Magnet Study

Prior treatment

• Participation in any other investigational drug trial or using any investigational drug (beginning within 30 days prior to baseline). Only in the exceptional circumstance that an investigational product is available through an EAP, CUP or similar AND for which a clear clinical benefit has been demonstrated in phase 3 study can an exception be made after discussion with the PI and TRICALS.
• Drug or alcohol abuse.
• 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.

Other illness

• Presence of frontotemporal dementia which prevents informed consent.
• Known allergy or hypersensitivity to lithium, or its excipients, or to the components of the placebo.
• 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.
• Addison disease.
• Brugada Syndrome or family history of Brugada Syndrome.
• 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.

Lab values

• Safety Laboratory Criteria at baseline: o ALT ≥ 5 times upper limit of normal (ULN) o AST ≥ 3 times ULN o Bilirubin ≥ 1.5 times ULN (Gilbert syndrome is accepted) o Estimated glomerular filtration rate (eGFR) < 50 mL / min / 1.73 m2 based on Cystatin C, if not available eGFR can also be calculated based on creatinine clearance. o Platelet concentration of < 100 x109 per L o Absolute neutrophil count of < 1x109 per L o Haemoglobin < 100 g/L (<6.2 mmol/L) o Both amylase & lipase ≥ 2 times ULN (suspected pancreatitis) o Lactate ≥ 2 times ULN (suspected lactate acidosis)
• Patients with the following co-medication: antipsychotics, digoxin and calcium antagonists, carbamazepine, methyldopa, verapamil and diltiazem.
• Plasma sodium <120 mmol/L
• 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.

Other

• Patients heterozygous or homozygous for the A-allele of rs12608932 (UNC13A)
• Hypothyroidism unresponsive to thyroid hormone supplementation.
• Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy.
• [No longer applicable since protocol version 3.2]

• Age ≥ 18 years at the time of screening.
• Diagnosis of ALS according to the revised El Escorial criteria (possible, probable-laboratory supported, probable or definite).
• Capable of providing informed consent and complying with trial procedures, including randomization to sub-studies.
• TRICALS risk profile ≥ -6.00 and ≤ -2.00 **
• 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.
• Women of childbearing potential* must have a negative pregnancy test at baseline and be non-lactating.
• Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug.
• 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.
• 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. Effective contraceptives are defined as having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label, including: abstinence, hormonal contraception, intrauterine device in place for ≥ 3 months (Appendix 1). Women of childbearing potential must have a negative pregnancy test at baseline, and be non-lactating. Women who are pregnant or are actively seeking to become pregnant, and women of reproductive potential who are not using effective contraceptives are excluded.