Amyotrophic Lateral Sclerosis
Conditions
Brief summary
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
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.
Interventions
DRUGLithium Carbonate 400 MG
Lithium carbonate vs placebo (2:1)
Sponsors
Stichting TRICALS Foundation
Fight MND
Research Foundation Flanders
MNDA
Thierry Latran Foundation
Ulla-Carin Lindquist Foundation
Luzon Foundation
Alan Davidson Foundation
My name'5 Doddie Foundation
Stichting ALS Nederland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind
Intervention model description
Participants will be randomised in a 2:1 ratio to receive either lithium carbonate or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥ 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
1. 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) 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, neuromuscular 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. Lithium carbonate study-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | endpoint or 24 months | A tracheostomy for ventilation is meant here |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores | endpoint or 24 months | 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. |
| Daily functioning, defined as mean change from baseline in ALSFRS-R total score. | endpoint or 24 months | 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. |
| Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard) | endpoint or 24 months | Slow vital capacity (SVC) is measured in litres, and as a % of predicted. A higher score reflects a better outcome. |
| Quality of life, defined as change from baseline on the EQ-5D Visual Analogue Scale (single-item scale) | endpoint or 24 months | 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 |
| Quality of life, defined as change from baseline on the EQ-5D | endpoint or 24 months | 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 |
| Neuropsychological status, defined as change from baseline on the ECAS | endpoint or 24 months | 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. |
| Neuropsychological status, defined as change from baseline on the ALS-FTD-Q. | endpoint or 24 months | ALS-FTD-Q (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire) is a validated instrument for the screening of behavioral disturbances in ALS. |
| Clinical disease stage, defined as mean time spent in each stage of the King's and ALS Milano-Torino staging systems. | endpoint or 24 months | 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. |
| Change from baseline in laboratory parameters: Urinary P75ECD (ectodomain of neurotrophin receptor p75), Neurofilament light and heavy chain, Plasma creatinine | endpoint or 24 months | Plasma creatinine is assessed to monitor kidney function |
| Tolerability defined as time-to-discontinuation of assigned treatment since randomization | endpoint or 24 months | the number of participants who discontinue study medication will be assessed to assess tolerability |
| 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). | endpoint or 24 months | (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. |
Countries
Australia, Belgium, Netherlands, Spain, Sweden, United Kingdom
Contacts
STUDY_CHAIRLeonard Van den Berg, MD
TRICALS Foundation
Outcome results
None listed