EXPErimental medicine Route To Success in Amyotrophic Lateral Sclerosis (EXPERTS-ALS)

Plain English Summary

Background and study aims
Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND), is a fatal disease affecting 1 in 300 people. ALS causes muscle wastage that gets worse over time, leading to loss of the ability to walk, talk, eat and eventually breathe. There is no cure or highly effective disease-slowing therapy for ALS.
Historically, drug trials for ALS have been unsuccessful. A process that can quickly screen drugs in people with ALS, rather than in cells or animal models, is believed will be better at selecting treatments for the large Phase III trials that are needed. EXPERTS-ALS is a UK multicentre study that will screen drugs for their potential to slow the progression of ALS, by looking at changes in blood test markers. Higher blood levels of a marker known as neurofilament light chain (NFL), a building block of nerve cells, are associated with faster rates of ALS disability. A drug will be recommended to go forward into Phase III trials if a large and important reduction in blood NFL levels is seen.

Who can participate?
Patients with a diagnosis of ALS aged at least 18 years old and over at the time of consent

What does the study involve?
EXPERTS-ALS is an adaptive trial, meaning that drugs can be added, assessed and removed as the trial is ongoing. Drugs will be selected for the study based on explicit criteria agreed upon by a group of experts. The data generated throughout the study will be analysed, and if a drug does not meet the team's pre-agreed criteria, it will be removed from the study. There will be no placebo/dummy drug. Participants will know what drug they are receiving and will take it for a maximum of 6 months. The study aims to test between 9-12 drugs over 5 years.

What are the possible benefits and risks of participating?
The results of this study will help to prioritise drugs for testing in larger clinical trials to inform the treatment of future patients with ALS. By taking part in the study, participants are directly helping to do this.

Taking part in EXPERTS-ALS will require participants to attend additional hospital appointments. Travel costs to EXPERTS-ALS appointments will be reimbursed if required. To try and minimise the burden, it will be possible for participants to attend the week 4 and week 8 study appointments remotely (via telephone or video call) unless there are drug-specific safety assessments required.

The study drugs are all repurposed medications which are used widely in other settings however participants may experience side effects from taking the study drugs. Possible side effects will be listed in the drug-specific PISs, and information on who to contact if side effects are experienced will be included. Participants will also be asked about any side effects experienced at their routine study visits. Depending on the drug, it may be possible to reduce the dose taken if a participant is struggling with side effects. Local study teams will review participants’ treatment regularly and may decide to pause or stop the medication if needed.

Fasting blood samples will be required at two time points, one before randomisation (at either the screening or baseline visit) and one at week 12. Participants will be required not to eat anything from 8.30 pm the night before their appointment and to drink only water. These appointments will be scheduled to take place in the morning to minimise inconvenience for participants.

Where is the study run from?
Royal Hallamshire Hospital, UK

When is the study starting and how long is it expected to run for?
February 2024 to September 2028

Who is funding the study?
EXPERTS-ALS is funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership.

Who is the main contact?
experts-als@sheffield.ac.uk

Study website

https://www.experts-als.uk/

Type

Scientific

Contact name

Dr Jennifer Petrie

ORCID ID

Contact details

Clinical Trials Research Unit
The University of Sheffield
30 Regent Street
Sheffield
S1 4DA
United Kingdom
None provided
experts-als@sheffield.ac.uk

Type

Scientific, Principal Investigator

Contact name

Prof Christopher McDermott

ORCID ID

Contact details

Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom
+44 (0)114 222 2295
c.j.mcdermott@sheffield.ac.uk

EudraCT/CTIS number

Nil known

IRAS number

1007791

ClinicalTrials.gov number

Nil known

Protocol/serial number

EXPERTS-ALS, IRAS 1007791, CPMS 55939

Scientific title

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

Acronym

EXPERTS-ALS

Study hypothesis

To determine:
- Whether a candidate drug is associated with a relevant decrease in mean group neurofilament light chain (NFL) level from baseline.
- How a candidate drug ranks compared with concurrently or previously randomised competitor drugs on its effect on mean NFL levels.

Secondary objectives:
- To evaluate the safety and tolerability of candidate drugs in patients with ALS.
- To assess the effect of candidate drugs on standard clinical measures of daily functioning (e.g. ALS revised functional rating scale ALSFRS-R) and clinical (King’s) stage.
- To create an ALS sample bioresource for further research.

Exploratory objectives:
- To explore survival without tracheostomy or non-invasive ventilation and compare it with the median prediction of survival without tracheostomy or non-invasive ventilation from the European Network for the Cure of ALS (ENCALS) survival prediction model.
- To explore the effect of candidate drugs on disability and quality of life.
- To explore respiratory function assessments and determine the feasibility and validity of remote, unsupervised respiratory function assessment as compared with supervised assessments.

Ethics approval(s)

Approved 08/04/2024, London - Harrow Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8154, (0)207 104 8357; harrow.rec@hra.nhs.uk), ref: 24/LO/0205

Study design

Randomized open-label parallel-group adaptive platform trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Study setting(s)

Hospital, Internet/virtual, Medical and other records, Telephone

Study type

Safety, Efficacy

Patient information sheet

Condition

Amyotrophic lateral sclerosis (ALS)

Intervention

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 1000mg once daily.

Nifedipine: LA/XL versions of nifedipine formulated for once-daily dosing will be used where possible. The starting and target dose is 30mg 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 2mg once per day and building up by 2mg per day at weekly intervals to a dose of 16mg 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.

Intervention type

Drug

Pharmaceutical study type(s)

Therapy

Phase

Phase II

Drug/device/biological/vaccine name(s)

Metformin, Nifedipine, Ropinirole

Primary outcome measure

Change in blood neurofilament light chain (NFL) levels measured using automated immunoassay analysed via the SIMOA HD-X instrument (Quanterix) from baseline to weeks 18 and 24

Secondary outcome measures

Secondary outcomes:
1. Change in daily functioning measured using the ALS revised functional rating scale (ALSFRS-R) score from baseline to weeks 12 and 24
2. Progression in the clinical stage by 1 stage or more measured using King’s staging system from baseline to week 24
3. Adverse events and serious adverse events measured using data recorded at each study visit during the trial

Exploratory outcomes:
1. Survival without tracheostomy or non-invasive ventilation at 12 months, compared with the ENCALS median prediction of survival without tracheostomy or non-invasive ventilation
2. Change in WHO Disability Assessment Schedule (WHODAS 2.0) and Quality of Life (WHOQOL-Bref) from baseline to 24 weeks (or early discontinuation of treatment) against a natural history cohort
3. In-person forced vital capacity (FVC) and peak cough flow (PCF), compared with remote FVC (rFVC) and remote PCF (rPCF) where readings are available within +/- 7 days of each other (FVC and PCF measured at screening, baseline, week 12 and week 24 post randomisation)

Overall study start date

16/02/2024

Overall study end date

30/09/2028

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Diagnosis of ALS according to Gold Coast criteria.
2. Age at least 18 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.

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Sex

Both

Target number of participants

700

Participant 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.

Recruitment start date

30/06/2024

Recruitment end date

31/03/2028

Countries of recruitment

United Kingdom

Study participating centre

-
-
United Kingdom

Organisation

Sheffield Teaching Hospitals NHS Foundation Trust

Sponsor details

Royal Hallamshire Hospital
Sheffield
S10 2JF
England
United Kingdom
+44 (0)114 2265941
dipak.patel12@nhs.net

Sponsor type

University/education

Website

https://www.sheffield.ac.uk/

ROR

https://ror.org/018hjpz25

Funder type

Government

Funder name

Efficacy and Mechanism Evaluation Programme

Alternative name(s)

NIHR Efficacy and Mechanism Evaluation Programme, EME

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

1. Peer reviewed scientific journals
2. Internal report
3. Conference presentation
4. Publication on website
5. Submission to regulatory authorities
6. Other
Anonymised data sets can be made available to other researchers. Participants are asked to consent to their anonymised data being used to support other research in the future and are informed that it may be shared with researchers outside of the research team, including potential international and commercial collaborations.

Intention to publish date

31/03/2028

Individual participant data (IPD) sharing plan

The data-sharing plans for the current study are unknown and will be made available at a later date.

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs