Efficacy and Safety of Cannabidiol Oral Solution for Aromatase Inhibitor-Related Joint Pain in Early Hormone-Receptor Positive Breast Cancer

Trial ID: 2023-505380-36-00
Protocol: CSET 2021/3373
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Hormone receptor positive breast cancer

Objectives

The primary objective of this study is to compare the effect of **cannabidiol** (CBD)-oral solution versus placebo on musculoskeletal symptoms associated with adjuvant aromatase inhibitor (AI) therapy in patients with early-stage hormone-receptor positive breast cancer. This is measured using the Brief Pain Inventory Short Form (BPI-SF). The clinical relevance of this objective lies in addressing AI-related joint pain, which is a common side effect that can significantly impact the quality of life and adherence to cancer treatment.

Secondary objectives include:

Evaluating the impact of CBD-oral solution on worst pain, pain interference with daily activities, functioning, stiffness, and pain of the knee and hips over 12 weeks.
Assessing the effect on global and cancer-specific aspects of quality of life, anxiety, depression, and AI adherence.
Determining the impact on the use of pain medications for musculoskeletal symptoms.
Assessing the short-term and long-term safety of CBD-oral solution, including potential side effects such as nausea, gastrointestinal symptoms, cognitive dysfunction, and psychiatric disorders, as well as evaluating long-term drug addiction.
Evaluating the psychological profile of patients in terms of risk perception and attitude in risk-taking situations.
Determining potential drug-drug interactions between AIs and CBD-oral solution through systematic serum assessments of AI and CBD metabolites.

Participants

The clinical trial involves a study population comprising **patients with stage I, II, III hormone-receptor positive breast cancer** who are receiving adjuvant aromatase inhibitors and experiencing AI-related musculoskeletal pain. The trial includes both male and female participants, with an age range of 18 years and older. The sponsor has not provided the total number of participants. Participants were selected based on their diagnosis and treatment regimen, specifically those taking a standard dose of one of the three approved aromatase inhibitors for a specified duration. The study population is characterized by their ability to comply with study visits and procedures, and they must have adequate bone marrow and organ function. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraception guidelines if of childbearing potential. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, 2x2 crossover study** to evaluate the efficacy and safety of cannabidiol (CBD) oral solution in managing joint pain associated with adjuvant endocrine therapy in patients with early-stage hormone-receptor positive breast cancer. The trial will span approximately 12 weeks for each participant, with the overall study expected to conclude by April 2026. Participants will be randomly assigned to receive either the CBD oral solution or a placebo, with a crossover to the alternate treatment after a specified period, ensuring each participant receives both treatments during the study.

The study will commence with an inclusion visit, where potential participants will undergo a screening process to confirm eligibility based on predefined criteria, including a reported average joint pain score of ≥ 4 out of 10 on the Brief Pain Inventory. Following successful screening, participants will be enrolled and randomized. The trial will include several follow-up visits to monitor efficacy and safety, with assessments conducted using tools such as the Brief Pain Inventory Short Form (BPI-SF) and the Western Ontario and McMaster Universities Osteoarthritis scale (WOMAC). The primary endpoint focuses on the efficacy of CBD in reducing AI-associated pain, while secondary endpoints include assessments of articular function, quality of life, anxiety, depression, and safety.

Participants are expected to remain in the study for the full 12-week treatment period unless specific conditions necessitate early termination, such as adverse events or withdrawal of consent. The end-of-study visit will involve final assessments and data collection to evaluate the overall impact of the treatment. Throughout the trial, adherence to the treatment regimen and study procedures will be closely monitored to ensure data integrity and participant safety. The study is structured to provide robust data on the potential benefits of CBD in managing musculoskeletal symptoms in this patient population.

Treatment

The clinical trial involves the administration of **LGP PURE CBD 200**, an experimental medication formulated as **oral drops**. The active substance in this medication is **cannabidiol** (CBD), a **phytocannabinoid** derived from the cannabis plant. The medication is administered orally, with a maximum daily dose of 20 mg/kg and a total maximum dose of 1680 mg/kg over a treatment period of 12 weeks. The primary objective is to assess the efficacy and safety of this formulation in alleviating musculoskeletal symptoms associated with adjuvant endocrine therapy in patients with early breast cancer. The study employs a randomized, double-blind, placebo-controlled, 2x2 crossover design.

The trial also includes a **placebo** comparator, which is a **caprylic/capric triglyceride liquid**. This substance serves as the placebo control in the study, allowing for a comparison of the effects of the active treatment against a non-active substance. The placebo is designed to mimic the appearance and administration route of the experimental medication, ensuring that the study remains blinded. The placebo does not contain any active pharmaceutical ingredients and is used to evaluate the true efficacy of the cannabidiol oral solution by providing a baseline for comparison.

Efficacy

The efficacy of cannabidiol (CBD) oral solution in the clinical trial will be assessed primarily through its impact on **aromatase inhibitor (AI)-associated pain** in patients with early breast cancer. The primary endpoint is the change in pain levels, measured by the Brief Pain Inventory Short Form (BPI-SF). A one-point difference in the BPI average joint pain score is considered a minimal important difference and clinically meaningful. Secondary endpoints include assessments of articular function, stiffness, and pain of knees and hips using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Quality of life will be evaluated through the EORTC QLQ-C30 and EORTC QLQ-BR45 questionnaires, along with the fatigue subscale EORTC QLQ-FA12. Anxiety and depression will be measured using the Hospital Anxiety and Depression Scale (HADS).

Adherence to the treatment regimen will be monitored through AI serum assessments and patient self-reporting via the Medication Intake Survey (MIS), collected at baseline and at weeks 12, 25, and 37. Safety assessments will be conducted by a trained research nurse, focusing on side effects such as nausea, constipation, cognitive dysfunction, and psychiatric side effects, using the CTCAE V.5 criteria. Risk-taking behavior will be evaluated with the DOSPERT scale, and daily pain medication consumption will be tracked through a participant-completed daily diary. Drug addiction potential will be assessed using the CAST questionnaire. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the overall impact of CBD on musculoskeletal symptoms related to AI therapy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient must understand, sign and date the written informed consent form (ICF) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedure as per protocol.
Patient must be affiliated to a social security system or beneficiary of the same.
Patient is ≥ 18 years-old at the time of study inclusion
Patient has histologically confirmed invasive Stage I, II, III breast cancer.
Patient has breast cancer that is positive for ER and/or PgR (nuclear staining of any intensity ≥ 10%)
Patients should be taking a standard dose of one of the three approved AIs (i.e., anastrozole, exemestane, or letrozole) for at least 21 days, and not more than 36 months before trial registration;
If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to randomization.
If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to randomization.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Patients should report an average joint pain score of ≥ 4 out of 10 on the Brief Pain Inventory (BPI, Appendix 2) within 7 days before registration.
Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative urine or serum pregnancy test (for β-hCG) within 7 days of randomization.
Women of CBP, defined as all women physiologically capable of becoming pregnant, must be willing to use highly effective methods of contraception. It is recommended that sexually active males use a condom during intercourse and it is strongly advised that they do not father a child in this period (a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid). In all patients, contraception must continue during the trial treatment and for 3 months after stopping it, due to AI treatment. For women, highly effective contraception methods include: a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of bilateral oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment; c. Placement of an intrauterine device (IUD). Notes: - Use of oral (estrogen and progesterone), transdermal, injected or implanted hormonal methods of contraception (as well as hormonal replacement therapy) is not allowed in this trial. - Women are considered of CBP unless: they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago.
Specific inclusion criteria for CBD use: 14. Patient has adequate bone marrow and organ function as defined by the following local laboratory values: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L b. Platelets ≥ 100 × 109/L c. Hemoglobin ≥ 9.0 g/dL d. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula. e. Alanine transaminase (ALT) ≤ 1.5 × Upper Limit Normal (ULN) f. Aspartate transaminase (AST) ≤ 1.5 × ULN g. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert’s Syndrome h. International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to randomization). i. Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements (the local laboratory value should be documented within normal limits after the correction) before randomization: i. Sodium ii. Potassium iii. Phosphorus iv. Magnesium v. Total Calcium 15. Standard 12-lead ECG values defined as the mean of the triplicate ECGs as locally assessed: d. QTcF interval (using Fridericia’s correction) at screening < 450 msec e. Mean resting heart rate 50-90 bpm (determined from the ECG)

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Exclusion Criteria

Patient with distant metastases of breast cancer beyond regional lymph nodes (M1 disease according to AJCC 8th edition).
Patient has not recovered from clinical and laboratory acute toxicities of chemotherapy, radiotherapy and/or surgery (i.e. patient has toxicities attributed to prior anti-neoplastic therapy NCI CTCAE version 5.0 grade ≥1 at day of randomization, excluding alopecia and amenorrhea)
Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before ICF signature. Note: Patients with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to randomization
Patient has previous history of bone fracture or surgery of the affected knees, hands or both within 6 months prior to enrolment or known rheumatologic diseases;
Patient has received opioids analgesics, systemic NSAIDs, topical analgesics, oral, intra-articular or intramuscular corticosteroids for treatment of joint pain or joint stiffness within 28 days prior registration;
Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
Patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment.
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection).
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigators judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ≤5 years.
Participation in a prior interventional study and received trial treatment with an investigational product (or used an investigational device) within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breastfeed during the trial.
Patient under guardianship or deprived of his liberty by a judicial or administrative decision or under justice protection or under curatorship or unable of giving his consent
Specific exclusion criteria for CBD use: 13. Patient with a known hypersensitivity to CBD or any of the excipients of CBD 14. Previous serious adverse reaction to any cannabinoid product such as cannabinoid related psychosis, panic attack or delirium. 15. Recreational or medicinal cannabis or synthetic cannabinoid-based medications (including Sativex®) within 2 weeks before study entry 16. Patient has previous or active psychological, psychiatric or central nervous system disorders, including epilepsy; schizophrenia or any other psychosis, severe borderline personality, patient with significant suicidal ideation. 17. Patient takes drugs as clobazam, valproate, or levodopa; 18. Patient has previous history of substance abuse or dependance to alchol, opioids, amphetamines, benzodiazepines and other illicit stimulants. 19. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: a. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry b. Documented cardiomyopathy c. Prior history of LVEF <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) which did not recover before study entry d. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting trial treatment) iii. Inability to determine the QTcF interval e. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block) f. Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg