Evaluation of Lithium Efficacy on Overall Survival in Patients with Amyotrophic Lateral Sclerosis: A Multi-Arm, Adaptive, Group-Sequential Trial
- Trial ID
- 2024-516559-41-00
- Protocol
- Magnet Lithium
- Sponsor
- Stichting TRICALS Foundation
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of each drug versus placebo on overall survival in patients with **Amyotrophic Lateral Sclerosis (ALS)**. Overall survival is defined as death from any cause or respiratory insufficiency. This objective is clinically relevant as it directly addresses the potential of the investigational drugs to extend life expectancy and improve respiratory function in ALS patients, a critical aspect of managing this progressive neurodegenerative disease.
Secondary objectives include:
- Assessing the effect of each drug versus placebo on a combined assessment of survival and measures of daily functioning using the ALS Functional Rating Scale (ALSFRS-R).
- Evaluating the effect on respiratory function, specifically **slow vital capacity (SVC)**.
- Investigating changes in plasma creatinine levels.
- Determining the time to reach advanced disease stages.
- Evaluating the safety and tolerability of each drug administered orally to ALS patients.
- Assessing changes in urinary P75ECD and plasma neurofilament light and heavy chain levels.
- Evaluating changes in cognitive functioning using the ECAS and ALS-FTD-Q scales.
- Assessing changes in quality of life using the EQ-5D scale.
- Determining the value of the compound muscle action potential (CMAP) scan to monitor disease progression.
Participants
The clinical trial involves a total of **96 participants** diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. The study population includes both male and female subjects, aged **18 years and older**, who meet the revised El Escorial criteria for ALS diagnosis. Participants are required to be capable of providing informed consent and complying with trial procedures. The trial does not include a vulnerable population. Lifestyle considerations such as the use of riluzole are accounted for, with participants either on a stable dose for at least 30 days prior to the baseline visit or having discontinued its use at least 30 days before the baseline. Women of childbearing potential must have a negative pregnancy test at baseline and be non-lactating, while men must agree to practice contraception during the trial and for at least three months after the last dose of the study drug. The selection process ensures that participants are suitable for the study's primary objective, which is to assess the efficacy of each drug versus placebo on overall survival in ALS patients.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **lithium** in patients with **Amyotrophic Lateral Sclerosis (ALS)**. This is a Phase III, multi-arm, adaptive, group-sequential trial with a randomized, double-blind, and placebo-controlled design. The primary objective is to assess the efficacy of the drug versus placebo on overall survival, defined as death from any cause or respiratory insufficiency. The trial is expected to run from September 22, 2021, to October 30, 2026, with a maximum treatment period of 24 months for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis according to the revised El Escorial criteria, and the ability to comply with trial procedures. Follow-up visits will be scheduled to monitor the primary and secondary endpoints, which include overall survival, daily functioning, respiratory function, quality of life, neuropsychological status, clinical disease stage, laboratory parameters, tolerability, and safety. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events.
The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with trial procedures, withdrawal of consent, or the occurrence of adverse events that necessitate discontinuation. The trial will ensure that all safety assessments, including neurological examinations, clinical laboratory evaluations, and monitoring of adverse events, are conducted in accordance with regulatory standards. The study will utilize a placebo group, with placebo capsules formulated to match the active product in appearance and composition, excluding the active substance.
Treatment
The clinical trial involves the administration of **Lithium** as the experimental medication. **Lithium** is provided in a repackaged form, specifically encapsulated and relabeled for the study. The pharmaceutical form is designated as PHF00082MIG, and the medication is administered orally. The maximum daily dose is set at 1200 mg, with a total maximum dose of 876 g over the course of the treatment. The treatment period is capped at 24 weeks. The study ensures that the administration of **Lithium** is monitored for compliance, with dosing schedules strictly adhered to as per the trial protocol.
The trial also includes a placebo group, where participants receive placebo capsules. These capsules are formulated with lactose and polyvinylpyrrolidone to match the mass of the active product, ensuring blinding of the study. The excipients used in the placebo are commonly utilized in the production of oral solid formulations, ensuring safety and consistency. The placebo is administered in a manner identical to the experimental medication, maintaining the integrity of the trial's double-blind design.
Efficacy
The efficacy of the investigational drugs in the clinical trial for patients with **Amyotrophic Lateral Sclerosis (ALS)** will be assessed using several primary and secondary endpoints. The primary endpoint is overall survival, defined as the time to death from any cause or respiratory insufficiency, which includes tracheostomy or the use of non-invasive ventilation for at least 22 hours per day for 10 consecutive days. Secondary endpoints include a composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores, mean change from baseline in ALSFRS-R total score for daily functioning, and mean change from baseline in respiratory function as measured by SVC (%predicted of normal according to the GLI-2012 reference standard).
Additional secondary endpoints involve changes from baseline in quality of life assessed by the Visual Analogue Scale and EQ-5D, neuropsychological status using the ECAS and ALS-FTD-Q, and clinical disease stage as defined by the King’s and ALS Milano-Torino staging systems. Laboratory parameters such as urinary P75ECD, neurofilament light and heavy chain, and plasma creatinine will also be evaluated. Tolerability will be assessed by time-to-discontinuation of assigned treatment since randomization, and safety will be monitored through neurological examinations, clinical laboratory evaluations, vital signs, and the frequency of adverse events (AEs) or serious adverse events (SAEs), categorized according to the Medical Dictionary for Regulatory Activities (MedDRA) and rated for severity and association with the study drug.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 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 ≥ -6.00 and ≤ -2.00 **
- 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
- 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)
- 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 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.
- Hypothyroidism unresponsive to thyroid hormone supplementation.
- Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy.
- [No longer applicable since protocol version 3.2]
- 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.
- 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.
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 22 Sept 2021 | 25 |
 The Netherlands | Not Recruiting | 22 Sept 2021 | — |
 Spain | Not Recruiting | 22 Sept 2021 | 15 |
 Sweden | Not Recruiting | 22 Sept 2021 | 15 |
| Netherlands | — | — | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
The placebo capsules will have a formulation with lactose and polyvinylpyrrolidone to compensate the api mass in the active product. all excipients are widely used in the manufacturing of oral solid formulations. | Placebo | N/A | — | — | — | N/A |
LITHIUM | Test | PHF00082MIG | ORAL | 1200 | 24 | SCP141094 |