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Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04302870
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2/Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University of Edinburgh
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Professor Chandran
Principal Investigator Affiliation	University of Edinburgh
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	United Kingdom
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Additional Details

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

Arms & Interventions

Arms

Experimental: Memantine

Experimental: Trazodone

Placebo Comparator: Placebo

Experimental: Amantadine

Interventions

Drug: - Memantine Hydrochloride Oral Solution

Memantine hydrocholoride taken once daily

Drug: - Trazodone Hydrochloride oral solution

Trazodone Hydrochloride taken once daily

Drug: - Placebo oral solution

Placebo taken once daily

Drug: - Amantadine Hydrochloride Oral Solution

Amantadine Hydrochloride taken once daily

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Portadown, County Armagh, United Kingdom

Status

Recruiting

Address

Southern Health and Social Care Trust, Craigavon Area Hospital

Portadown, County Armagh, BT63 5QQ

Site Contact

Raeburn Forbes

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