when or if taking placebo.

Clinical pain will be assessed at multiple times throughout the study, and eligibility will be re-assessed at two weeks into the treatment period. It is possible that subjects will not be able to participate in the study after 14 days of of treatment. The treatment period will take approximately 16 weeks and then a follow-up period for approximately 2 weeks. In addition to treatment, participants will have clinical assessments, blood draws, questionnaires, daily pain diaries, sensory testing, as well as have functional connectivity magnetic resonance imaging (fcMRI).


Condition or disease Intervention/treatment Phase
Osteoarthritis, Knee Osteoarthritis of the Knee Drug: Placebo Drug: Cannabidiol (CBD) Drug: Tetrahydrocannabinol (Marinol® or generic equivalent (e.g., dronabinol) Phase 2

Detailed Description:

The study hypothesizes that:

  • CBD alone will exert a peripheral anti-inflammatory effect by decreasing levels of Interleukin (IL)-6
  • THC alone will modify central nervous system (CNS) pain via decreasing insula to Default Mode Network (DMN) connectivity
  • CBD plus THC will do both.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a single-site, 2x2 factorial double-blind, randomized clinical trial with 200 participants (160 completers).
Masking: Double (Participant, Investigator)
Masking Description: Some of the treatment phase will be blinded by the study team.
Primary Purpose: Basic Science
Official Title: Cannabinoid Interactions With Central and Peripheral Pain Mechanisms in Osteoarthritis of the Knee
Actual Study Start Date : February 22, 2022
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : July 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

Arm Intervention/treatment
Placebo Comparator: Placebo Drug: Placebo

Placebo drug will be taken similarly to the THC and CBD and be matched to keep the trial blinded.

Participants will be instructed to eat a meal or snack greater than one hour after taking study drug.


Experimental: Cannabidiol (CBD)
Up to 150 mg/day.
Drug: Cannabidiol (CBD)

Epidiolex doses will be 0.37 milliliter (mL) for seven days of treatment and then 0.75 mL two times a day (b.i.d) for the remaining days of this treatment.

Participants will be instructed to eat a meal or snack greater than one hour after taking study drug.

Other Name: Epidiolex

Experimental: Tetrahydrocannabinol (THC)
Up to 10 mg/day.
Drug: Tetrahydrocannabinol (Marinol® or generic equivalent (e.g., dronabinol)

Dronabinol Capsules doses will be 2.5 mg b.i.d. for seven days of treatment and then 5 mg b.i.d. for the remaining days of this treatment.

Participants will be instructed to eat a meal or snack greater than one hour after taking study drug.

Other Name: Dronabinol

Experimental: CBD plus THC
Up to 150 mg/day CBD plus up to 10 mg/day THC.
Drug: Cannabidiol (CBD)

Epidiolex doses will be 0.37 milliliter (mL) for seven days of treatment and then 0.75 mL two times a day (b.i.d) for the remaining days of this treatment.

Participants will be instructed to eat a meal or snack greater than one hour after taking study drug.

Other Name: Epidiolex

Drug: Tetrahydrocannabinol (Marinol® or generic equivalent (e.g., dronabinol)

Dronabinol Capsules doses will be 2.5 mg b.i.d. for seven days of treatment and then 5 mg b.i.d. for the remaining days of this treatment.

Participants will be instructed to eat a meal or snack greater than one hour after taking study drug.

Other Name: Dronabinol




Primary Outcome Measures :
  1. Default mode network (DMN) to insula connectivity via functional connectivity magnetic resonance imaging (fcMRI) [ Time Frame: Day 15, and approximately day 99 of treatment ]
    Functional connectivity difference maps of insula to DMN connectivity using Independent Component Analysis and seed based connectivity. A reduction in the Z-score as a result of treatment will serve as the primary outcome measure.

  2. Change in pre-post measurements of inflammatory marker IL-6. [ Time Frame: Day 15, and approximately day 99 of treatment ]
    Serum IL-6



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to read and speak English to allow for written informed consent, phenotyping, and patient-reported outcomes measures
  • Diagnosis of osteoarthritis (OA) of the knee by a medical provider (confirmed by checking medical records)
  • Chronic knee pain, defined as moderate to severe knee pain that is greater or equal to (≥) 4 on average using a 0-10 numeric rating scale (NRS) for ≥ 6-month duration
  • No use of cannabis or CBD in the past in the month prior to study enrollment as per self-report
  • Fibromyalgia (FM) Survey Criteria score available. The questionnaire will be assessed by the research team for scoring. We will recruit enough patients to satisfy the spectrum of FM scores in four quartiles based on our previously existing data. Once a quartile is filled (approximately 40 patients enrolled), then we will not include more people from that quartile.
  • Right-handed
  • Self-reported normal visual acuity or correctable (with corrective lenses- glasses or contacts) to at least 20/40 for reading instructions in the MRI and visual sensitivity testing
  • No contraindications to magnetic resonance imaging (MRI) (for example (e.g.), metal implants)
  • Able to lie still on their back for 1-1.5 hours during MRI
  • Willingness to refrain from pain medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen for 12 hours prior to neuroimaging and Quantitative Sensory Testing (QST)
  • Willingness to refrain from alcohol and nicotine before QST and neuroimaging (alcohol and nicotine consumption is allowed after testing is completed)
  • Willingness to refrain from physical activity or exercise that would cause significant muscle and/or joint soreness for 48 hours prior to testing (routine exercise or activity that does not lead to soreness is acceptable)
  • Willingness to maintain a stable treatment regimen for chronic knee OA pain during the clinical trial (e.g., not initiating a new course of physical therapy)
  • No use of adjunctive pain medications or stable chronic daily use of adjunctive pain medications (excluding opioids)
  • Willingness to avoid grapefruit juice or food products for the duration of the study;
  • Females of reproductive potential must agree to use acceptable birth control from the screening visit and until the completion study drug administration. Sexually active male participants and/or their female partners must agree to use effective contraception during study drug treatment of the male participant. Male participants may also agree not to donate sperm during study drug treatment

Exclusion Criteria:

  • Individuals who are actively applying for or in litigation for compensation or disability and other aspects associated with potential secondary gain per self-report
  • Inability to provide written informed consent
  • Previous total knee arthroplasty
  • Planned total knee arthroplasty within the time frame of the study
  • Severe physical impairment (e.g., blindness, deafness, paraplegia)
  • Co-morbid medical conditions that may significantly impair physical functional status (e.g., history of non-skin malignancy, or autoimmune disorder)
  • Use of cannabis or CBD in the past month per self-report and/or drug screen
  • Current opioid use (excepting tramadol) per self-report and/or drug screen
  • Current valproate, clobazam, or warfarin use per self-report or medical records
  • Current use of moderate or strong inhibitors of cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19, strong inducers of CYP3A4 or CYP2C19, moderate or strong inhibitors/inducers of CYP2C9, and narrow therapeutic index drugs (e.g., cyclosporine, amphotericin B). Participants will also not be allowed to start using these drugs during the study period if they wish to stay in the study
  • Self-reported allergies to sesame oil or cannabis/cannabinoids
  • Self-reported medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study (e.g., schizophrenia, malignancy, psychosis, suicidal ideation, history of substance abuse; note that stable anxiety and depression are not exclusions)
  • Pregnant or nursing
  • Liver failure
  • Self-reported liver cirrhosis
  • Active diagnosis or current symptoms of hepatitis by self-report
  • Self-reported uncontrolled diabetes
  • Blood pressure at screening above 180 systolic and/or 120 diastolic
  • Resting heart rate at screening less than 50 beats per minute (bpm) or greater than 100 bpm;
  • Elevated liver enzymes and bilirubin (measured via blood test at screening):

    • Serum total bilirubin ≥ 2.5 milligrams per deciliter (mg/dL); or,
    • Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 3x upper limit normal (ULN); or,
    • Alkaline phosphatase ≥ 2 times ULN
  • Severe cardiovascular disease (examples: history of myocardial infarction, unstable angina, severe coronary artery disease, congestive heart failure, or severe valvular abnormalities) that is self-reported by patient or by medical record
  • Severe claustrophobia precluding MRI
  • Unable to fit in or lie comfortably in MRI
  • Diagnosed peripheral neuropathy
  • Diagnosed or self-reported epilepsy or history of seizures
  • Current head injury or history of head injury (e.g., traumatic brain injury)
  • Any impairment, activity, behavior, or situation that in the judgment of the study team would prevent satisfactory completion of the study protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04992624


Contacts
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Contact: Chelsea Merillat 734-998-7023 cmerilla@umich.edu
Contact: Richard Harris, PhD 734-998-6996 reharris@umich.edu

Locations
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United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Anna Piasecki    734-998-7020    panna@umich.edu   
Sponsors and Collaborators
Richard Harris
National Center for Complementary and Integrative Health (NCCIH)
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Richard Harris, PhD University of Michigan
Principal Investigator: Steve Harte, PhD University of Michigan
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Responsible Party: Richard Harris, Associate Professor of Anesthesiology and Associate Professor of Internal Medicine, University of Michigan
ClinicalTrials.gov Identifier: NCT04992624    
Other Study ID Numbers: HUM000180986
1R01AT010381-01A1 ( U.S. NIH Grant/Contract )
1K01DA049219-01A1 ( U.S. NIH Grant/Contract )
First Posted: August 5, 2021    Key Record Dates
Last Update Posted: November 1, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Richard Harris, University of Michigan:
Cannabidiol
Tetrahydrocannabinol
Additional relevant MeSH terms:
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Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic 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