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Motor Neuron Disease, Amyotrophic Lateral SclerosisPhase 2/3MND-SMARTNCT04302870

Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

A Phase 2/3 study testing Memantine Hydrochloride Oral Solution, Trazodone Hydrochloride oral solution and Amantadine Hydrochloride Oral Solution in people with Motor Neuron Disease, Amyotrophic Lateral Sclerosis, run by University of Edinburgh at 22 sites in United Kingdom.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

MND-SMART is investigating whether selected drugs can slow down the progression of motor neuron 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Memantine Hydrochloride Oral Solution, Trazodone Hydrochloride oral solution and Amantadine Hydrochloride Oral Solution
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
1,150 participants
Where
22 sitesUnited Kingdom
Study dates
27 Feb 2020to Dec 2030
Phase
Phase 2/3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Participants will be considered eligible for randomisation if they fulfil all the core inclusion criteria and none of the exclusion criteria as defined below. In addition, investigators must simultaneously check and ensure participants do not meet any of the drug specific exclusion criteria. If exclusion criteria are met for an arm, participants can still be considered for other arms and randomised accordingly to eligible arms.

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.

Trial locations and contacts

22 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Professor Chandran contact

0131 465 9612

siddharthan.chandran@ed.ac.uk

Amy Stenson contact

0131 242 9122

astenson@exseed.ed.ac.uk

22 sites in 1 country

United Kingdom22 sites, 22 recruiting

  • Aberdeen Royal Infirmary

    Aberdeen

    Callum Duncan

    Recruiting

  • University Hospitals of Birmingham NHS Foundation Trust

    Birmingham, B15 2TH

    Venkatamaran Srinivasan

    Recruiting

  • University Hospitals Sussex NHS Foundation Trust

    Brighton

    Andrew Barritt

    Recruiting

  • West Suffolk NHS Foundation Trust

    Bury St Edmunds, IP33 2QZ

    Francesca Crawley

    Recruiting

  • Cambridge University Hospitals NHS Foundation Trust

    Cambridge, CB2 0QQ

    Rhys Roberts

    Recruiting

  • Cardiff and Vale University Local Health Board

    Cardiff, CF14 4XW

    Ken Dawson

    Recruiting

  • Clinical Research Centre , Ninewells Hospital

    Dundee

    Ian Morrison

    Recruiting

  • Anne Rowling Regenerative Neurology Clinic

    Edinburgh, EH16 4SB

    Judith Newton, 0131 465 9517, loth.mndsmart@nhslothian.scot.nhs.uk

    Recruiting

  • Royal Devon and Exeter Hospital

    Exeter

    Timothy Harrower

    Recruiting

  • Queen Elizabeth University Hospital Clinical Research Facility

    Glasgow

    George Gorrie

    Recruiting

  • NHS Highland Clinical Research Facility, Raigmore Hospital

    Inverness

    Javier Carod Artal

    Recruiting

  • East Suffolk and North Essex NHS Foundation Trust

    Ipswich, CO4 5JL

    Clare Galton

    Recruiting

  • Royal London Hospital

    London, E1 1FR

    Aleks Radunovic

    Recruiting

  • St George's University Hospitals NHS Foundation Trust

    London, SW17 0QT

    Pablo Garcia Reitboeck

    Recruiting

  • King's College Hospital NHS Foundation Trust

    London

    Ammar Al-Chalabi

    Recruiting

  • Newcastle upon Tyne Hospitals NHS Foundation Trust

    Newcastle upon Tyne, NE7 7DN

    Tim Williams

    Recruiting

  • Norfolk and Norwich University Hospitals NHS Foundation Trust

    Norwich, NR4 7UY

    Godwin Mamutse

    Recruiting

  • University Hospitals of Dorset NHS Trust

    Poole

    Charles Hillier

    Recruiting

  • Southern Health and Social Care Trust, Craigavon Area Hospital

    Portadown, County Armagh, BT63 5QQ

    Raeburn Forbes

    Recruiting

  • Clinical Research Facility Salford Royal NHS Foundation Trust

    Salford

    Hisham Hamdalla

    Recruiting

  • Sheffield Teaching Hospitals NHS Foundation Trust

    Sheffield

    Christopher McDermott

    Recruiting

  • Clinical Research Facility University Hospital Southampton

    Southampton

    Ashwin Pinto

    Recruiting

Other trials in United Kingdom

About this study

MND-SMART is investigating whether selected drugs can slow down the progression of motor neuron 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. 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.

Read more

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.

Read the detailed description

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

Being tested
Memantine Hydrochloride Oral Solution, Trazodone Hydrochloride oral solution, Placebo oral solution, Amantadine Hydrochloride Oral Solution, Tacrolimus 1Mg Cap
Medical subject headings
Amyotrophic Lateral Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Memantine Hydrochloride Oral SolutionDrug

    Memantine hydrocholoride taken once daily

  • Trazodone Hydrochloride oral solutionDrug

    Trazodone Hydrochloride taken once daily

  • Placebo oral solutionDrug

    Placebo taken once daily

  • Amantadine Hydrochloride Oral SolutionDrug

    Amantadine Hydrochloride taken once daily

  • Tacrolimus 1Mg CapDrug

    Tacrolimus 1Mg overencapsulated tablet taken once daily

  • Placebo capsuleDrug

    Placebo taken once daily

Study groups in NCT04302870
Study groupRoleWhat they receive
MemantineExperimentalNot described
Receives: Drug: Memantine Hydrochloride Oral Solution
TrazodoneExperimentalNot described
Receives: Drug: Trazodone Hydrochloride oral solution
Placebo (liquid)Placebo comparatorNot described
Receives: Drug: Placebo oral solution
AmantadineExperimentalNot described
Receives: Drug: Amantadine Hydrochloride Oral Solution
TacrolimusExperimentalNot described
Receives: Drug: Tacrolimus 1Mg Cap
Placebo (tablet)Placebo comparatorNot described
Receives: Drug: Placebo capsule

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in decline of ALS-FRS(R) over 18months

    Co-primary outcome measure

    Measured: 18 months

  2. Survival

    Co-primary outcome measure

    Measured: 18 months

Secondary outcomes (6)

  1. Cognition and behaviour

    Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)

    Measured: 18 months

  2. Respiratory function - Forced vital capacity

    Change in FVC

    Measured: 18 months

  3. King's ALS Clinical stage

    Time to reach King's stage IV, scale range I - V

    Measured: 18 months

  4. Changes in anxiety and depression

    Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42

    Measured: 18 months

  5. Changes in Quality of Life

    Measured using EQ-5D-5L

    Measured: 18 months

  6. Safety and tolerability of IMPs

    Measured using adverse events

    Measured: 18 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Mar 2020
  2. Study start27 Feb 2020
  3. Primary completionDec 2030 (estimated)
  4. Study completionDec 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
1,150 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04302870
Sponsor's protocol ID
AC18082
Acronym
MND-SMART
Status last verified
Mar 2026
First submitted
4 Mar 2020
Last updated
4 Mar 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: To ensure data transparency, the results of any closed comparisons will be published in a peer reviewed journal as soon as it is possible when the integrity of the trial will not be affected. Individual level participant data will be shared ,after deidentification, upon receipt of a valid request. Some data may be shared prior to the publication of study results depending on the requirements, however no end point data will be released without explicit need and permission from the TSC. Each data request form will be individually reviewed to ensure the proposal has a valid rationale and appropriate methodology. Only data required for the project will be shared. A summary of results will be provided to all participants via newsletters and the trial website.

Publications

  • Pal S, Chataway J, Swingler R, Macleod MR, Carragher NO, Hardingham G, Selvaraj BT, Smith C, Wong C, Newton J, Lyle D, Stenson A, Dakin RS, Ihenacho A, Colville S, Mehta AR, Stallard N, Carpenter JR, Parker RA, Keerie C, Weir CJ, Virgo B, Morris S, Waters N, Gray B, MacDonald D, MacDonald E, Parmar MKB, Chandran S; MND SMART Investigators. Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial. Lancet Neurol. 2024 Nov;23(11):1097-1107. doi: 10.1016/S1474-4422(24)00326-0. Epub 2024 Sep 19.

    PubMed 39307154

  • Wong C, Gregory JM, Liao J, Egan K, Vesterinen HM, Ahmad Khan A, Anwar M, Beagan C, Brown FS, Cafferkey J, Cardinali A, Chiam JY, Chiang C, Collins V, Dormido J, Elliott E, Foley P, Foo YC, Fulton-Humble L, Gane AB, Glasmacher SA, Heffernan A, Jayaprakash K, Jayasuriya N, Kaddouri A, Kiernan J, Langlands G, Leighton D, Liu J, Lyon J, Mehta AR, Meng A, Nguyen V, Park NH, Quigley S, Rashid Y, Salzinger A, Shiell B, Singh A, Soane T, Thompson A, Tomala O, Waldron FM, Selvaraj BT, Chataway J, Swingler R, Connick P, Pal S, Chandran S, Macleod M. Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus. BMJ Open. 2023 Feb 1;13(2):e064169. doi: 10.1136/bmjopen-2022-064169.

    PubMed 36725099

  • Parker RA, Weir CJ, Pham TM, White IR, Stallard N, Parmar MKB, Swingler RJ, Dakin RS, Pal S, Chandran S. Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART). Trials. 2023 Jan 16;24(1):29. doi: 10.1186/s13063-022-07007-z.

    PubMed 36647114

  • Wong C, Dakin RS, Williamson J, Newton J, Steven M, Colville S, Stavrou M, Gregory JM, Elliott E, Mehta AR, Chataway J, Swingler RJ, Parker RA, Weir CJ, Stallard N, Parmar MKB, Macleod MR, Pal S, Chandran S. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease. BMJ Open. 2022 Jul 7;12(7):e064173. doi: 10.1136/bmjopen-2022-064173.

    PubMed 35798516

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Memantine Hydrochloride Oral Solution, Trazodone Hydrochloride oral solution and Amantadine Hydrochloride Oral Solution in people with Motor Neuron Disease, Amyotrophic Lateral Sclerosis, run by University of Edinburgh at 22 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 22 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Professor Chandran (0131 465 9612, siddharthan.chandran@ed.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in decline of ALS-FRS(R) over 18months (time frame: 18 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04302870, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2026; AzTrials last refreshed its copy on 30 Oct 2026.

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