Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Motor Neuron Disease, Amyotrophic Lateral Sclerosis Clinical Trial

— MND-SMART  

Official title:

Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04302870
• Other study ID #: AC18082
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 27, 2020
• Est. completion date: December 2026

Study information

• Verified date: November 2023
• Source: University of Edinburgh
• Contact: Professor Chandran
• Phone: 0131 465 9612
• Email: siddharthan.chandran[@]ed.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: December 2026
• Est. primary completion date: September 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Motor Neuron Disease, Amyotrophic Lateral Sclerosis

Intervention

Drug:
• Memantine Hydrochloride Oral Solution
Memantine hydrocholoride taken once daily
• Trazodone Hydrochloride oral solution
Trazodone Hydrochloride taken once daily
• Placebo oral solution
Placebo taken once daily
• Amantadine Hydrochloride Oral Solution
Amantadine Hydrochloride taken once daily

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	University Hospitals of Birmingham NHS Foundation Trust	Birmingham
United Kingdom	University Hospitals Sussex NHS Foundation Trust	Brighton
United Kingdom	West Suffolk NHS Foundation Trust	Bury Saint Edmunds
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Cardiff and Vale University Local Health Board	Cardiff
United Kingdom	Clinical Research Centre , Ninewells Hospital	Dundee
United Kingdom	Anne Rowling Regenerative Neurology Clinic	Edinburgh
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Queen Elizabeth University Hospital Clinical Research Facility	Glasgow
United Kingdom	NHS Highland Clinical Research Facility, Raigmore Hospital	Inverness
United Kingdom	East Suffolk and North Essex NHS Foundation Trust	Ipswich
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	Royal London Hospital	London
United Kingdom	St George's University Hospitals NHS Foundation Trust	London
United Kingdom	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne
United Kingdom	Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich
United Kingdom	University Hospitals of Dorset NHS Trust	Poole
United Kingdom	Southern Health and Social Care Trust, Craigavon Area Hospital	Portadown	County Armagh
United Kingdom	Clinical Research Facility Salford Royal NHS Foundation Trust	Salford
United Kingdom	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield
United Kingdom	Clinical Research Facility University Hospital Southampton	Southampton

Sponsors (4)

Lead Sponsor	Collaborator
University of Edinburgh	NHS Lothian, University College, London, University of Warwick

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in decline of ALS-FRS(R) over 18months	Co-primary outcome measure	18 months
Primary	Survival	Co-primary outcome measure	18 months
Secondary	Cognition and behaviour	Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)	18 months
Secondary	Respiratory function - Forced vital capacity	Change in FVC	18 months
Secondary	King's ALS Clinical stage	Time to reach King's stage IV, scale range I - V	18 months
Secondary	Changes in anxiety and depression	Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42	18 months
Secondary	Changes in Quality of Life	Measured using EQ-5D-5L	18 months
Secondary	Safety and tolerability of IMPs	Measured using adverse events	18 months