Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)

Inclusion Criteria:

1. ≥ 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, includingrandomization 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 riluzolemust be on a stable dose for at least 30 days prior to the baseline visit, orstopped taking riluzole at least 30 days prior to the baseline visit.

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

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

8. Men must not plan to father a child or to provide sperm for donation for theduration 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***, surgicallysterile 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% peryear when used consistently and correctly and, when applicable, in accordance withthe product label, including: abstinence, hormonal contraception, intrauterinedevice in place for ≥ 3 months Appendix 1). Women of childbearing potential musthave a negative pregnancy test at baseline, and be non-lactating. Women who arepregnant or are actively seeking to become pregnant, and women of reproductivepotential who are not using effective contraceptives are excluded.

Exclusion Criteria:

1. Laboratory Criteria at baseline:

• ALT (alanine transaminase) ≥ 5 times upper limit of normal (ULN)

• AST (aspartate aminotransferase) ≥ 3 times ULN

• Bilirubin ≥ 1.5 times ULN

• Estimated glomerular filtration rate (eGFR) < 50 mL / min / 1.73 m2 based onCystatin C, if not available eGFR can also be calculated based on creatinineclearance.

• Platelet concentration of < 100 x109 per L

• Absolute neutrophil count of < 1x109 per L

• Haemoglobin < 100 g/L (<6.2 mmol/L)

• Amylase & lipase ≥ 2 times ULN (suspected pancreatitis)

• Lactate ≥ 2 times ULN (suspected lactate acidosis)

2. Moderate to severe hepatic impairment according to Child-Pugh classification (ClassB 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 atracheostomy.

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

7. Clinically significant history of unstable or severe cardiac (e.g. congestive heartfailure, coronary insufficiency and arrhythmias), oncological, hepatic or renaldisease, neuromuscular diseases, significant pulmonary disorder or other medicallysignificant illness.

8. Drug or alcohol abuse.

9. Unstable psychiatric illness defined as psychosis or untreated major depressionwithin 90 days of the screening visit. This exclusion criterion is based on a priorpsychiatric diagnosis that is unstable as determined by the subject's treatingPsychiatrist.

10. Presence of frontotemporal dementia which prevents informed consent.

Lithium carbonate study-specific exclusion criteria:

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

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

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

4. Addison disease.

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

6. Brugada Syndrome or family history of Brugada Syndrome.

7. Plasma sodium <120 mmol/L