- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06008249
Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
August 21, 2023 updated by: Stichting TRICALS Foundation
A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS)
The objective of this phase III, placebo-controlled platform study is to investigate the efficacy of drugs for patients with ALS (Amyotrophic lateral sclerosis).
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Estimated)
171
Phase
- Phase 3
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Roel Vink, PhD
- Phone Number: +31 6 50177777
- Email: magnet@tricals.org
Study Contact Backup
- Name: Leonard van den Berg, MD
- Phone Number: 0031 0887557939
- Email: L.H.vandenBerg@umcutrecht.nl
Study Locations
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Adelaide, Australia, SA 5042
- Not yet recruiting
- Flinders Medical Centre
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Brisbane, Australia, QLD 4029
- Not yet recruiting
- Royal Brisbane and Women'S Hospital
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Parkdale, Australia, VIC 3195
- Not yet recruiting
- Calvary Health Care Bethlehem
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Perth, Australia, WA 6009
- Not yet recruiting
- Perron Institute
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Sydney, Australia, NSW 2050
- Recruiting
- The University of Sydney (Royal prince Alfred hospital)
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Sydney, Australia, NSW 2139
- Not yet recruiting
- Concord hospital Sydney
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Contact:
- Eleanor Ramsey
- Email: eleanor.ramsey@sydney.edu.au
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Leuven, Belgium, 3000
- Recruiting
- University Hospital Leuven
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Contact:
- Nikita Lamaire
- Email: nikita.lamaire@uzleuven.be
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Utrecht, Netherlands, 3584 CX
- Recruiting
- University Medical Center Utrecht
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Contact:
- Valerie van Eck
- Email: V.D.vanEck@umcutrecht.nl
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Barcelona, Spain, 08907
- Recruiting
- Bellvitge University Hospital
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Contact:
- Monica Povedano, MD
- Email: mpovedano@bellvitgehospital.cat
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Stockholm, Sweden, 171 64
- Recruiting
- Karolinska University Hospital
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Contact:
- Charlotta Molin Edlund
- Email: charlotta.molin-edlund@regionstockholm.se
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London, United Kingdom, SE5 9RS
- Recruiting
- King's College Hospital
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Contact:
- Theresa Chiwera
- Email: tchiwera@nhs.net
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London, United Kingdom, WC1N 3BG
- Not yet recruiting
- University College London Hospital NHS
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Contact:
- Andrea Malaspina, MD
- Email: a.malaspina@nhs.net
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Stoke-on-Trent, United Kingdom, ST4 6QG
- Not yet recruiting
- University Hospitals of North Midlands NHS Trust
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Contact:
- Thomas Lambert, MD
- Email: Thomas.Lambert@uhnm.nhs.uk
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
No
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Lithium carbonate
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.
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Lithium carbonate vs placebo (2:1)
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Placebo Comparator: Placebo
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.
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Lithium carbonate vs placebo (2:1)
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What is the study measuring?
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)
Time Frame: endpoint or 24 months
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A tracheostomy for ventilation is meant here
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endpoint or 24 months
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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
Time Frame: endpoint or 24 months
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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.
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endpoint or 24 months
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Daily functioning, defined as mean change from baseline in ALSFRS-R total score.
Time Frame: endpoint or 24 months
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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.
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endpoint or 24 months
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Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard)
Time Frame: endpoint or 24 months
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Slow vital capacity (SVC) is measured in litres, and as a % of predicted.
A higher score reflects a better outcome.
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endpoint or 24 months
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Quality of life, defined as change from baseline on the EQ-5D Visual Analogue Scale (single-item scale)
Time Frame: endpoint or 24 months
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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
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endpoint or 24 months
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Quality of life, defined as change from baseline on the EQ-5D
Time Frame: endpoint or 24 months
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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
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endpoint or 24 months
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Neuropsychological status, defined as change from baseline on the ECAS
Time Frame: endpoint or 24 months
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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.
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endpoint or 24 months
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Neuropsychological status, defined as change from baseline on the ALS-FTD-Q.
Time Frame: endpoint or 24 months
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ALS-FTD-Q (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire) is a validated instrument for the screening of behavioral disturbances in ALS.
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endpoint or 24 months
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Clinical disease stage, defined as mean time spent in each stage of the King's and ALS Milano-Torino staging systems.
Time Frame: endpoint or 24 months
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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.
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endpoint or 24 months
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Change from baseline in laboratory parameters: Urinary P75ECD (ectodomain of neurotrophin receptor p75), Neurofilament light and heavy chain, Plasma creatinine
Time Frame: endpoint or 24 months
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Plasma creatinine is assessed to monitor kidney function
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endpoint or 24 months
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Tolerability defined as time-to-discontinuation of assigned treatment since randomization
Time Frame: endpoint or 24 months
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the number of participants who discontinue study medication will be assessed to assess tolerability
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endpoint or 24 months
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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).
Time Frame: endpoint or 24 months
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(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.
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endpoint or 24 months
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Study Chair: Leonard Van den Berg, MD, TRICALS Foundation
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
August 9, 2021
Primary Completion (Estimated)
June 1, 2026
Study Completion (Estimated)
June 1, 2026
Study Registration Dates
First Submitted
August 14, 2023
First Submitted That Met QC Criteria
August 21, 2023
First Posted (Actual)
August 23, 2023
Study Record Updates
Last Update Posted (Actual)
August 23, 2023
Last Update Submitted That Met QC Criteria
August 21, 2023
Last Verified
August 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Metabolic Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Spinal Cord Diseases
- TDP-43 Proteinopathies
- Proteostasis Deficiencies
- Sclerosis
- Motor Neuron Disease
- Amyotrophic Lateral Sclerosis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Central Nervous System Depressants
- Enzyme Inhibitors
- Tranquilizing Agents
- Psychotropic Drugs
- Antidepressive Agents
- Antimanic Agents
- Lithium Carbonate
Other Study ID Numbers
- MAGNET
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
IPD Plan Description
Pending on privacy regulations.
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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