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

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. 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.

For the Open Label Extension:
Inclusion criteria:
1. Completion of the end of study visit (month 24) in the MAGNET lithium study,
while on study medication
2. Signed informed consent for participation in the lithium extension
3. Capable of providing informed consent and complying with trial procedures
4. The same inclusion criteria of the MAGNET master protocol and MAGNET lithium
subprotocol apply, with the exception of the TRICALS risk profile.

1. 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) Creatinine clearance < 50 mL /
min (Cockroft-Gault) 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)

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 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.
4. Hypothyroidism unresponsive to thyroid hormone supplementation.
5. Subjects using non-invasive ventilation (NIV, >=22 h per day) or having a
tracheostomy.
6. [No longer applicable since protocol version 3.2]
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.

Lithium subprotocol specific 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 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


For the Open Label Extension:
1. Judgement by the investigator that the patient is an unsuitable candidate,
or that the patient is unable or unlikely to comply with the dosing schedule or
study evaluations
2. The same exclusion criteria of the MAGNET master protocol and MAGNET lithium
subprotocol apply