Cannabidiol and Management of Endometriosis Pain

NCT04527003 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: STUDY00013752
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Endometriosis; CBD; Pelvic Pain

Keywords

endometriosis; CBD; pelvic pain

Outcome Measures

Primary Outcomes (1)

• 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.

  8 weeks

Study Arms (3)

Group A - Placebo

PLACEBO COMPARATOR

Norethindrone acetate (5mg daily) + Placebo

Drug: Norethindrone Acetate; Other: Placebo

Group B - Low Dose CBD

ACTIVE COMPARATOR

Norethindrone acetate (5mg daily) + Low dose CBD (10mg sublingual daily)

Drug: Cannabidiol (CBD) Extract; Drug: Norethindrone Acetate

Group C - High Dose CBD

ACTIVE COMPARATOR

Norethindrone acetate (5mg daily) + High dose CBD (20mg sublingual daily)

Drug: Cannabidiol (CBD) Extract; Drug: Norethindrone Acetate

Interventions

Cannabidiol (CBD) Extract DRUG

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.

Group B - Low Dose CBD; Group C - High Dose CBD

Norethindrone Acetate DRUG

Norethindrone is a form of progesterone, a female hormone important for regulating ovulation and menstruation.

Group A - Placebo; Group B - Low Dose CBD; Group C - High Dose CBD

Placebo OTHER

a substance or treatment which is designed to have no therapeutic value

Group A - Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Gender Eligibility Details: Females ages 18-45 years at the time of enrollment who have a surgical diagnosis with direct visualization and/or histopathologic confirmation of endometriosis with associated moderate to severe endometriosis related pain
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Females ages 18-45 years at the time of enrollment
• A surgical diagnosis with direct visualization and/or histopathologic confirmation of endometriosis with associated moderate to severe endometriosis related pain ( \> 3 on a VAS)
• Is not expected to undergo gynecological surgery or other surgical procedure for treatment of endometriosis during the study period
• Agrees to use approved contraception during the entire study if not surgically sterile
• 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.
• 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

You may not qualify if:

• Women that are pregnant, breastfeeding or trying to conceive
• 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.
• Women that are currently using Cannabis based products or have used them within 30 days of enrollment
• Non-English speaking or inability to read and understand English
• Women with a BMI \> 35 kg/m2
• 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
• Women with chronic alcohol use (defined as \> 3 drinks per day, averaged over one week)
• 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
• 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
• Women with suicidal ideation or uncontrolled depression within the past year
• Known history of or suspected breast cancer on screening physical exam
• History of or active deep venous thrombosis or pulmonary embolism
• History of or active arterial thromboembolic event (e.g. stroke, myocardial infarction)
• Multiple (\> 3) risk factors for arterial vascular disease (e.g. uncontrolled hypertension, diabetes mellitus, hypercholesterolemia, obesity and smoking)
• Current use of a progestin-containing contraceptive implant

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead

Study Sites (1)

Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Related Publications (17)

• Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.

  PMID: 22819144 BACKGROUND

• Giudice LC, Kao LC. Endometriosis. Lancet. 2004 Nov 13-19;364(9447):1789-99. doi: 10.1016/S0140-6736(04)17403-5.

  PMID: 15541453 BACKGROUND

• Behera M, Vilos GA, Hollett-Caines J, Abu-Rafea B, Ahmad R. Laparoscopic findings, histopathologic evaluation, and clinical outcomes in women with chronic pelvic pain after hysterectomy and bilateral salpingo-oophorectomy. J Minim Invasive Gynecol. 2006 Sep-Oct;13(5):431-5. doi: 10.1016/j.jmig.2006.05.007.

  PMID: 16962527 BACKGROUND

• Rafique S, Decherney AH. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017 Sep;60(3):485-496. doi: 10.1097/GRF.0000000000000292.

  PMID: 28590310 BACKGROUND

• Lamvu G, Soliman AM, Manthena SR, Gordon K, Knight J, Taylor HS. Patterns of Prescription Opioid Use in Women With Endometriosis: Evaluating Prolonged Use, Daily Dose, and Concomitant Use With Benzodiazepines. Obstet Gynecol. 2019 Jun;133(6):1120-1130. doi: 10.1097/AOG.0000000000003267.

  PMID: 31135725 BACKGROUND

• Fasinu PS, Phillips S, ElSohly MA, Walker LA. Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents. Pharmacotherapy. 2016 Jul;36(7):781-96. doi: 10.1002/phar.1780.

  PMID: 27285147 BACKGROUND

• Hermanson DJ, Marnett LJ. Cannabinoids, endocannabinoids, and cancer. Cancer Metastasis Rev. 2011 Dec;30(3-4):599-612. doi: 10.1007/s10555-011-9318-8.

  PMID: 22038019 BACKGROUND

• Bouaziz J, Bar On A, Seidman DS, Soriano D. The Clinical Significance of Endocannabinoids in Endometriosis Pain Management. Cannabis Cannabinoid Res. 2017 Apr 1;2(1):72-80. doi: 10.1089/can.2016.0035. eCollection 2017.

  PMID: 28861506 BACKGROUND

• Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014 Sep-Oct;20(5):737-47. doi: 10.1093/humupd/dmu025. Epub 2014 Jun 11.

  PMID: 24920437 BACKGROUND

• Rocha MG, e Silva JC, Ribeiro da Silva A, Candido Dos Reis FJ, Nogueira AA, Poli-Neto OB. TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain. Reprod Sci. 2011 Jun;18(6):511-5. doi: 10.1177/1933719110391279. Epub 2010 Dec 15.

  PMID: 21160085 BACKGROUND

• Bohonyi N, Pohoczky K, Szalontai B, Perkecz A, Kovacs K, Kajtar B, Orban L, Varga T, Szegedi S, Bodis J, Helyes Z, Koppan M. Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis. Mol Pain. 2017 Jan-Dec;13:1744806917705564. doi: 10.1177/1744806917705564.

  PMID: 28478727 BACKGROUND

• Sanchez AM, Vigano P, Mugione A, Panina-Bordignon P, Candiani M. The molecular connections between the cannabinoid system and endometriosis. Mol Hum Reprod. 2012 Dec;18(12):563-71. doi: 10.1093/molehr/gas037. Epub 2012 Aug 24.

  PMID: 22923487 BACKGROUND

• Devinsky O, Verducci C, Thiele EA, Laux LC, Patel AD, Filloux F, Szaflarski JP, Wilfong A, Clark GD, Park YD, Seltzer LE, Bebin EM, Flamini R, Wechsler RT, Friedman D. Open-label use of highly purified CBD (Epidiolex(R)) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018 Sep;86:131-137. doi: 10.1016/j.yebeh.2018.05.013. Epub 2018 Jul 11.

  PMID: 30006259 BACKGROUND

• Ewing LE, Skinner CM, Quick CM, Kennon-McGill S, McGill MR, Walker LA, ElSohly MA, Gurley BJ, Koturbash I. Hepatotoxicity of a Cannabidiol-Rich Cannabis Extract in the Mouse Model. Molecules. 2019 Apr 30;24(9):1694. doi: 10.3390/molecules24091694.

  PMID: 31052254 BACKGROUND

• Millar SA, Stone NL, Yates AS, O'Sullivan SE. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front Pharmacol. 2018 Nov 26;9:1365. doi: 10.3389/fphar.2018.01365. eCollection 2018.

  PMID: 30534073 BACKGROUND

• Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018 Nov;84(11):2477-2482. doi: 10.1111/bcp.13710. Epub 2018 Aug 7.

  PMID: 30001569 BACKGROUND

• Roslawski MJ, Remmel RP, Karanam A, Leppik IE, Marino SE, Birnbaum AK. Simultaneous Quantification of 13 Cannabinoids and Metabolites in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry in Adult Epilepsy Patients. Ther Drug Monit. 2019 Jun;41(3):357-370. doi: 10.1097/FTD.0000000000000583.

  PMID: 30520828 BACKGROUND

Related Links

• HIGHLIGHTS OF PRESCRIBING INFORMATION. EPIDIOLEX ® (cannabidi ol) oral solution, CX \[pending DEA scheduling action\] Initial U.S. Approval: XXXX \[pending controlled substance scheduling\]

MeSH Terms

Conditions

Endometriosis; Pelvic Pain

Interventions

Cannabidiol; Norethindrone Acetate

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cannabinoids; Terpenes; Hydrocarbons; Organic Chemicals; Norethindrone; Norpregnenes; Norpregnanes; Norsteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

This study struggled with recruitment and terminated early, leading to very small numbers of subjects per treatment group.

Results Point of Contact

• Title: Dr. Kristin Riley
• Organization: MSHersheyMC

kriley1@pennstatehealth.psu.edu

7175316647

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Obstetrics and Gynecology

Study Record Dates

• First Submitted: August 21, 2020
• First Posted: August 26, 2020
• Study Start: December 4, 2020
• Primary Completion: May 29, 2024
• Study Completion: June 26, 2024
• Last Updated: April 4, 2025
• Results First Posted: April 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)