An international multi-center clinical trial to investigate the efficacy of multiple drug compounds in patients with amyotrophic lateral sclerosis

Trial ID: ISRCTN15671139

Other - Phase 3 - No longer available

Background and study aims Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. The aim of this study is to simultaneously investigate the effectiveness and safety of multiple drugs for ALS. We do this by using so-called 'study arms'. Each study arm investigates the effectiveness and safety of one drug or a combination of drugs. Once it is clear which arm of the study they are participating in, participants will be assigned a drug or placebo by drawing lots. A placebo is a substance without an active substance, a 'fake substance'. Currently one arm is active that investigates the effect of lithium carbonate vs placebo in ALS. Lithium is a substance currently registered for use in bipolar disorders. This is a psychiatric disease that causes severe mood swings. Lithium affects multiple biological mechanisms involved in ALS. Previous research has shown that the drug is not effective in all patients with ALS, but may be beneficial in patients with a variation in the UNC13A gene (1 in 6 patients has this variation). Lithium is not currently being prescribed for ALS outside of this study. Who can participate? Patients aged 18 years and over with ALS What does the study involve? The participants will be randomly allocated to either placebo or an active drug and are required to visit the clinic every 3 months for a maximum duration of 24 months. Patients are required to take the study medication orally on a daily basis. During each hospital visit the patient is required to undergo blood tests, provide a urine sample, undergo an interview and lung function testing. Electrocardiography and neurological examinations will be performed every 12 months. What are the possible benefits and risks of participating? Participants receiving the study medication may benefit from a delay in loss of function due to ALS. The blood tests require a single needle to be placed into the arm to draw blood. This may cause some discomfort. The risks following blood collection are bruising, bleeding or infection from the site. Participants should maintain pressure on the site for at least 5 minutes and not use the affected arm to lift anything heavy for 24 hours after the blood test. There is no potential harm involved with the other medical assessments (e.g. urine sample, questionnaires, lung function). Administration of lithium carbonate for this study is not anticipated to induce any potential risk other than the potential side-effects as have been listed previously but may benefit subjects participating in this study. Note that lithium may interact with other medications. In the previous studies, lithium carbonate was relatively well-tolerated by patients with ALS. Perhaps in part due to the fact that the target dose was relatively low. Given the fact that the side effects were modest and that the potential survival benefit is very large, there is sufficient evidence to proceed with a confirmatory trial, which is the objective of this study. Where is the study run from? Stichting TRICALS Foundation (Netherlands) When is the study starting and how long is it expected to run for? January 2021 to June 2026 Who is funding the study? Stichting TRICALS Foundation (Netherlands) Who is the main contact? Prof. Leonard van den Berg, magnet@tricals.org

Conditions

• Amyotrophic lateral sclerosis (ALS)
• Nervous System Diseases
• Motor neuron disease

Eligibility

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

• 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

Sponsor

Stichting TRICALS Foundation

Source: https://www.isrctn.com/

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