Clinical trial NCT04302870: Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
Official title: Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Motor Neuron Disease, Amyotrophic Lateral Sclerosis
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: University College, London
name: University of Warwick
name: NHS Lothian
First posted: 2020-03-10
Enrollment: 1150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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/

Eligibility criteria: 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.

Primary outcomes:
measure: Change in decline of ALS-FRS(R) over 18months
timeFrame: 18 months
measure: Survival
timeFrame: 18 months
Secondary outcomes:
measure: Cognition and behaviour
timeFrame: 18 months
measure: Respiratory function - Forced vital capacity
timeFrame: 18 months
measure: King's ALS Clinical stage
timeFrame: 18 months
measure: Changes in anxiety and depression
timeFrame: 18 months
measure: Changes in Quality of Life
timeFrame: 18 months
measure: Safety and tolerability of IMPs
timeFrame: 18 months
Other outcomes:
Locations:
city: Portadown
country: United Kingdom
facility: Southern Health and Social Care Trust, Craigavon Area Hospital
state: County Armagh
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Birmingham
country: United Kingdom
facility: University Hospitals of Birmingham NHS Foundation Trust
city: Brighton
country: United Kingdom
facility: University Hospitals Sussex NHS Foundation Trust
city: Bury Saint Edmunds
country: United Kingdom
facility: West Suffolk NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University Local Health Board
city: Dundee
country: United Kingdom
facility: Clinical Research Centre , Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Anne Rowling Regenerative Neurology Clinic
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital Clinical Research Facility
city: Inverness
country: United Kingdom
facility: NHS Highland Clinical Research Facility, Raigmore Hospital
city: Ipswich
country: United Kingdom
facility: East Suffolk and North Essex NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
city: Poole
country: United Kingdom
facility: University Hospitals of Dorset NHS Trust
city: Salford
country: United Kingdom
facility: Clinical Research Facility Salford Royal NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: Clinical Research Facility University Hospital Southampton
Study officials:
affiliation: University of Edinburgh
name: Professor Chandran
role: STUDY_DIRECTOR
References:
citation: 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.