Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
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ClinicalTrials.gov Identifier: NCT06008249 |
Recruitment Status :
Recruiting
First Posted : August 23, 2023
Last Update Posted : August 23, 2023
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Condition or disease | Intervention/treatment | Phase |
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Amyotrophic Lateral Sclerosis | Drug: Lithium Carbonate 400 MG | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 171 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Participants will be randomised in a 2:1 ratio to receive either lithium carbonate or placebo |
Masking: | Double (Participant, Investigator) |
Masking Description: | Double-blind |
Primary Purpose: | Treatment |
Official Title: | A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS) |
Actual Study Start Date : | August 9, 2021 |
Estimated Primary Completion Date : | June 2026 |
Estimated Study Completion Date : | June 2026 |
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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Drug: Lithium Carbonate 400 MG
Lithium carbonate vs placebo (2:1) |
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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Drug: Lithium Carbonate 400 MG
Lithium carbonate vs placebo (2:1) |
- 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 ]A tracheostomy for ventilation is meant here
- 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 ]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. [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: endpoint or 24 months ]Plasma creatinine is assessed to monitor kidney function
- Tolerability defined as time-to-discontinuation of assigned treatment since randomization [ Time Frame: 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). [ Time Frame: 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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:
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06008249
Contact: Roel Vink, PhD | +31 6 50177777 | magnet@tricals.org | |
Contact: Leonard van den Berg, MD | 0887557939 ext 0031 | L.H.vandenBerg@umcutrecht.nl |
Australia | |
Flinders Medical Centre | Not yet recruiting |
Adelaide, Australia, SA 5042 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
Royal Brisbane and Women's Hospital | Not yet recruiting |
Brisbane, Australia, QLD 4029 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
Calvary Health Care Bethlehem | Not yet recruiting |
Parkdale, Australia, VIC 3195 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
Perron Institute | Not yet recruiting |
Perth, Australia, WA 6009 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
The University of Sydney (Royal prince Alfred hospital) | Recruiting |
Sydney, Australia, NSW 2050 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
Concord hospital Sydney | Not yet recruiting |
Sydney, Australia, NSW 2139 | |
Contact: Eleanor Ramsey eleanor.ramsey@sydney.edu.au | |
Belgium | |
University Hospital Leuven | Recruiting |
Leuven, Belgium, 3000 | |
Contact: Nikita Lamaire nikita.lamaire@uzleuven.be | |
Netherlands | |
University Medical Center Utrecht | Recruiting |
Utrecht, Netherlands, 3584 CX | |
Contact: Valerie van Eck V.D.vanEck@umcutrecht.nl | |
Spain | |
Bellvitge University Hospital | Recruiting |
Barcelona, Spain, 08907 | |
Contact: Monica Povedano, MD mpovedano@bellvitgehospital.cat | |
Sweden | |
Karolinska University Hospital | Recruiting |
Stockholm, Sweden, 171 64 | |
Contact: Charlotta Molin Edlund charlotta.molin-edlund@regionstockholm.se | |
United Kingdom | |
King's College Hospital | Recruiting |
London, United Kingdom, SE5 9RS | |
Contact: Theresa Chiwera tchiwera@nhs.net | |
University College London Hospital NHS | Not yet recruiting |
London, United Kingdom, WC1N 3BG | |
Contact: Andrea Malaspina, MD a.malaspina@nhs.net | |
University Hospitals of North Midlands NHS Trust | Not yet recruiting |
Stoke-on-Trent, United Kingdom, ST4 6QG | |
Contact: Thomas Lambert, MD Thomas.Lambert@uhnm.nhs.uk |
Study Chair: | Leonard Van den Berg, MD | TRICALS Foundation |
Responsible Party: | Stichting TRICALS Foundation |
ClinicalTrials.gov Identifier: | NCT06008249 |
Other Study ID Numbers: |
MAGNET |
First Posted: | August 23, 2023 Key Record Dates |
Last Update Posted: | August 23, 2023 |
Last Verified: | August 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Undecided |
Plan Description: | Pending on privacy regulations. |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Motor Neuron Disease Amyotrophic Lateral Sclerosis Sclerosis Pathologic Processes Neurodegenerative Diseases Nervous System Diseases Neuromuscular Diseases Spinal Cord Diseases Central Nervous System Diseases TDP-43 Proteinopathies Proteostasis Deficiencies |
Metabolic Diseases Lithium Carbonate Antidepressive Agents Psychotropic Drugs Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antimanic Agents Tranquilizing Agents Central Nervous System Depressants Physiological Effects of Drugs |