The objective of this phase III, placebo-controlled platform study is to investigate the efficacy of drugs for patients with ALS (Amyotrophic lateral sclerosis).
This study uses an innovative multi-arm, adaptive trial design to investigate the efficacy of multiple treatments simultaneously. Currently one study-arm is active, investigating the efficacy and safety of lithium carbonate versus placebo in patients with ALS. Only patients with a specific UNC13A genotype (approximately 1 in 6 ALS patients) are eligible to participate.
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, 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.
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 on
Cystatin C, if not available eGFR can also be calculated based on creatinine
clearance.
- 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 (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, neuromuscular 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 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 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