Effect of Cannabinoids on Pain in Fabry Disease Patients

Study Overview
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Brief Summary
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Fabry Disease (FD) is a rare lysosomal storage disorder due to the absence or deficiency of hydrolase α-galactosidase A (α-Gal A) activity in lysosomes. This dysfunction results in progressive accumulation of glycosphingolipids in a wide variety of cells, resulting in major organ system damage. Patients with Fabry disease can suffer from neuropathic pain, since lysosomal accumulation affects small unmyelinated nerve fibers. Neuropathic pain is one of the prominent and debilitating symptoms significantly interfering with life quality in FD patients. Current treatment of Fabry patients with neuropathic pain is deficient, as they respond poorly to a conventional pain therapy, often require a high-dose opioids treatment and presentation to the Emergency Department. Sativex® has been shown to be a successful treatment option in neuropathic pain of different origin with minimal neuropsychological influence: in multiple sclerosis (MS), chemotherapy-induced neuropathic pain and other. It contains Δ-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) and has recently been licensed in Switzerland for treatment of neuropathic chronic pain in MS. Sativex® is an oral spray.

Detailed Description
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Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A. Patients suffering from Fabry's disease may suffer from neuropathic pain, since the lysosomal accumulation of lipids can also take place in the small nerve fibers. Typically, neuropathic pain occurs in late childhood or adolescence and disappears after several years, probably due to the irreversible destruction of the small nerve fibers. The pain management of Fabry patients suffering from neuropathic pain is inadequate, as patients often do not respond well to conventional pain therapies. Aim of this study: The aim of this study is to find out how strongly the investigational drug Sativex® (active ingredients: tetrahydrocannabinol (THC) and cannabidiol (CBD)) can influence the pain that can be caused by Fabry's disease. For this purpose, the investigational drug is compared with a placebo drug. The latter is a drug without an active ingredient. These studies provide us with important information on the origin of the pain and at the same time on the mechanism of action of Sativex®. This makes it possible to develop new forms of therapy in the future. Procedure: A total of 22-30 patients are divided into two groups of 11-15 patients each. Both groups will undergo the same test program. This will be divided into two phases: In the first phase, which will last 8 weeks, one group will receive Sativex® while the other group will receive a placebo. In the second phase, which will also last 8 weeks, the group that previously received the investigational drug will now receive the placebo and the previous placebo group will now receive the investigational drug. The study is double-blind, i.e. neither the patient nor the investigator knows who is receiving the investigational drug or the placebo. Patients are randomly assigned to the groups. Throughout the treatment, patients maintain their usual pain management regimen. (see Study Schedule) For 14 weeks, patients will fill out their pain diary daily. Every two weeks a blood sample is taken to determine the levels of cannabinoid metabolites. At the beginning, at the end of the first and after the second phase, the patient will fill out various questionnaires on neuropathic pain and improvement of quality of life. This will be used to assess whether pain relief is achieved. Translated with www.DeepL.com/Translator (free version)

Official Title
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Effect of Cannabinoids on Pain in Fabry Disease Patients; a Prospective, Randomized, Double-blind, Placebo-controlled, Crossover, Multicenter Study

Conditions
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Pain, Neuropathic

Intervention / Treatment
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* Drug: Cannabis sativa L., folium cum flore
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Age: 18-70 years Patients with genetically confirmed Fabry disease On treatment with Enzyme Replacement Therapy (ERT) Sufficient command of German language Pain duration of more than 3 months Stable analgesic regimen for at least 2 weeks preceding the study entry day Baseline worst last week pain intensity ≥4 on numerical rating scale (NRS) Signed and dated informed consent ERT or chaperone therapy at a stable dose for at least 3 last months Exclusion Criteria: • Known hypersensitivity or allergy to cannabinoids. Women who are pregnant or breast feeding; intention to become pregnant during the course of the study, lack of safe contraception, defined as: female subjects of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not willing or able to use any other second (additional) considered sufficiently reliable by the investigator in individual cases. Female subjects who are surgically sterilized/hysterectomized or post-menopausal for longer than 2 years are not considered as being of child bearing potential. Dementia Other pain not of neuropathic origin thought by the investigator to be of nature or severity to interfere with the patient's assessment of neuropathic pain due to Fabry disease. Patients with known or suspected non-compliance, drug or alcohol abuse, including Marijuana cigarettes. Patients with known schizophrenia, other psychotic disorders, personality disorders or another severe psychiatric disorder or positive family history with these disorders, except depression. Patients with another clinically significant disease (e.g. renal failure, hepatic dysfunction, severe cardiovascular or convulsive diseases). Participation in another study with investigational drugs within the 30 days preceding and during the present study. Previous enrolment into the current study Enrolment of the investigator, his/her family members, employees and other dependent persons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>oral spray | Drug: Placebo<br>* Muscle Relaxation<br>* Other names: Spasmolytic;|
| Active Comparator: Sativex®<br>.It contains Δ-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) | Drug: Cannabis sativa L., folium cum flore<br>* Muscle Relaxation<br>* Other names: Spasmolytic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NRS | NRS is a straightforward commonly used method to illustrate pain. | Daily NRS score after 28 days will be compared to baseline NRS score, evaluated before titration phase starts | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QST | Pain thresholds using the quantitative sensory testing. | At baseline and after 28 days of treatment with study drug and placebo, respectively. | 
| WHO-Quality of life score (WHOQOL-BREF) | Improvement of quality of life. | Between baseline and treatment after 28 days. | 
| Patient global impression of change (PGIC) | Improvement of quality of life. | For the average pain of treatment week 4. | 
| Short form McGrill Paint Questionnaire (SF-MPQ) | Improvement of neuropathic pain. | Compared between baseline and average pain of treatment after 28 days. | 
| Douleur Neuropathic en 4 questions (DN4-Questionnaire) | Improvement of neuropathic pain. | Compared between baseline and treatment week 4. | 
| Profile of Mood States (POMS questionnaire) | Change in Profile of Mood States. | Between baseline and treatment week 4. | 
| Insomnia severity Index | Change in Insomnia severity score. | Between baseline and treatment after 28 days. |