Endometriosis, CBD, Pelvic Pain
Conditions
Keywords
endometriosis, CBD, pelvic pain
Brief summary
The investigators are looking to conduct a study looking at the effects of cannabidiol (CBD) in patients with endometriosis. It is believed that CBD will improve both pain and quality of life. The study will last a total of 12 weeks and involve several onsite visits in addition to daily pain assessments.
Detailed description
The proposal is to conduct a randomized double-blind placebo-controlled pilot study to evaluate the effectiveness of cannabidiol on the management of endometriosis-related pain. Subjects will be pre-screened from new and existing patients as well as from referral sites for the diagnosis of endometriosis. Potential subjects will be pre-screened for moderate to severe endometriosis associated pain (VAS \> 3) greater than 6 months. Those meeting all inclusion and exclusion criteria that who are willing to participate will receive a detailed history and physical exam, appropriate bloodwork and undergo informed consented at the Screening Visit. Baseline survey data will be collected. During Screening, the patient's will be asked to complete their daily electronic diaries and screened for daily reporting adherence. Randomized subjects will receive either (1) placebo (2) low dose CBD (3) high dose CBD. This study will include an 8-week intervention period during which subjects will be asked to record daily electronic VAS scores, pain medication use and a number of other parameters. Subjects will return at week 12 for a 4 week post-treatment visit, where they can also chose to enroll in an optional pharmacokinetic study. Participants will complete the Endometriosis Health Profile-30 (EHP-30), Patient Global Assessments (PGAs), the Patient Global Impression of Change (PGIC) surveys and, if partnered and sexually active, the Female Sexual Function Index at various time points. Patients will also have bloodwork done to assess for circulating markers of inflammation, circulating CBD concentration levels and liver dysfunction throughout the study duration. Subjects will be screened for side effects and asked to record pain medication use throughout the duration of the study. Study drug compliance will be assessed. At the completion of the study, all subjects will be offered the opportunity to do pharmacokinetic testing with sublingual CBD until a maximum number of 4 patients are enrolled. The testing will include 24 hours of monitoring with sequential blood draws to determine the pharmacokinetic parameters of sublingual CBD after administration and one salivary pH. They will be discharged at 24 hours and asked to return to the clinic at 48 hours for one final lab draw.
Interventions
Cannabis is a well-known plant that contains more than 500 identified phytochemicals of which over 100 are cannabinoids. The most widely studied is 9-tetrahydrocannabinol (9-THC), which is the major psychoactive component of Cannabis, but Cannabidiol (CBD) has been increasingly favored for its reduced side effect profile and potential health benefits. CBD was first isolated from Cannabis in the 1940s. CBD, unlike 9-THC, does not bind to CB1 and CB2 receptors, which accounts for its lack of typical psychotropic effects, but is still appears to work via alternative mechanisms via the endocannabinoid system.
Norethindrone is a form of progesterone, a female hormone important for regulating ovulation and menstruation.
OTHERPlacebo
a substance or treatment which is designed to have no therapeutic value
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind of study team (PI, Sub-I's and all research staff) and subjects. Randomization will be completed by Investigational Pharmacy and will keep the blind.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
1. Females ages 18-45 years at the time of enrollment 2. A surgical diagnosis with direct visualization and/or histopathologic confirmation of endometriosis with associated moderate to severe endometriosis related pain ( \> 3 on a VAS) 3. Is not expected to undergo gynecological surgery or other surgical procedure for treatment of endometriosis during the study period 4. Agrees to use approved contraception during the entire study if not surgically sterile 5. Patients using oral contraceptives, vaginal ring, injectable progesterone and/or GnRH agonists/antagonist for contraception and/or management of endometriosis, can be included if both they and their primary provider agree to stopping their medication and transitioning to Norethindrone acetate (NETA) as the primary treatment of endometriosis throughout the study period. 6. Patients using Long-acting reversible contraceptives (LARCs) for contraception and/or management of endometriosis can be included if both they and their primary provider agree to initiate Norethindrone (NETA) as the primary treatment of endometriosis throughout the study period
Exclusion criteria
1. Women that are pregnant, breastfeeding or trying to conceive 2. Women with chronic daily opioid use and any chronic pain or frequently reoccurring pain condition, other than endometriosis, that is treated with opioids for \> 14 days per month. 3. Women that are currently using Cannabis based products or have used them within 30 days of enrollment 4. Non-English speaking or inability to read and understand English 5. Women with a BMI \> 35 kg/m2 6. Women with known liver disease, such as hepatitis, or with screening LFTS (AST/ALT) \> 3 times above the upper limits of normal (ULN) in the past year 7. Women with chronic alcohol use (defined as \> 3 drinks per day, averaged over one week) 8. Women with chronic use of drugs (defined as \> 10 days/month) that cause somnolence/sedation such as benzodiazepines or Central Nervous System (CNS) depressants that are unwilling or unable to discontinue the medications for the washout period and the duration of the study 9. Women who are currently taking Clobazam or Valproate and are unwilling/unable to discontinue the medication for the washout period and the duration of the study 10. Women with suicidal ideation or uncontrolled depression within the past year 11. Known history of or suspected breast cancer on screening physical exam 12. History of or active deep venous thrombosis or pulmonary embolism 13. History of or active arterial thromboembolic event (e.g. stroke, myocardial infarction) 14. Multiple (\> 3) risk factors for arterial vascular disease (e.g. uncontrolled hypertension, diabetes mellitus, hypercholesterolemia, obesity and smoking) 15. Current use of a progestin-containing contraceptive implant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Score Area Under the Curve (AUC) | 8 weeks | Pain will be self-reported daily using the Visual Analog Scale, a 100mm horizontal line on which the patient's pain intensity is represented by a point between the extremities of 0 (no pain) and 100 (worst pain). Although the daily collection is based on the 0-100 point scale, the primary study endpoint is calculated as the area under the curve per patient using the trapezoidal rule, with an AUC range per patient of 0-5600 over 8 weeks. |
Countries
United States
Participant flow
Pre-assignment details
Between screening and randomization, subjects entered a run-in phase collecting daily electronic diaries. Subjects were excluded from randomization if they were not at least 80% adherent with completion of the daily diaries.
Participants by arm
| Arm | Count |
|---|---|
| Group A - Placebo Norethindrone acetate (5mg daily) + Placebo
Norethindrone Acetate: Norethindrone is a form of progesterone, a female hormone important for regulating ovulation and menstruation.
Placebo: a substance or treatment which is designed to have no therapeutic value | 4 |
| Group B - Low Dose CBD Norethindrone acetate (5mg daily) + Low dose CBD (10mg sublingual daily)
Cannabidiol (CBD) Extract: Cannabis is a well-known plant that contains more than 500 identified phytochemicals of which over 100 are cannabinoids. The most widely studied is 9-tetrahydrocannabinol (9-THC), which is the major psychoactive component of Cannabis, but Cannabidiol (CBD) has been increasingly favored for its reduced side effect profile and potential health benefits. CBD was first isolated from Cannabis in the 1940s. CBD, unlike 9-THC, does not bind to CB1 and CB2 receptors, which accounts for its lack of typical psychotropic effects, but is still appears to work via alternative mechanisms via the endocannabinoid system.
Norethindrone Acetate: Norethindrone is a form of progesterone, a female hormone important for regulating ovulation and menstruation. | 3 |
| Group C - High Dose CBD Norethindrone acetate (5mg daily) + High dose CBD (20mg sublingual daily)
Cannabidiol (CBD) Extract: Cannabis is a well-known plant that contains more than 500 identified phytochemicals of which over 100 are cannabinoids. The most widely studied is 9-tetrahydrocannabinol (9-THC), which is the major psychoactive component of Cannabis, but Cannabidiol (CBD) has been increasingly favored for its reduced side effect profile and potential health benefits. CBD was first isolated from Cannabis in the 1940s. CBD, unlike 9-THC, does not bind to CB1 and CB2 receptors, which accounts for its lack of typical psychotropic effects, but is still appears to work via alternative mechanisms via the endocannabinoid system.
Norethindrone Acetate: Norethindrone is a form of progesterone, a female hormone important for regulating ovulation and menstruation. | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Group A - Placebo | Group B - Low Dose CBD | Group C - High Dose CBD | Total |
|---|---|---|---|---|
| Age, Continuous | 31.7 years STANDARD_DEVIATION 6.2 | 24.4 years STANDARD_DEVIATION 7.3 | 28.9 years STANDARD_DEVIATION 5.4 | 28.7 years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 4 | 2 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Pain Score Area Under the Curve (AUC)
Pain will be self-reported daily using the Visual Analog Scale, a 100mm horizontal line on which the patient's pain intensity is represented by a point between the extremities of 0 (no pain) and 100 (worst pain). Although the daily collection is based on the 0-100 point scale, the primary study endpoint is calculated as the area under the curve per patient using the trapezoidal rule, with an AUC range per patient of 0-5600 over 8 weeks.
Time frame: 8 weeks
Population: Subjects who completed the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - Placebo | Pain Score Area Under the Curve (AUC) | 2254 score on a scale*days |
| Group B - Low Dose CBD | Pain Score Area Under the Curve (AUC) | 2211 score on a scale*days |
| Group C - High Dose CBD | Pain Score Area Under the Curve (AUC) | 1042 score on a scale*days |