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Testing drugs to slow down motor neurone disease progression

Motor Neurone Disease - Systematic Multi-Arm Adaptive Randomised Trial

Phase2; Phase3 Interventional University of Edinburgh · NCT04302870

This study is testing if the drug amantadine can help slow down motor neurone disease and improve survival for people living with it.

Quick facts

PhasePhase2; Phase3
Study typeInterventional
Enrollment1150 (estimated)
Ages18 Years and up
SexAll
SponsorUniversity of Edinburgh Academic / other
Locations22 sites (Portadown, County Armagh and 21 other locations)
Trial IDNCT04302870 on ClinicalTrials.gov

What this trial studies

MND-SMART is a multi-arm adaptive trial investigating the effectiveness of various approved drugs, including amantadine, in slowing the progression of motor neurone disease (MND) and improving survival rates. The trial employs an adaptive design, allowing for the removal of ineffective treatments and the addition of new ones based on emerging results. Participants are randomly assigned to receive either the drug or a placebo, with the current focus on evaluating amantadine against a placebo. This approach aims to optimize treatment options for patients with MND.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with a confirmed diagnosis of motor neurone disease, including various subtypes like ALS.

Not a fit: Patients diagnosed with Frontotemporal Dementia or significant psychiatric disorders may not benefit from this study.

Why it matters

Potential benefit: If successful, this trial could lead to improved treatment options that slow disease progression and enhance survival for patients with motor neurone disease.

How similar studies have performed: Previous studies have shown varying success with similar adaptive trial designs, but the specific approach of MND-SMART is relatively novel.

Eligibility criteria

Show full inclusion / exclusion 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.

Where this trial is running

Portadown, County Armagh and 21 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Motor Neuron Disease, Amyotrophic Lateral Sclerosis
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.