MAGNET

A Multi-arm, Adaptive, Group-sequential trial NETwork to evaluate drug efficacy in patients with Amyotrophic Lateral Sclerosis (MAGNET)

Sub-protocol title: Randomized double-blind placebo-controlled phase 3 trial of Lithium Carbonate in Amyotrophic Lateral Sclerosis 

UK Chief Investigator

Professor Ammar Al-Chalabi

Research summary

The aim of this platform trial study is to simultaneously investigate the efficacy and safety of multiple drugs for ALS (Amyotrophic Lateral Sclerosis). We do this by using so-called 'study arms'. Each study arm investigates the efficacy and safety of one drug or a combination of drugs. Once it is clear which arm of the study you are participating in, you will be assigned a drug or placebo by drawing lots. A placebo is a substance without an active substance, a 'fake substance'.

Currently one arm is active that investigates the effect of lithium carbonate vs placebo in ALS. Lithium is a substance currently registered for use in bipolar disorders. This is a psychiatric disease that causes severe mood swings. Lithium affects multiple biological mechanisms involved in ALS. Previous research has shown that the drug is not effective in all patients with ALS, but may be beneficial in patients with a variation in the UNC13A gene (1 in 6 patients has this variation). Lithium is not currently being prescribed for ALS outside of this study.

Current status

Open to recruitment

Recruitment target

44 participants in the UK; up to 171 participants globally

Click here to see how many participants have been recruited into this study in the UK to date (external link to the NIHR public study search) 

Recruitment groups

Patients with Amyotrophic Lateral Sclerosis (ALS), a type of MND

Locations

• London - King's College Hospital, Principal Investigator: Ammar Al-Chalabi. Site open for recruitment out-of-area

• London - University College London, Principal Investigator: Andrea Malaspina. Site in set-up, opening soon

• London - St George's, Principal Investigator: Clare Galtrey. Site in set-up, opening soon

• Sheffield, Principal Investigator: Chris McDermott. Site in set-up, opening soon

• Stoke, Principal Investigator: Tom Lambert. Site open for recruitment out-of-area

Information about study sites

Contact details

Email: magnet@tricals.org

Key dates

Recruitment open date: 13 February 2023

Planned recruitment end date: 01 February 2024

Inclusion / exclusion criteria

Key inclusion criteria:

1. Age ≥18 years at the time of screening

2. Diagnosis of ALS according to the revised El Escorial criteria (possible, probable-laboratory supported, probable or definite)

3. Capable of providing informed consent and complying with trial procedures, including randomization to sub-studies

4. TRICALS risk profile >-6.0 and <-2.0 **

5. The use of riluzole will be permitted during the study. Subjects taking riluzole must be on a stable dose for at least 30 days prior to the baseline visit, or stopped taking riluzole at least 30 days prior to the baseline visit

6. Women of childbearing potential must have a negative pregnancy test at baseline and be non-lactating

7. Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug

8. Men must not plan to father a child or to provide sperm for donation for the duration of the trial and 3 months after the last dose of study drug

9. Women must not be able to become pregnant (e.g. post-menopausal, surgically sterile or using effective birth control methods) for the duration of the study.

Key exclusion criteria:

For all subjects:

1. Safety Laboratory Criteria at baseline:

1.1. ALT ≥5 times upper limit of normal (ULN)

1.2. AST ≥3 times ULN

1.3. Bilirubin ≥1.5 times ULN

1.4. Creatinine clearance <50 ml/min (Cockroft-Gault) based on Cystatin C

1.5. Platelet concentration of < 100 x109 per L

1.6. Absolute neutrophil count of < 1x109 per Lo Haemoglobin <100 g/L (<6.2 mmol/L)

1.7. Amylase & lipase ≥2 times ULN (suspected pancreatitis)

1.8. Lactate ≥2 times ULN (suspected lactate acidosis)

2. Moderate to severe hepatic impairment according to Child-Pugh classification (Class B or higher; score ≥ 7). Child-Pugh classification is based on bilirubin, albumin, International Normalized Ratio (INR) and presence of encephalopathy or ascites

3. Participation in any other investigational drug trial or using investigational drug (within 30 days prior to screening)

4. Hypothyroidism unresponsive to thyroid hormone supplementation

5. Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy

6. Subjects taking edaravone within 30 days prior to screening. Edaravone is approved by the FDA, but remains an investigational product in Europe and Australia

7. Clinically significant history of unstable or severe cardiac (e.g. congestive heart failure, coronary insufficiency and arrhythmias), oncological, hepatic or renal disease, neuromusculair diseases, significant pulmonary disorder or other medically significant illness

8. Drug or alcohol abuse

9. Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit. This exclusion criterion is based on a prior psychiatric diagnosis that is unstable as determined by the subject’s treating psychiatrist

10. Presence of frontotemporal dementia which prevents informed consent

For lithium carbonate:

1. Patients heterozygous or homozygous for the A-allele of rs12608932 (UNC13A)

2. Known allergy or hypersensitivity to lithium, or its excipients, or to the components of the placebo

3. Brain injury with posttraumatic epilepsy or neurologic deficit, excluding a concussion in the medical history. Brain infarction is an exclusion criterion, a transient ischemic attack is not

4. Addison disease

5. Patients with the following co-medication: antipsychotics, digoxin and calcium antagonists, carbamazepine, methyldopa, verapamil and diltiazem

6. Brugada Syndrome or family history of Brugada Syndrome

7. Plasma sodium <120 mmol/L 

Funder

Stichting TRICALS Foundation 

Sponsor

Stichting TRICALS Foundation 

Study design

Interventional, randomised controlled trial

Intervention

• Drug: Lithium carbonate  

• Placebo

Phase

3

Outcome measures

Primary outcome measure

• Overall survival, defined as time to death from any cause or respiratory insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days)

Secondary outcome measures

1. Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores

2. Daily functioning, defined as mean change from baseline in ALSFRS-R total score

3. Respiratory function, defined as mean change from baseline in SVC (% predicted of normal according to the GLI-2012 reference standard)

4. Quality of life, defined as change from baseline on the Visual Analogue Scale (single-item scale) and EQ-5D

5. Neuropsychological status, defined as change from baseline on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q)

6. Clinical disease stage, defined as mean time spent in each stage of the King’s and ALS Milano-Torino staging systems

7. Change from baseline in laboratory parameters:

7.1. Urinary P75ECD

7.2. Neurofilament light and heavy chain

7.3. Plasma creatinine

8. Tolerability, defined as time-to-discontinuation of the assigned treatment since randomization

9. Safety based on the safety assessments including physical neurological examinations, clinical laboratory evaluations, vital signs and frequency of adverse events (AEs) or serious adverse events (SAEs). (S)AEs will be categorized according to the Common Terminology Criteria for Adverse Events and will be rated for severity and association with the study drug