Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Study Overview
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Brief Summary
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MND-SMART is investigating whether selected drugs can slow down the progression of motor neurone disease (MND) and improve survival. The study is 'multi-arm' meaning more than one treatment will be tested at the same time. The trial started with 3 arms; drug 1 (memantine), drug 2 (trazodone) and placebo (dummy drug). A third drug, amantadine, was added in April 2023. The first two drugs, memantine and trazodone, were removed from the trial in September 2023 due to lack of benefit. The trial currently has 2 recruiting arms; amantadine and placebo. This allows the evaluation of each drug versus placebo. Participants will be randomly allocated to either of the recruiting arms. Medicines being tested are already approved for use in other conditions. MND-SMART has an 'adaptive' design. This means medicines being studied can change according to emerging results. Treatments shown to be ineffective can be dropped and new drugs can be added over the duration of the study. This will allow many treatments, over time, to be efficiently and definitively evaluated. The medicines being tested have been selected following a rigorous process involving a systematic, unbiased, and comprehensive review of past clinical trials data, as well as information from pre-clinical research (studies in laboratories), for MND and other related neurodegenerative disorders. Drugs have been ranked for inclusion in MND-SMART by a group of independent MND experts according to set criteria. These include consideration of how the drugs work, their safety profiles, and the quality of previous studies. New drugs will be selected for investigation in MND-SMART based on continuous review of constantly updated scientific evidence as well as findings from state-of-the-art human stem cell based drug discovery platforms. These can be added by substantial amendment to the protocol.

Detailed Description
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For further information, please visit: https://mnd-smart.org/

Official Title
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Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Conditions
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Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Memantine Hydrochloride Oral Solution
* Drug: Trazodone Hydrochloride oral solution
* Drug: Placebo oral solution
* Drug: Amantadine Hydrochloride Oral Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of MND (including the following subtypes: ALS by El Escorial Criteria (possible, probable, and definite), Primary Lateral Sclerosis, and Progressive Muscular Atrophy) Over 18 Women of childbearing potential according to Clinical Trials Facilitation and Coordination Group (CTFG) guidelines must have a negative pregnancy test within 7 days prior to, or at, the baseline visit Women of childbearing potential and fertile men must be using an appropriate method of contraception to avoid any unlikely teratogenic effects of the selected drugs from time of consent, to 4 weeks after treatment inclusive Willing and able to comply with the trial protocol and ability to understand and complete questionnaires Written informed consent (this can be signed by a proxy in the case of limb dysfunction) Exclusion Criteria: Patients diagnosed with Frontotemporal Dementia (FTD-MND) or any other significant psychiatric disorder that prevents informed consent being given. Patients in the manic phase of bipolar disorder. Alcoholism (self-reported) Active suicide ideation assessed using the Columbia-Suicide Severity Rating Scale On concurrent investigational medication (including biological therapy) Known hypersensitivity, including hereditary fructose intolerance, or adverse reaction to the active substances and their excipients (SPCs section 6.1) or any past medical history contraindicating use of any of the IMPs Pregnancy or breast-feeding females If ALT, ALP, bilirubin or GGT >3 times the upper limit of normal. If creatinine clearance (creatinine clearance or eGFR) <35 ml/min. If TSH <0.2mU/l (if possible to test free T4, then Serum free T4 >25pmol/l) corrected QT interval on 12 lead ECG >500 ms Active Epilepsy History of proven peptic ulcer confirmed on endoscopy Patient's diagnosed with ventricular arrhythmias, significant heart block (at the investigator's discretion) or in the immediate recovery period after myocardial infarction (< 6 weeks). Already taking any of the IMPs in this protocol Patient's contraindicated to any of the IMPs according to SPC section 4.3 Taking a medication that interacts with the active substances and their excipients according to the SPCs, including but not limited to; Dextromethorphan, Amantadine; Ketamine, Monoamineoxidase inhibitors ((MAOIs), Rasagiline, Selegiline, Safinamide, Tranylcypromine, Phenelzine, Isocarboxazid, Moclobemide). Patients who the PI considers will not be able to comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Memantine<br> | Drug: Memantine Hydrochloride Oral Solution<br>* Memantine hydrocholoride taken once daily<br>|
| Experimental: Trazodone<br> | Drug: Trazodone Hydrochloride oral solution<br>* Trazodone Hydrochloride taken once daily<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo oral solution<br>* Placebo taken once daily<br>|
| Experimental: Amantadine<br> | Drug: Amantadine Hydrochloride Oral Solution<br>* Amantadine Hydrochloride taken once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in decline of ALS-FRS(R) over 18months | Co-primary outcome measure | 18 months | 
| Survival | Co-primary outcome measure | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition and behaviour | Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS) | 18 months | 
| Respiratory function - Forced vital capacity | Change in FVC | 18 months | 
| King's ALS Clinical stage | Time to reach King's stage IV, scale range I - V | 18 months | 
| Changes in anxiety and depression | Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42 | 18 months | 
| Changes in Quality of Life | Measured using EQ-5D-5L | 18 months | 
| Safety and tolerability of IMPs | Measured using adverse events | 18 months |