Table 2.

MND-SMART eligibility criteria (protocol version 6.0)

Inclusion criteria
Confirmed diagnosis of MND (including the following subtypes: amyotrophic lateral sclerosis by El Escorial criteria (possible, probable and definite), primary lateral sclerosis and progressive muscular atrophy). Over 18 years of age. Women of childbearing potential 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
Diagnosis of 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 or any medical history contraindicating use of any of the investigational medicinal products (IMPs). Pregnancy or breastfeeding females. If ALT, ALP, bilirubin or GGT>3 times the upper limit of normal; creatinine clearance (creatinine clearance or eGFR)<30 mL/min; or serum free T4>25 pmol/L or TSH<0.2 mU/L.	If corrected QT interval on 12 lead ECG>450 ms. Diagnosis of ventricular arrhythmias, heart block or in the immediate recovery period after myocardial infarction (<6 weeks). Already taking any of the IMPs in the protocol. Contraindications to any of the IMPs according to summary of product characteristics (SPC). Taking a medication that interacts with the active substances and their excipients according to the SPCs, including but not limited to; dextromethorphan, amantadine; ketamine, monoamine-oxidase inhibitors ((MAOIs): rasagiline, selegiline, safinamide, tranylcypromine, phenelzine, isocarboxazid, moclobemide). Patients who the PI considers will not be able to comply with the study protocol.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyltransferase; MND, motor neuron disease; MND-SMART, Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial; PI, Principal Investigator; TSH, thyroid-stimulating hormone.