Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The objective of this phase III, placebo-controlled platform study is to investigate the efficacy of drugs for patients with ALS (Amyotrophic lateral sclerosis).

Detailed Description
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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.

Official Title
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A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Lithium Carbonate 400 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years at the time of screening. Diagnosis of ALS according to the revised El Escorial criteria (possible, probable-laboratory supported, probable or definite). Capable of providing informed consent and complying with trial procedures, including randomization to sub-studies. TRICALS risk profile > -6.0 and < -2.0 ** 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. Women of childbearing potential* must have a negative pregnancy test at baseline and be non-lactating. Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug. 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. 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: 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) 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. Participation in any other investigational drug trial or using investigational drug (within 30 days prior to screening). Hypothyroidism unresponsive to thyroid hormone supplementation. Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy. Subjects taking edaravone within 30 days prior to screening. Edaravone is approved by the FDA, but remains an investigational product in Europe and Australia. 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. Drug or alcohol abuse. 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. Presence of frontotemporal dementia which prevents informed consent. Lithium carbonate study-specific exclusion criteria: Patients heterozygous or homozygous for the A-allele of rs12608932 (UNC13A) Known allergy or hypersensitivity to lithium, or its excipients, or to the components of the placebo. 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. Addison disease. Patients with the following co-medication: antipsychotics, digoxin and calcium antagonists, carbamazepine, methyldopa, verapamil and diltiazem. Brugada Syndrome or family history of Brugada Syndrome. Plasma sodium <120 mmol/L

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised in a 2:1 ratio to receive either lithium carbonate or placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lithium carbonate<br>Lithium carbonate 400 mg capsules will be taken once daily, starting with one capsule (400 mg daily) initially titrated up to two or three capsules daily, depending on blood lithium levels. The target range for the lithium plasma level will be between ≥0.4 mmol/l and ≤ 0.8 mmol/l. Maximum duration is 24 months. | Drug: Lithium Carbonate 400 MG<br>* Lithium carbonate vs placebo (2:1)<br>|
| Placebo Comparator: Placebo<br>Patients start with 1 capsule to be taken once daily, with subsequent sham dose adjustments made to patients on placebo to maintain blinding in clinical sites. | Drug: Lithium Carbonate 400 MG<br>* Lithium carbonate vs placebo (2:1)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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) | A tracheostomy for ventilation is meant here | endpoint or 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores | The ALSFRS-R (Amyotrophic Lateral Sclerosis Rating Scale-revised) is a 12 item participant self-report measure that monitors ALS disease progression, where a higher score reflects a better outcome. | endpoint or 24 months | 
| Daily functioning, defined as mean change from baseline in ALSFRS-R total score. | The ALSFRS-R (Amyotrophic Lateral Sclerosis Rating Scale-revised) is a 12 item participant self-report measure that monitors ALS disease progression, where a higher score reflects a better outcome. | endpoint or 24 months | 
| Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard) | Slow vital capacity (SVC) is measured in litres, and as a % of predicted. A higher score reflects a better outcome. | endpoint or 24 months | 
| Quality of life, defined as change from baseline on the EQ-5D Visual Analogue Scale (single-item scale) | The EQ-5D-5L (EuroQol 5 Dimension 5 Level) questionnaire is a standardised measure of health-related Quality of Life, using a Visual Analogue Scale. A higher score relates to a better outcome | endpoint or 24 months | 
| Quality of life, defined as change from baseline on the EQ-5D | The EQ-5D-5L (EuroQol 5 Dimension 5 Level) questionnaire is a standardised measure of health-related Quality of Life. A lower score relates to a better outcome | endpoint or 24 months | 
| Neuropsychological status, defined as change from baseline on the ECAS | ECAS (Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen) is a multidomain assessment questionnaire used in ALS to assess cognitive and behavioural changes where a higher score relates to a better outcome. | endpoint or 24 months | 
| Neuropsychological status, defined as change from baseline on the ALS-FTD-Q. | ALS-FTD-Q (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire) is a validated instrument for the screening of behavioral disturbances in ALS. | endpoint or 24 months | 
| Clinical disease stage, defined as mean time spent in each stage of the King's and ALS Milano-Torino staging systems. | The King's Staging Scale is a clinical staging system defining four stages of ALS assessed by way of a semi-structured interview with the participant. | endpoint or 24 months | 
| Change from baseline in laboratory parameters: Urinary P75ECD (ectodomain of neurotrophin receptor p75), Neurofilament light and heavy chain, Plasma creatinine | Plasma creatinine is assessed to monitor kidney function | endpoint or 24 months | 
| Tolerability defined as time-to-discontinuation of assigned treatment since randomization | the number of participants who discontinue study medication will be assessed to assess tolerability | endpoint or 24 months | 
| Safety based on the safety assessments including 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. | endpoint or 24 months |