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    Summary
    EudraCT Number:2020-000579-19
    Sponsor's Protocol Code Number:MAGNET
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-29
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2020-000579-19
    A.3Full title of the trial
    A Multi-arm, Adaptive, Group-sequential trial NETwork to evaluate drug efficacy in patients with Amyotrophic Lateral Sclerosis (ALS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international multi-center clinical trial to investigate the efficacy of multiple drug compounds in patients with Amyotrophic Lateral Sclrerosis (ALS).
    A.3.2Name or abbreviated title of the trial where available
    MAGNET
    A.4.1Sponsor's protocol code numberMAGNET
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorStichting TRICALS Foundation
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportStichting ALS Nederland
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportFight MND
    B.4.2CountryAustralia
    B.4.1Name of organisation providing supportFWO
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportMNDA
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportThierry Latran Foundation
    B.4.2CountryEuropean Union
    B.4.1Name of organisation providing supportUlla-Carin Lindquist Foundation
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationStichting TRICALS Foundation
    B.5.2Functional name of contact pointOperations office
    B.5.3 Address:
    B.5.3.1Street AddressGoeman Borgesiuslaan 77
    B.5.3.2Town/ cityUtrecht
    B.5.3.3Post code3515 ET
    B.5.3.4CountryNetherlands
    B.5.6E-mailmagnet@tricals.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLithium Carbonate
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLithium carbonate
    D.3.9.1CAS number 554-13-2
    D.3.9.3Other descriptive nameLITHIUM CARBONATE
    D.3.9.4EV Substance CodeSUB14375MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis
    E.1.1.1Medical condition in easily understood language
    Amyotrophic Lateral Sclerosis (ALS) / Motor Neurone Disease / Lou Gehrig's Disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the efficacy of each drug versus placebo on overall survival, defined as death from any cause or respiratory insufficiency, in patients with ALS.

    Open label extension phase:
    To assess the efficacy of lithium carbonate on overall survival, defined as death from any cause or respiratory insufficiency, in patients with ALS during the open label phase
    E.2.2Secondary objectives of the trial
    Secondary objectives, the effect of each drug versus placebo on:
    • a combined assessment of survival and measures of daily functioning (ALS functional rating scale [ALSFRS-R])
    • on ALSFRS-R
    • on respiratory function (SVC)
    • on plasma creatinine
    • on the time to reach advanced disease stages
    • the safety and tolerability of each drug administered orally to patients with ALS
    • change in urinary P75EDC
    • change in plasma neurofilament light and heavy chain
    • change in plasma pharmacodynamic markers (e.g. HERV-K expression)

    Lithium specific (UMC Utrecht only):
    To determine the value of the compound muscle action potential (CMAP) scan to monitor disease progression

    Open label extension phase, to assess during the open label phase:
    - the effect of lithium carbonate on a combined assessment of survival and measures of daily functioning (ALSFRS-R)
    - the effect of lithium carbonate on ALSFRS-R
    - the long-term safety of lithium carbonate
    - quality of life (EQ5D)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 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 10). 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.

    Open label extension phase:
    1. Completion of the end of study visit (month 24) in the MAGNET lithium study, while on study medication
    2. Signed informed consent for participation in the lithium extension
    3. Capable of providing informed consent and complying with trial procedures
    4. The same inclusion criteria of the MAGNET master protocol and MAGNET lithium subprotocol apply, with the exception of the TRICALS risk profile
    E.4Principal exclusion criteria
    For all subjects:

    1. 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
    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 Amylase & lipase ≥ 2 times ULN (suspected pancreatitis)
    o 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, neuromusculair 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.


    For Lithium carbonate:
    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

    Open label extension phase:
    1. Judgement by the investigator that the patient is an unsuitable candidate, or that the patient is unable or unlikely to comply with the dosing schedule or study evaluations
    2. The same exclusion criteria of the MAGNET master protocol and MAGNET lithium subprotocol apply
    E.5 End points
    E.5.1Primary end point(s)
    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).

    Open label extension phase:
    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) during the open label phase
    E.5.1.1Timepoint(s) of evaluation of this end point
    For each sub-study, there is one pre-planned, event-driven, interim analysis when approximately 60% of the required events are available. If the trial cannot be terminated early, the trial continues until the required number of events is reached or until 24 months after the last enrolled patient, whichever occurs first. Patients are required to visit the clinic every 3 months for a maximum duration of 24 months. In case of the lithium sub-study, if treatment is futile, the trial can be stopped after an average of 28.0 months since first enrolled patient with an average sample size of 137 patients. In this scenario, the probability for individual patients to remain in the trial for 18 months or more is 11.3% and to complete 24 months of follow-up is 1.8%.
    E.5.2Secondary end point(s)
     Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores.
     Daily functioning, defined as mean change from baseline in ALSFRS-R total score.
     Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard).
     Quality of life, defined as change from baseline on the Visual Analogue Scale (single-item scale) and EQ-5D.
     Neuropsychological status, defined as change from baseline on the ECAS and ALS-FTD-Q.
     Clinical disease stage, defined as mean time spent in each stage of the King’s and ALS Milano-Torino staging systems.
     Change from baseline in laboratory parameters:
     Urinary P75ECD
     Neurofilament light and heavy chain
     Plasma creatinine
     Tolerability defined as time-to-discontinuation of assigned treatment since randomization.
     Safety based on the safety assessments including physical neurological examinations, clinical laboratory evaluations, vital signs and frequency of adverse events (AEs) or serious adverse events (SAEs). (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.

    Open label extension phase:
    - Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores during the open label phase.
    - Daily functioning, defined as mean change from baseline in ALSFRS-R total score during the open label phase.
    - Long-term safety of lithium carbonate during the open label phase
    - Quality of life during the open label phase (EQ5D)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoints will be evaluated after the study is finished.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    multi-arm
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    United Kingdom
    Belgium
    Netherlands
    Spain
    Sweden
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 131
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Patients with incurable disease
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 82
    F.4.2.2In the whole clinical trial 171
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who have completed the 24-month MAGNET lithium substudy end of study visit and who are still on study medication are eligible for participation in the MAGNET lithium open-label extension study (lithium extension)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-25
    P. End of Trial
    P.End of Trial StatusOngoing
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