Cannabidiol for Postoperative Opioid Reduction in Primary Total Knee Arthroplasty

Osteoarthritis, Knee Clinical Trial

— CORK  

Official title:

Cannabidiol for Postoperative Opioid Reduction in Primary Total Knee Arthroplasty - a Randomized, Two by Two Factorial, Double-blind, Placebo-controlled Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06234631
• Other study ID #: HUM00239715
• Secondary ID: 1U01AR083132-01
• Status: Recruiting
• Phase: Phase 2
• Start date: March 13, 2024
• Est. completion date: January 2029

Study information

• Verified date: March 2024
• Source: University of Michigan
• Contact: Kendall Dubois
• Phone: 734-232-0324
• Email: kendalld[@]med.umich.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this study is to better understand how daily treatment with cannabidiol (CBD) affects the need for opioid pain medication, as well as pain, inflammation and other related symptoms, after knee replacement surgery. The information collected in this study is necessary to help understand whether CBD may be a useful medication before and/or after surgery. The study hypothesis is that CBD exerts opioid-sparing effects through anti-inflammatory, analgesic, and anxiolytic mechanisms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 380
• Est. completion date: January 2029
• Est. primary completion date: January 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Willing and able to read, understand, and sign the informed consent (English)
• Willingness to participate in all study measures and restrictions, including patient-reported outcomes and longitudinal follow-up
• Scheduled for surgery: primary total knee arthroplasty
• Primary diagnosis of osteoarthritis of the surgical knee
• Individuals of reproductive potential must agree to use acceptable birth control (defined in manual of operating procedures). This includes currently practicing an effective form of two types of birth control for women of childbearing potential, which are defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly from the screening visit until 28 days after the last study drug administration.
• Participants must also agree not to donate sperm or eggs during study drug administration
• Ability to take and to swallow the study medication and be willing to adhere to the treatment regimen
• Agreement to adhere to Lifestyle Considerations (see protocol) throughout study duration

Exclusion Criteria:

• Revision or bilateral total knee arthroplasty
• Individuals receiving or actively applying for worker's compensation or disability and other aspects associated with potential secondary gain
• Severe physical impairment or clinically significant illness (e.g., blindness, paraplegia)
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., current non-skin malignancies, solid organ transplant in the past year)
• Illicit drug use (other than cannabis). Unreported opioid use would be exclusionary but reported prescribed opioid use is allowed (e.g. patient denies opioid use but is found to be positive on the urine drug screen)
• Use of cannabis products in the past 30 days (self-report and confirmed with urinalysis). Note - may be rescreened with appropriate wash-out period (see protocol)
• High daily preoperative opioid dose
• Individuals with major neurological disorders, such as dementia, Parkinson's disease, cognitive impairment, epilepsy, history of traumatic brain injury/head injury, and seizures
• Individuals with significant illness (e.g., cancer) and/or clinically significant labs (e.g. labs measured by complete blood count (CBC) and basic chemistry with values meaningfully outside of the normal range [abnormal levels to be reviewed by the Principal Investigator or prescribing provider])
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study (e.g., psychosis, suicidal ideation; note that stable anxiety and depression are not exclusions)
• Pregnant or nursing women (total joint arthroplasty is typically not indicated in this group of patients)
• Self-reported liver cirrhosis
• Self-reported uncontrolled diabetes
• Self-reported active hepatitis (any etiology, including infectious, autoimmune, or alcohol-related)
• Blood pressure at screening above 180 millimeters of mercury (mmHg) systolic and/or 120 mmHg diastolic; if value exceeds the set point, potential participants will have repeat assessment within 5 minutes for up to two additional measurements.
• Resting heart rate at screening less than 50 beats per minute (bpm) or greater than 100 bpm; if value exceeds the set point, potential participants will have repeat assessment within 5 minutes for up to two additional measurements.
• Elevated liver enzymes and bilirubin (measured by blood test at screening)
• Serum total bilirubin = 2.5 milligrams (mg) per deciliter (dL) (mg/dL); or,
• Alanine transaminase (ALT) or Alanine transaminase (AST) = 3x upper limit normal (ULN); or,
• Alkaline phosphatase = 2x ULN
• Severe cardiovascular disease (e.g., current unstable angina, current congestive heart failure, or current severe valvular abnormalities) that is self-reported by patient or in medical record
• Current valproate, clobazam, or warfarin use per self-report or medical records
• Current use of strong inducers of cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19, or CYP2C19 substrates with a narrow therapeutic index
• Self-reported allergies to sesame oil, strawberries, opioids, or cannabis/cannabinoids
• Any impairment, activity, behavior, or situation that in the judgment of the study team would prevent satisfactory completion of the study protocol
• Self-reported severe side effects to opioids precluding the use of opioids for post-surgical pain and/or clear plan not to use any opioids after surgery
• Participation in other clinical trials over the course of this study

Related Conditions & MeSH terms

• Knee Replacement Surgery
• Osteoarthritis, Knee

Intervention

Drug:
• Epidiolex oral solution
Participants assigned to CBD will take the medication one hour before or two hours after eating a meal. If participants can't tolerate the full-strength dose, the participant can decrease the dosing to 0.75 milliliter twice a day. If this is still not well tolerated, dosing can further be decreased to 0.75 milliliter once per day in the evening.

Other:
• Placebo
Participants will be instructed to take one hour before or two hours after eating a meal.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Henry Ford Health System	Detroit	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Chad Brummett	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total postoperative opioid consumption (measured in oral morphine equivalents) during the 28 days after surgery		28 days (after surgery)
Secondary	The number of treatment-emergent adverse events (TEAEs)		Five weeks of study treatment (Days 1 - 36)
Secondary	Proportion of participants with at least one treatment-emergent adverse events (TEAEs)		Five weeks of study treatment (Days 1 - 36)
Secondary	The Number of serious adverse events (SAEs)		Five weeks of study treatment (Days 1 - 36)
Secondary	Proportion of participants with at least one serious adverse event (SAE)		Five weeks of study treatment (Days 1 - 36)
Secondary	Number of deaths due to any cause		Five weeks of study treatment (Days 1 - 36)
Secondary	Frequency of deaths due to any cause		Five weeks of study treatment (Days 1 - 36)
Secondary	Proportion of participants that prematurely discontinue study medications because of TEAE		Five weeks of study treatment (Days 1 - 36)
Secondary	Percentage of participants that meet or exceed the thresholds of liver enzymes	Protocol eligibility exclusion includes: Serum total bilirubin = 2.5 milligrams (mg) per deciliter (dL) (mg/dL); Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 3x upper limit normal (ULN); Alkaline phosphatase = 2x ULN	Five weeks of study treatment (Days 1 - 36)
Secondary	Total postoperative opioid consumption (measured in oral morphine equivalents (OME)) during the 28 days after surgery and the pre-operative phase	This is the same outcome as the primary outcome but this secondary endpoint will address the effect of pre-operatively administered CBD and Placebo.	36 days (pre-post operative)
Secondary	Worst pain intensity for surgical site between groups during 7-day epochs from day of surgery through end of active intervention	This is a scale from 0-10 (numerical rating scale, 10 worse pain) in which the participants rate the worse pain.	Days 8-36 (post-surgery)
Secondary	Anxiety based on the Patient-Reported Outcomes Measurement Information System (PROMIS)-29+2 profile v2.1	There are 4-questions on this survey regarding anxiety. Participants answer the questions from never (1) to always (5). Scores range from 4-20 with a higher score indicating higher levels of anxiety.	pre-op days 1-7
Secondary	Anxiety based on the Patient-Reported Outcomes Measurement Information System (PROMIS)-29+2 profile v2.1	There are 4-questions on this survey regarding anxiety. Participants answer the questions from never (1) to always (5). Scores range from 4-20 with a higher score indicating higher levels of anxiety.	post-op days 8-36
Secondary	Sleep disturbance on the PROMIS-29+2 v.2.1	There are 4-questions on this survey regarding sleep disturbance with a likert type scale.; Scores range from 4-20 with a higher score indicating higher levels of sleep disturbance.	pre-op days 1-7
Secondary	Sleep disturbance on the PROMIS-29+2 v.2.1	There are 4-questions on this survey regarding sleep disturbance with a likert type scale.; Scores range from 4-20 with a higher score indicating higher levels of sleep disturbance.	post-op days 8-36
Secondary	Change in Interleukin-6 (IL-6) levels in the blood (University of michigan site only)		Baseline, up to day 36 (post -surgery)