Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

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 EscorialCriteria (possible, probable, and definite) or Gold Coast Criteria, Primary LateralSclerosis, and Progressive Muscular Atrophy

• Over 18

• Women of childbearing potential according to CTFG guidelines must have a negativepregnancy test within 7 days prior to, or at, the baseline visit

• Women of childbearing potential and fertile men must be using an appropriate methodof contraception to avoid any unlikely teratogenic effects of the selected drugsfrom time of consent, to 4 weeks after treatment inclusive

• Willing and able to comply with the trial protocol and ability to understand andcomplete questionnaires

• Written informed consent (in the case of limb dysfunction verbal consent can begiven in the presence of a witness who can sign)

Core Exclusion Criteria:

• Patients diagnosed with Frontotemporal Dementia (FTD-MND) or any other significantpsychiatric 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 theinvestigator's discretion)) or in the immediate recovery period after myocardialinfarction (< 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 adversereaction to the active substances and their excipients (as per SPCs for thiscomparison) or any past medical history contraindicating use of the IMP in thiscomparison

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 familyhistory), congestive heart failure, bradyarrhythmias, and electrolyte abnormalities

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

• 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, proteaseinhibitors) 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 adversereaction to the active substances and their excipients (as per SPCs for thiscomparison) or any past medical history contraindicating use of the IMP in thiscomparison

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