A multi-centre, Bayesian phase II, open label, randomised drug prioritisation platform trial using blood neurofilament light (NFL) chain levels as a surrogate outcome for biological efficacy in patients with ALS
Amyotrophic lateral sclerosis (ALS)
The EXPERTS-ALS protocol describes an overarching trial design to evaluate the effect of candidate drugs on blood NFL levels in patients with ALS receiving usual standard of care. The protocol is deliberately flexible, allowing: ● as broad a range of ALS patients to be recruited; ● participant randomisation between only those treatment arms that are not believed by the enrolling doctor to be contraindicated (e.g., by particular co-morbid conditions or concomitant medications); and ● treatment arms to be added or removed according to the emerging evidence from within the trial. The current treatment arms are metformin, nifedipine and ropinirole. Metformin: Where possible, prolonged-release tablets should be used. The starting dose is 500mg once daily, taken with the evening meal. After 14 days the dose should be increased to 1000 mg once daily. Nifedipine: LA/XL versions of nifedipine formulated for once-daily dosing will be used where possible. The starting and target dose is 30 mg LA/XL once daily. As a precaution against potential hypotension, it is recommended that the dose be taken at bedtime. Ropinirole: Where possible, prolonged-release tablets should be used. Ropinirole HCl extended-release in a starting dose of 2 mg once per day and building up by 2 mg per day at weekly intervals to a dose of 16 mg per day. Randomisation is completed by a member of the local study team by accessing a web-based randomisation system provided by the University of Sheffield Clinical Trials Research Unit. Follow-up visits are completed at week 4*, week 8*, week 12, week 18 and week 24 post-randomisation. *May be completed remotely by telephone call. Survival status will be collected at 12 months post-randomisation via a review of medical records. Updated 16/06/2026: The current treatment arms are metformin, nifedipine, ropinirole, doxycycline and salbutamol. Doxycycline: The starting and target dose is 50 mg (capsule) once daily. Dispersible tablets may be used if a par
1. Diagnosis of ALS according to Gold Coast criteria. 2. Age at least 18 years at the time of consent. 3. ENCALS prognosis risk score of -6.0 to -2.0 as calculated from the results of the screening visit. 4. Those taking riluzole must be on a stable dose for at least 30 days prior to the baseline visit or must have chosen not to take it for the study duration. 5. Must be able to be randomised to at least two of the open arms after reviewing contraindications, current medication and the IMP-specific eligibility criteria as detailed in the IMP-specific appendices. 6. Fertile persons must use adequate contraception if required by the IMPs (see protocol Section 5.8 and IMP-specific appendices for details). 7. Persons of childbearing potential must have a negative pregnancy test prior to randomisation.
Current exclusion criteria as of 14/03/2025: 1. Clinically significant history of unstable or severe cardiac, oncological, hepatic or renal disease or other medically significant illness which, in the opinion of the local investigator*, is a contraindication to participation. 2. Presence of an active disorder (other than ALS) which is known to independently raise NFL levels. 3. Treatment with IMP in any other investigational drug trial within 30 days prior to screening. 4. Pre-existing use of current EXPERTS-ALS IMPs or drugs in the same class as current EXPERTS-ALS IMPs that would result in the patient not being able to be randomised between a minimum of two arms. 5. Contraindications to IMPs that would result in the patient not being able to be randomised between a minimum of two arms. Refer to IMP-specific appendices for details. 6. Use of non-invasive ventilation >22 hr/day or invasive ventilation. 7. Pregnant or breastfeeding 8. Unable to comply with trial procedures. _____ Previous exclusion criteria: 1. Clinically significant history of unstable or severe cardiac, oncological, hepatic or renal disease or other medically significant illness which, in the opinion of the local investigator*, is a contraindication to participation. 2. Presence of an active disorder (other than ALS) which is known to independently raise NFL levels. 3. Participation in any other investigational drug trial within 30 days prior to screening. 4. Pre-existing use of current EXPERTS-ALS IMPs or drugs in the same class as current EXPERTS-ALS IMPs that would result in the patient not being able to be randomised between a minimum of two arms. 5. Contraindications to IMPs that would result in the patient not being able to be randomised between a minimum of two arms. Refer to IMP-specific appendices for details. 6. Use of non-invasive ventilation >22 hr/day or tracheostomy ventilation. 7. Pregnant or breastfeeding 8. Unable to comply with trial procedures.