Amyotrophic lateral sclerosis (ALS) Nervous System Diseases Motor neuron disease
Conditions
Interventions
Lithium carbonate or placebo are supplied as white hard gelatin capsules size 00 filled with white to off-white powder. Each capsule contains 400 mg of lithium carbonate or placebo. Capsules will be t
Sponsors
Stichting TRICALS Foundation
Eligibility
Sex/Gender
All
Inclusion criteria
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. 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
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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). For each sub-study, there is one pre-planned, event-driven, interim analysis when approximately 60% of the required events are available. If the trial cannot be terminated early, the trial continues until the required number of events is reached or until 24 months after the last enrolled patient, whichever occurs first. Patients are required to visit the clinic every 3 months for a maximum duration of 24 months. In case of the lithium sub-study, if treatment is futile, the trial can be stopped after an average of 28.0 months since first enrolled patient with an average sample size of 137 patients. In this scenario, the probability for individual patients to remain in the trial for 18 months or more is 11.3% and to complete 24 months of follow-up is 1.8%. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores, measured quarterly for a maximum duration of 24 months 2. Daily functioning, defined as mean change from baseline in ALSFRS-R total score, measured quarterly for a maximum duration of 24 months 3. Respiratory function, defined as mean change from baseline in SVC (% predicted of normal according to the GLI-2012 reference standard), measured quarterly for a maximum duration of 24 months 4. Quality of life, defined as change from baseline on the Visual Analogue Scale (single-item scale) and EQ-5D, measured quarterly for a maximum duration of 24 months 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), measured yearly 6. Clinical disease stage, defined as mean time spent in each stage of the King’s and ALS Milano-Torino staging systems, measured quarterly for a maximum duration of 24 months 7. Change from baseline in laboratory parameters: 7.1. Urinary P75ECD, measured quarterly for a maximum duration of 24 months 7.2. Neurofilament light and heavy chain, measured quarterly for a maximum duration of 24 months 7.3. Plasma creatinine, measured quarterly for a maximum duration of 24 months 8. Tolerability, defined as time-to-discontinuation of the assigned treatment since randomization, continuously for a maximum duration of 24 months 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, continuously for a maximum duration of 24 months | — |
Countries
Australia, Belgium, England, Ireland, Netherlands, Spain, Sweden, United Kingdom
Contacts
Public ContactLeonard van den Berg
Outcome results
None listed