Amyotrophic Lateral Sclerosis
Conditions
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 ==65 years) yes F.1.3.1 Number of subjects for this age range 131
Exclusion criteria
Exclusion criteria: For all subjects: 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) < 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) 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 [No longer applicable since protocol version 3.2] 7.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. 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 Open label extension phase: 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to assess the efficacy of each drug versus placebo on overall survival, defined as death from any cause or respiratory insufficiency, in patients with ALS. Open label extension phase: To assess the efficacy of lithium carbonate on overall survival, defined as death from any cause or respiratory insufficiency, in patients with ALS during the open label phase;Secondary Objective: Secondary objectives, the effect of each drug versus placebo on: •a combined assessment of survival and measures of daily functioning (ALS functional rating scale [ALSFRS-R]) •on ALSFRS-R •on respiratory function (SVC) •on plasma creatinine •on the time to reach advanced disease stages •the safety and tolerability of each drug administered orally to patients with ALS •change in urinary P75EDC •change in plasma neurofilament light and heavy chain •change in plasma pharmacodynamic markers (e.g. HERV-K expression) Lithium specific (UMC Utrecht only): To determine the value of the compound muscle action potential (CMAP) scan to monitor disease progression Open label extension phase, to assess during the open label phase: -the effect of lithium carbonate on a combined assessment of survival and measures of daily functioning (ALSFRS-R) -the effect of lithium carbonate on ALSFRS-R -the long-term safety of lithium carbonate -quality of life (EQ5D);Primary end point(s): 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). Open label extension phase: 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) during the open label phase;Timepoint(s) of evaluation of this end point: For each sub-study, there is one pre-planned, event-driven, interim analysis whe | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ? Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores. ? Daily functioning, defined as mean change from baseline in ALSFRS-R total score. ? Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard). ? Quality of life, defined as change from baseline on the Visual Analogue Scale (single-item scale) and EQ-5D. ? Neuropsychological status, defined as change from baseline on the ECAS and ALS-FTD-Q. ? Clinical disease stage, defined as mean time spent in each stage of the King’s and ALS Milano-Torino staging systems. ? Change from baseline in laboratory parameters: ? Urinary P75ECD ? Neurofilament light and heavy chain ? Plasma creatinine ? Tolerability defined as time-to-discontinuation of assigned treatment since randomization. ? 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 study drug. Open label extension phase: - Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores during the open label phase. - Daily functioning, defined as mean change from baseline in ALSFRS-R total score during the open label phase. - Long-term safety of lithium carbonate during the open label phase - Quality of life during the open label phase (EQ5D);Timepoint(s) of evaluation of this end point: The secondary endpoints will be evaluated after the study is finished. | — |
Countries
Australia, Belgium, Netherlands, Spain, Sweden, United Kingdom
Contacts
Public ContactOperations office
Stichting TRICALS Foundation
Outcome results
None listed