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

INTERVENTION: Randomization will be stratified by genotype and patients will be randomly allocated in a 2:1 fashion to either active treatment or a matched placebo for a maximum duration of 24 months. Other active arms may be added in the future. Initial sample size is 171 patients with ALS. Lithium specific: The treatment is lithium carbonate capsules or placebo (2:1). Capsules will be taken once daily, starting with one capsule (400 mg daily) initially titrated up to two or three capsules daily over the first four weeks of treatment, depending on blood lithium levels. The lithium levels will be titrated to a blood plasma level between and including 0.4 to 0.8 mmol/L. In the exceptional case when plasma lithium levels exceed 0.8 mmol/l on two consecutive occasions while on the minimum dose of 1 capsule per day (400mg per day), this will be accepted if concentrations remain <= 1.0 mmol/l (for patients 65 years or older) or <= 1.5 mmol/l (for patients >= 18 ‐ < 65 years). If values exceed these limits the investigational product must be permanently discontinued. Additionally, when patients display symptoms of a lithium intoxication (as evaluated by the unblinded lithium physician and based on changes in LiSERS questionnaire outcome), the investigational product will also be permanently discontinued. Patients cannot be rechallenged. Open Label Extensie: idem to lithium specific intervention without a placebo treatment. In other words: all patients will receive lithium carbonate. CONDITION: ; ALS ; MND 10029317 PRIMARY OUTCOME: The primary endpoint is 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). Secondary ; endpoints will be functional decline, respiratory function, quality of life, ; tolerability and safety. ; ; Open Label Extension: idem.; SECONDARY OUTCOME: • To assess the effect of each drug versus placebo on a combined assessment of ; survival and measures of daily functioning (ALS functional rating scale ; [ALSFRS‐R]) ; • To assess the effect of each drug versus placebo on ALSFRS‐R ; • To assess the effect of each drug versus placebo on respiratory function (SVC) ; • To assess the effect of each drug versus placebo on plasma creatinine ; • To assess the effect of each drug versus placebo on the time to reach ; advanced disease stages ; • To evaluate the safety and tolerability of each drug administered orally to ; patients with ALS ; • To assess the effect of each drug versus placebo on change in urinary P75ECD ; • To assess the effect of each drug versus placebo on change in plasma ; neurofilament light and heavy chain ; • To assess the effect of each drug versus placebo on change in cognitive ; functioning (ECAS & ALS‐FTD‐Q) ; • To assess the effect of each drug versus placebo on change in quality of life ; (EQ‐5D) ; ; Lithium specific (UMC Utrecht only): ; To determine the value of the compound muscle action potential (CMAP) scan to ; monitor disease progression ; ; Open Label Extension: ; ‐ 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).; 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 aft