Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease progression of Amyotrophic Lateral sclerosis or motor neurone Disease : the EMERALD trial

Berzenn Urbi, Simon Broadley, Richard Bedlack, Ethan Russo, Arman Sabet

British Medical Journal Open, 2019, 9, e029449.

doi : 10.1136/bmjopen-2019-029449

 

Abstract

Introduction : Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3–5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted.

Methods and analysis : The Efficacy of cannabis-based Medicine Extract in slowing the disease progression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol- low- tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration
of <2 years, age between 25 and 75 years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire.

Ethics and dissemination The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal.
Trial registration number : NCT03690791

Strengths and limitations of this study
►► This study will evaluate the efficacy of cannabis in slowing amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) progression.
►► This study will also evaluate the efficacy of cannabis in improving the quality of life and in managing ALS/ MND-associated symptoms such as pain, spasticity and weight loss.
►► This study is limited by not using a biomarker.
►► This study has limitations in generalisibility as it only focuses on enrolling early-stage ALS/MND patients, i.e.ie, <2 years of symptom onset.

 

Background

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neuromuscular disorder that results in the degeneration of the motor neurons in the cortex, brain stem and spinal cord.1 2 It is characterised by progressive weakness and wasting of skeletal muscles and loss of the ability to swallow or speak.2 It commonly affects patients between 50 and 65 years of age.2–4 The aetiology of ALS is largely unknown, although there is robust evidence demonstrating genetic or inherited causes accounting for 5% to 10% of the ALS population.5 The average life expectancy from diagnosis is 3–5 years, but a small percentage of persons with ALS (pALS) may survive longer.2 3

More than 30 gene mutations have been linked to ALS such as SOD1, TARDBP (TDP-43), FUS/TLS and C9orf72.5 Despite these advances, the pathophysiology of sporadic ALS remains unknown. Theories proposed include reduced glutamate uptake resulting in excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation and dysregulation of cellular metabolism.6

The activation of the endocannabinoid system (ECS) has been demonstrated to reduce excitotoxicity, oxidative cell damage and neuroinflammation.7 8 ECS is a vital physiological neuromodulatory system in human beings; it is involved in regulating homeostasis. ECS is widely expressed in different parts of the human body, particularly in the brain and spinal cord. ECS regulates physiological processes such as pain, emotions, stress, neural development, inflammation, appetite and sleep cycles.9 ECS has two major cannabinoid (CB) receptors – CB1 and CB2. CB1 receptors are extremely abundant in the nervous system while CB2 receptors are more present in immune cells.10

Endogenous CBs (CBs that are intrinsic to humans) activate the ECS and have important roles in the naturalistic defence of the nervous system.11 Anadamide and 2-arachidonoylglycerol, known as endocannabinoids, are presumed to have key roles in slowing ALS progression. Endocannabinoids accumulated in the spinal cord of ALS mice with SOD1 mutations12 13 and acted as protective
responses when the disease was progressing. It is therefore proposed that by introducing exogenous CBs such as delta-9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD), there is a possibility of slowing ALS progression.

Preclinical studies have explored the relationship between ECS and ALS progression using transgenic mice with SOD1 and TDP-43 mutations.12 14–17 The administration of THC, an exogenous endocannabinoid that partially activates CB1 receptors18 in transgenic SOD1 mice (either before or during the onset of symptoms) reduced motor impairment by 6% and extended survival by 5%.15 Similarly, the administration of WIN55,212–2 (a CB1/CB2 receptor agonist) in transgenic SOD1 mice after symptom onset significantly slowed disease progression. 12 The genetic ablation of fatty acid amide hydrolase enzymes, which eventually increases endocannabinoid levels, also slowed disease progression and ameliorated disease signs.12

Activating CB2 receptors is also believed to slow ALS progression.11 CB2 receptors block beta-amyloid- induced microglial activation which mediates excitotoxicity and neuronal damage.19 To further support this claim, AM1241 (a selective CB2 receptor agonist) was administered to transgenic SOD1 mice after disease onset and demonstrated significant slowing of the disease.14 Also, the administration of AM1241 3 mg/kg produced a 56% increase in survival interval and 11% increase in lifespan of SOD1 mice.16

CB2 receptors also regulate the human immune system. Neuroinflammation is proposed as a possible mechanism in pathophysiology of ALS; hence, regulating the immune system to counteract inflammation via CB2 receptors may positively modify disease progression.20 The relationship of ECS in TDP-43, one of the genetic mutations causing ALS and frontotemporal dementia has been investigated. 21 Upregulation of CB2 receptors in the spinal cord of TDP-43 mice was demonstrated. This supports the premise that CB2 receptors are involved in the ALS pathogenesis, possibly as endogenous protective response.

There are case studies and anecdotal reports indicating improvement of symptoms in patients with confirmed ALS by using cannabis.20 In a survey of pALS, respondents admitted that cannabis moderately reduced disease-associated symptoms such as appetite loss, depression, pain, spasticity and drooling.22

Human clinical trials have investigated CBs in pALS. However, these trials mainly focused on symptom management rather than disease modification. One study showed symptomatic benefits in areas of sleep, appetite and spasticity. 23 It also demonstrated the safety of using THC in pALS. Another clinical trial explored the effects of THC (Marinol) in ALS patients with cramps,24 but the differences seen were not statistically significant. The authors pointed out that their results might be negative due to the small THC (Marinol) doses used and the short treatment period (2 weeks), making them too small/short for significant changes to show up.24 A more recent clinical trial has demonstrated significant reduction of ALS-related spasticity with 25CBs and a larger clinical trial is underway. CBs are largely regarded as safe for the ALS population. 23–25 Given the potential therapeutic benefits, further investigation is warranted. The most logical next step is to conduct a human clinical trial.26 This study was designed
to explore the efficacy of cannabis-based medicine extract (CBME) in slowing ALS progression and improving symptom control.

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bmjopen-2019-029449