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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06008249




Registration number
NCT06008249
Ethics application status
Date submitted
14/08/2023
Date registered
23/08/2023
Date last updated
23/08/2023

Titles & IDs
Public title
Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
Scientific title
A Multi-arm, Adaptive, Group-sequential Trial NETwork to Evaluate Drug Efficacy in Patients With Amyotrophic Lateral Sclerosis (ALS)
Secondary ID [1] 0 0
MAGNET
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyotrophic Lateral Sclerosis 0 0
Condition category
Condition code
Neurological 0 0 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Lithium Carbonate 400 MG

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.

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.


Treatment: Drugs: Lithium Carbonate 400 MG
Lithium carbonate vs placebo (2:1)
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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)
Timepoint [1] 0 0
endpoint or 24 months
Secondary outcome [1] 0 0
Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores
Timepoint [1] 0 0
endpoint or 24 months
Secondary outcome [2] 0 0
Daily functioning, defined as mean change from baseline in ALSFRS-R total score.
Timepoint [2] 0 0
endpoint or 24 months
Secondary outcome [3] 0 0
Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard)
Timepoint [3] 0 0
endpoint or 24 months
Secondary outcome [4] 0 0
Quality of life, defined as change from baseline on the EQ-5D Visual Analogue Scale (single-item scale)
Timepoint [4] 0 0
endpoint or 24 months
Secondary outcome [5] 0 0
Quality of life, defined as change from baseline on the EQ-5D
Timepoint [5] 0 0
endpoint or 24 months
Secondary outcome [6] 0 0
Neuropsychological status, defined as change from baseline on the ECAS
Timepoint [6] 0 0
endpoint or 24 months
Secondary outcome [7] 0 0
Neuropsychological status, defined as change from baseline on the ALS-FTD-Q.
Timepoint [7] 0 0
endpoint or 24 months
Secondary outcome [8] 0 0
Clinical disease stage, defined as mean time spent in each stage of the King's and ALS Milano-Torino staging systems.
Timepoint [8] 0 0
endpoint or 24 months
Secondary outcome [9] 0 0
Change from baseline in laboratory parameters: Urinary P75ECD (ectodomain of neurotrophin receptor p75), Neurofilament light and heavy chain, Plasma creatinine
Timepoint [9] 0 0
endpoint or 24 months
Secondary outcome [10] 0 0
Tolerability defined as time-to-discontinuation of assigned treatment since randomization
Timepoint [10] 0 0
endpoint or 24 months
Secondary outcome [11] 0 0
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).
Timepoint [11] 0 0
endpoint or 24 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 exclusion criteria:

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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
9/08/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2026
Actual
Sample size
Target
171
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Flinders Medical Centre - Adelaide
Recruitment hospital [2] 0 0
Royal Brisbane and Women's Hospital - Brisbane
Recruitment hospital [3] 0 0
Calvary Health Care Bethlehem - Parkdale
Recruitment hospital [4] 0 0
Perron Institute - Perth
Recruitment hospital [5] 0 0
The University of Sydney (Royal prince Alfred hospital) - Sydney
Recruitment hospital [6] 0 0
Concord hospital Sydney - Sydney
Recruitment postcode(s) [1] 0 0
SA 5042 - Adelaide
Recruitment postcode(s) [2] 0 0
QLD 4029 - Brisbane
Recruitment postcode(s) [3] 0 0
VIC 3195 - Parkdale
Recruitment postcode(s) [4] 0 0
WA 6009 - Perth
Recruitment postcode(s) [5] 0 0
NSW 2050 - Sydney
Recruitment postcode(s) [6] 0 0
NSW 2139 - Sydney
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Leuven
Country [2] 0 0
Netherlands
State/province [2] 0 0
Utrecht
Country [3] 0 0
Spain
State/province [3] 0 0
Barcelona
Country [4] 0 0
Sweden
State/province [4] 0 0
Stockholm
Country [5] 0 0
United Kingdom
State/province [5] 0 0
London
Country [6] 0 0
United Kingdom
State/province [6] 0 0
Stoke-on-Trent

Funding & Sponsors
Primary sponsor type
Other
Name
Stichting TRICALS Foundation
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Stichting ALS Nederland
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Fight MND
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Research Foundation Flanders
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
MNDA
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Thierry Latran Foundation
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Ulla-Carin Lindquist Foundation
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Luzon Foundation
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
Alan Davidson Foundation
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
My name'5 Doddie Foundation
Address [9] 0 0
Country [9] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/study/NCT06008249
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Leonard Van den Berg, MD
Address 0 0
TRICALS Foundation
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Roel Vink, PhD
Address 0 0
Country 0 0
Phone 0 0
+31 6 50177777
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT06008249