Effect of Cannabinoids on Pain in Fabry Disease Patients

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

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.

Study Overview

• Status: Recruiting
• Conditions: Pain, Neuropathic
• Intervention / Treatment: Drug: Placebo; Drug: Cannabis sativa L., folium cum flore

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Anticipated): 22
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Albina Nowak, PD; Phone Number: +41432538872; Email: albina.nowak@usz.ch

Study Locations

• Switzerland
  • Zürich, Switzerland
    • Recruiting
    • University Hospital Zurich Usz
    • Contact: Albina Nowak; Email: albina.nowak@usz.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Albina Nowak, MD
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Albina A Nowak, PH, University of Zurich

Publications and helpful links

General Publications

• Rolke R, Baron R, Maier C, Tolle TR, Treede -DR, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006 Aug;123(3):231-243. doi: 10.1016/j.pain.2006.01.041. Epub 2006 May 11. Erratum In: Pain. 2006 Nov;125(1-2):197.
• Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L, Lauder H, Ehler E. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014 Aug;18(7):999-1012. doi: 10.1002/j.1532-2149.2013.00445.x. Epub 2014 Jan 13.
• Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain. 2003 Mar;102(1-2):1-8. doi: 10.1016/s0304-3959(03)00006-x. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2022
• Primary Completion (Anticipated): December 29, 2023
• Study Completion (Anticipated): December 29, 2023

Study Registration Dates

• First Submitted: December 8, 2020
• First Submitted That Met QC Criteria: March 24, 2021
• First Posted (Actual): March 29, 2021

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Neuromuscular Diseases; Peripheral Nervous System Diseases; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Neuralgia; Fabry Disease; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Parasympatholytics
• Other Study ID Numbers: Cannabinoids in Fabry pain

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No