Cannabidiol for the Treatment of Pelvic Pain in Endometriosis (DREAMLAND)

Study Overview
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Brief Summary
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The objective of this work is to conduct a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of cannabis extract in women with endometriosis who have already undergone hormonal contraceptive treatment and surgery without satisfactory response.

Detailed Description
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The Dreamland study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), controlled by disease stage, participant and investigator blinded, single-site superiority trial of oral cannabis extract (CBD). CBD will be given orally starting at 10 mg daily and up-titrated to a maximum dose of 150 mg daily. Dose up-titration will be based on clinical response or side effects, whichever comes first. After 63 days of treatment, gradual withdrawal will be performed during one week. Then, at 70 days, there will be an open-label extension wherein all participants from control group will be offered a course of CBD according to the same previous protocol. This research intends to : Assess whether the daily use of CBD, for nine weeks, will reduce the pain level of these women. Assess whether the daily use of CBD, for nine weeks, will modify pain threshold. Assess whether the daily use of CBD, for nine weeks, will interfere in psychological symptoms. Assess the possible adverse effects of using CBD

Official Title
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Cannabidiol in the Treatment of Women With Chronic Pelvic Pain Secondary to Endometriosis

Conditions
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Endometriosis, Pelvic Pain

Intervention / Treatment
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* Drug: Cannabis Derivatives
* Drug: Placebo
* Drug: Hormonal Contraceptive Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with chronic pelvic pain secondary to endometriosis surgically treated, with refractory symptoms, and who are taking complementary hormone therapy; Women over 18 years of age who wish to participate in the clinical trial; Willingness to voluntarily participate in the study to accept randomization to either of the two treatment arms; Participating exclusively in this clinical trial during the study period; Possess a telephone (cell or landline) that may be available to receive daily calls throughout the study period; Signature of the Free and Informed Consent Term (TCLE) approved by the Local Research Ethics Committee. Exclusion Criteria: Chronic, severe or uncompensated medical conditions, such as: insulin-dependent diabetes (types 1 or 2); uncontrolled high blood pressure, lung disease such as asthma or other chronic obstructive pulmonary disease; hematological diseases, liver diseases, chronic kidney disease in advanced stage (grade 3, 4 and 5), metabolic disturbances and immunosuppression; Use of any medication with potential interaction with CBD/THC (such as chloroquine, clobazan, warfarin, or valproic acid) or history of undesirable reactions prior to the use of this medications; Inability to use oral medication; Pregnancy or lactation; History of alcohol or drug addiction; Smoking in the last three years; Marijuana use in the past three months or a lifetime history of dependence; Inability to cooperate with investigators due to cognitive impairment or mental status.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabis Derivatives<br>Cannabis Derivatives (98% CBD, 2% THC) will be given orally starting at 10 mg daily and up-titrated to a maximum dose of 150 mg daily. Dose up-titration will be based on clinical response or side effects, whichever comes first. After 63 days of treatment, gradual withdrawal will be performed during one week. All patients will take hormonal contraceptives, preferably progestagen-only. All participants will perform invasive and non-invasive procedures with the nursing team. The invasive will be blood collections, to evaluate laboratory parameters. The non-invasive ones refer to the measurement of height, weight, body temperature, and sleep pattern, as will pain threshold. In addition, they will be monitored through weekly self-assessment scales, applied remotely, electronically (cell phones or computers), with an estimated duration of ten minutes each, which will have their responses recorded in an electronic database, by the study coordination team. | Drug: Cannabis Derivatives<br>* CBD 10 mg (up-titrated until 150mg or adverse effects) daily for 9 weeks<br>Drug: Hormonal Contraceptive Agents<br>* All participants will be given hormonal contraceptive.<br>|
| Placebo Comparator: Placebo<br>Placebo will be given at the same protocol described before. The bottle, label, color and density of the contents will be the same. All patients will take hormonal contraceptives, preferably progestagen-only. Then, at 70 days, there will be an open-label extension wherein all participants from control group will be offered a course of active treatment according to the same previous protocol. All participants will perform invasive and non-invasive procedures with the nursing team. The invasive will be blood collections, to evaluate laboratory parameters. The non-invasive ones refer to the measurement of height, weight, body temperature, and sleep pattern, as will pain threshold. In addition, they will be monitored through weekly self-assessment scales, applied remotely, electronically (cell phones or computers), with an estimated duration of ten minutes each, which will have their responses recorded in an electronic database, by the study coordination team. | Drug: Placebo<br>* Placebo 10 mg (up-titrated until 150mg or adverse effects) daily for 9 weeks<br>Drug: Hormonal Contraceptive Agents<br>* All participants will be given hormonal contraceptive.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with pain change of 30% | Proportion of women with at least 30% of change in pain intensity. Pain intensity measured through visual analogue scale. | Time points for assess: Week 1, Week 3, Week 4, Week 5, Week 7, Week 8, Week 9; Data will be reported through study completion, an average of 1 year | 
| Proportion of patients with pain change of 50% | Proportion of women with at least 50% of change in pain intensity. Pain intensity measured through visual analogue scale. | Time points for assess: Week 1, Week 3, Week 4, Week 5, Week 7, Week 8, Week 9; Data will be reported through study completion, an average of 1 year | 
| Quantitative change in pain intensity | Absolute variation of pain intensity measured through visual analogue scale | Time points for assess: Week 1, Week 3, Week 4, Week 5, Week 7, Week 8, Week 9; Data will be reported through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain threshold change | Changes in the thermal peripheral pain thresholds: the range of temperatures at which a participant begins to perceive heat as painful: comparison between the beginning (day 0) and the end of the protocol (day 63). | Day 0, Day 63 | 
| Central sensitization change | Changes in the score from Central Sensitization Inventory between the beginning (day 0) and the end of the protocol (day 63). Total scores ranging from 0-100. Higher scores mean a worse outcome. Score higher than 40 suggest central sensitization. | Day 0, Day 63 | 
| Brief measure for assessing generalized anxiety disorder | Changes in the score from Generalized Anxiety Disorder (GAD7) scale between the beginning (day 0) and the end of the protocol (day 63). Total scores ranging from 0-21. Higher scores mean a worse outcome. Scores higher than 10 suggest generalized anxiety disorder. | Day 0, Day 63 | 
| Measure of the degree of depression severity | Changes of scores for depressive symptoms over time during the study period (day 0-63) using Patient ́s Health Questionnaire-9 (PHQ-9). Total scores ranging from 0-27. Higher scores mean a worse outcome. Scores less than or equal to 4 suggest minimal depression. | Day 0, Day 63 | 
| Alanine aminotransferase (ALT) | Change in ALT concentration in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Aspartate aminotransferase (AST) | Change in AST concentration in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Glucose | Change in glucose concentration (glycemia) in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Bilirubin | Change in bilirubin concentration in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Cannabidiol (CBD) | Change in CBD concentration in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Tetrahydrocannabinol (THC) | Change in THC concentration in plasma | Week 0, Week 1, Week 5, Week 9. | 
| Side effects | Occurrence of side effects over time during the study period (day 0-63) | Week 0, Week 1 (Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7), Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9. Participants will be able to establish contact with a team doctor especially to report side effects. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cannabis, Endometriosis, Pelvic Pain