MND-SMART

Motor neurone disease systematic multi-arm adaptive randomised trial (MND-SMART)

UK Chief Investigator

Professor Siddharthan Chandran

Research summary

MND-SMART stands for Motor Neuron Disease – Systematic Multi-arm Adaptive Randomised Trial. The study is a platform trial. 

Multi-arm means that, unlike typical clinical trials which test a single treatment, MND-SMART will test more than one at the same time. Trial participants taking the different treatments will be compared with a group who receive a dummy drug, called a placebo.

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. This is a phase 2 / 3 trial which means if drugs appear to be effective, they will seamlessly transition into phase 3 without the need for additional permissions or trial participants needing to complete a phase 2 trial and join a separate phase 3 trial.

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. A fourth drug, tacrolimus, was added in March 2025 in Edinburgh and across all sites in April 2025. The first two drugs, memantine and trazodone, were removed from the trial in September 2023 due to lack of benefit. The trial currently has 4 recruiting arms: amantadine, liquid placebo (matched to amantadine), tacrolimus, and tablet placebo (matched to tacrolimus). This allows the evaluation of each drug versus placebo. Participants will be randomly allocated between the treatment arms they are eligible for. Medicines being tested are already approved for use in other conditions.

Current status

Open to recruitment

Recruitment target

Up to 1,150 participants

Click here to see how many patients have been recruited into this study to date (external link to the NIHR public study search) 

Recruitment groups

Patients with MND

Locations

Scotland:

• Aberdeen, Principal Investigator: Callum Duncan. Site open for local recruitment only

• Dundee, Principal Investigator: Ian Morrison. Site open for local recruitment only

• Edinburgh, Principal Investigator: Suvankar Pal. Site open for local recruitment only

• Glasgow, Principal Investigator: George Gorrie. Site open for local recruitment only

• Inverness, Principal Investigator: Javier Carod Artal. Site open for local recruitment only

England:

• Birmingham, Principal Investigator: Venkatamaran Srinivasan. To be confirmed if site is open for recruitment locally or out-of-area

• Brighton, Principal Investigator: Andrew Barritt. Site open for local recruitment only

• Bury St Edmunds, Principal Investigator: Francesca Crawley. To be confirmed if site is open for recruitment locally or out-of-area

• Cambridge, Principal Investigator: Rhys Roberts. To be confirmed if site is open for recruitment locally or out-of-area

• Exeter, Principal Investigator: Tim Harrower. To be confirmed if site is open for recruitment locally or out-of-area

• Ipswich, Principal Investigator: Clare Galton. To be confirmed if site is open for recruitment locally or out-of-area

• London - St George's Hospital, Principal Investigator: Pablo Garcia Reitboeck. Site potentially open for recruitment out-of-area 

• London - Royal London Hospital, Principal Investigator: Aleks Radunovic. To be confirmed if site is open for recruitment locally or out-of-area

• London - University College Hospital, Principal Investigator: Andrea Malaspina. Site open for recruitment out-of-area 

• London - King's College Hospital, Principal Investigator: Ammar Al-Chalabi. Site open for recruitment out-of-area

• Newcastle, Principal Investigator: Tim Williams. Site open for local recruitment only

• Norwich, Principal Investigator: Godwin Mamutse. Site open for recruitment out-of-area

• Poole, Principal Investigator: Charles Hillier. To be confirmed if site is open for recruitment locally or out-of-area

• Salford, Principal Investigator: Hisham Hamdalla. Site open for recruitment out-of-area

• Sheffield, Principal Investigator: Chris McDermott. Site open for local recruitment only

• Southampton, Principal Investigator: Ashwin Pinto. To be confirmed if site is open for recruitment locally or out-of-area

Wales:

• Cardiff, Principal Investigator: Ken Dawson. Site open for local recruitment (South Wales network) only

Northern Ireland:

• Craigavon Area Hospital, Principal Investigator: Raeburn Forbes. To be confirmed if site is open for recruitment locally or out-of-area

Information about study sites

Contact details

Website: www.mnd-smart.org

Email: loth.mndsmart@nhslothian.scot.nhs.uk 

Telephone: 0131 242 9122

Key dates

Recruitment open date: 20 February 2020

Planned recruitment end date: 02 November 2026

Inclusion / exclusion criteria

Core Inclusion criteria:

• Confirmed diagnosis of MND. This includes the following subtypes: ALS by El Escorial Criteria (possible, probable, and definite) or Gold Coast Criteria, Primary Lateral Sclerosis, and Progressive Muscular Atrophy

• Over 18

• Women of childbearing potential according to 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 (in the case of limb dysfunction verbal consent can be given in the presence of a witness who can sign)

Core Exclusion Criteria:

• Patients diagnosed with Frontotemporal Dementia (FTD-MND) or any other significant psychiatric disorder that prevents informed consent being given.

• Alcoholism (current self-reported - at the investigator's discretion)

• Active suicide ideation assessed using the Columbia-Suicide Severity Rating Scale

• On concurrent investigational devices and medication (including biological therapy)

• 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)

• If corrected QT interval on 12 lead ECG >500 ms

• 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).

• Patients who the PI considers will not be able to comply with the study protocol.

Amantadine Exclusion Criteria:

• Patients in the manic phase of bipolar disorder.

• Patients with history of proven peptic ulcer confirmed on endoscopy

• Patients with active epilepsy

• Already taking the IMP in this comparison

• Known hypersensitivity, including hereditary fructose intolerance, or adverse reaction to the active substances and their excipients (as per SPCs for this comparison) or any past medical history contraindicating use of the IMP in this comparison

Tacrolimus Exclusion Criteria:

• Poorly controlled hypertension (Systolic BP>180 mmHg or Diastolic BP>100mmHg)

• Poorly controlled diabetes (HbA1c>6.4% or 48mmol/mol)

• Hypertrophic cardiomyopathy or history of QT prolongation (including family history), congestive heart failure, bradyarrhythmias, and electrolyte abnormalities

• History of bleeding disorders or significant haematological or immune diseases including, congenital or acquired immune deficiency, anaemia (Hb<130g/L for males and Hb<120 g/L in females) and thrombocytopenia (platelet count <150 × 109/L), use of other biological agents and immunosuppressant medications including oral/IV steroids

• Active or chronic infection (at PI discretion)

• History of Hepatitis B or C

• History of lymphoma and active malignancy

• Risk of dehydration due to reduced oral intake and lack of parenteral route

• Patient's contraindicated to tacrolimus according to SPC section 4.3

• Use of concomitant medications that interacts with tacrolimus according to the SPC, including but not limited to strong CYP3A4 inhibitors (i.e. azoles, protease inhibitors) or CYP3A4 inducers (rifampicin, phenytoin, carbamazepine), barbiturates, macrolides, digoxin, statins, PPI inhibitors, ergotamine, tricyclic antidepressants, herbal supplements (St. John's wort, extracts of Schisandra sphenanthera)

• Inability to swallow capsules

• Already taking the IMP in this comparison

• Known hypersensitivity, including lactose and gelatin intolerance, or adverse reaction to the active substances and their excipients (as per SPCs for this comparison) or any past medical history contraindicating use of the IMP in this comparison

• Receipt of a live attenuated vaccine within four weeks prior to receipt of tacrolimus. These include, but are not limited to live influenza vaccine (Fluenz Tetra), Shingles (varicella zoster virus) Zostavax, Varicella (Varilrix, Varilvax), Oral typhoid (Ty21a), and yellow fever vaccines.

Funders

• MND Scotland

• Euan MacDonald Centre for MND Research

• My Name'5 Doddie Foundation

Sponsor

NHS Lothian

Study design

Interventional; multi-arm, multi-stage, adaptive, randomised controlled trial

Current interventions

• Drug: Amantadine

• Drug: Tacrolimus

• Liquid placebo (matched to amantadine) 

• Tablet Placebo (matched to tacrolimus)

Phase

2/3

Outcome measures

Co-primary outcome measures

• Slope of decline in Amyotrophic Lateral Sclerosis Functional Rating Scale (Revised) (ALS-FRS(R)) over 18 months.

• Survival.

Secondary outcomes

• Time to King's stage 4a (nutritional failure).

• Time to King's stage 4b (respiratory failure).

• Cognitive function and behaviour assessed by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

• Respiratory function measured by forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP).

• Anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS).

• Quality of life evaluation – EQ-5D-5L.