Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
- Conditions
- Motor Neuron Disease, Amyotrophic Lateral Sclerosis
- Interventions
- Drug: Placebo oral solutionDrug: Tacrolimus 1Mg CapDrug: Placebo capsule
- Registration Number
- NCT04302870
- Lead Sponsor
- University of Edinburgh
- Brief 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). 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.
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
For further information, please visit: https://mnd-smart.org/
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1150
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Memantine Memantine Hydrochloride Oral Solution - Trazodone Trazodone Hydrochloride oral solution - Placebo (liquid) Placebo oral solution - Amantadine Amantadine Hydrochloride Oral Solution - Tacrolimus Tacrolimus 1Mg Cap - Placebo (tablet) Placebo capsule -
- Primary Outcome Measures
Name Time Method Change in decline of ALS-FRS(R) over 18months 18 months Co-primary outcome measure
Survival 18 months Co-primary outcome measure
- Secondary Outcome Measures
Name Time Method Cognition and behaviour 18 months Using Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
Respiratory function - Forced vital capacity 18 months Change in FVC
King's ALS Clinical stage 18 months Time to reach King's stage IV, scale range I - V
Changes in anxiety and depression 18 months Measured using the hospital anxiety and depression scale (HADS), scale range 0 - 42
Changes in Quality of Life 18 months Measured using EQ-5D-5L
Safety and tolerability of IMPs 18 months Measured using adverse events
Trial Locations
- Locations (22)
Southern Health and Social Care Trust, Craigavon Area Hospital
🇬🇧Portadown, County Armagh, 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
Scroll for more (12 remaining)Southern Health and Social Care Trust, Craigavon Area Hospital🇬🇧Portadown, County Armagh, United KingdomRaeburn ForbesContact