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    Summary
    EudraCT Number:2018-002722-22
    Sponsor's Protocol Code Number:TUDCA-ALS
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-02-28
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-002722-22
    A.3Full title of the trial
    Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS)
    A.3.2Name or abbreviated title of the trial where available
    TUDCA-ALS
    A.4.1Sponsor's protocol code numberTUDCA-ALS
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03800524
    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 SponsorIRCCS ISTITUTO CLINICO HUMANITAS
    B.1.3.4CountryItaly
    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 supportEuropean Commission
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMediolanum Cardio Research
    B.5.2Functional name of contact pointDr. Maria Cristina Jori
    B.5.3 Address:
    B.5.3.1Street AddressVia G. Carducci, 19
    B.5.3.2Town/ city20123 MILANO (ITALY)
    B.5.4Telephone number+39 02 6125141
    B.5.5Fax number+39 02 92853602
    B.5.6E-mailjori@mcr-med.com
    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 Yes
    D.2.1.1.1Trade name Taurolite
    D.2.1.1.2Name of the Marketing Authorisation holderBruschettini s.r.l.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1844
    D.3 Description of the IMP
    D.3.1Product nameTaurolite
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTauroursodeoxycholic acid
    D.3.9.1CAS number 14605-22-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    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
    A neurological disease affecting the nerve cells responsible for controlling voluntary muscle movement.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of tauroursodeoxycholic acid (TUDCA) in slowing disease progression in patients with amyotrophic lateral sclerosis (ALS) during the treatment period compared to the lead-in phase, as measured by the ALS disease functional rating scale - revised version (ALSFRS-R).
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    - To assess the efficacy of TUDCA in slowing disease progression and functional impairment in patients with ALS as measured by survival time, the ALSAQ-40 questionnaire, forced vital capacity (FVC), the EQ-5D and muscle force.
    - To assess the long term safety and tolerability of TUDCA for up to 18 months in patients with ALS.

    The exploratory objectives of this study are:
    - To evaluate the effect of TUDCA on possible biomarkers: cerebrospinal fluid (CSF) and serum neurofilament levels, serum MMP-9 expression, and plasma creatinine levels.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Probable laboratory-supported, probable, or definite ALS, as defined by El Escorial Revised ALS diagnostic criteria
    2. Disease duration ≤ 18 months
    3. No swallowing difficulty (4 at ALSFRS-R swallowing subscore)
    4. Able to perform reproducible pulmonary function tests
    5. Forced vital capacity ≥70% of normal
    6. Stable on riluzole treatment for 3 months in the lead-in period or no riluzole treatment (if not tolerated)
    7. Signed informed consent
    Patients already taking riluzole are eligible candidates, as well as those who start it for the purposes of en-tering the trial.
    E.4Principal exclusion criteria
    8. Treatment with edaravone
    9. Other causes of neuromuscular weakness
    10. Presence of other neurodegenerative diseases
    11. Significant cognitive impairment, clinical dementia or psychiatric illness
    12. Severe cardiac or pulmonary disease
    13. Other diseases precluding functional assessments
    14. Other life-threatening diseases
    15. At the time of screening, any use of non-invasive ventilation (e.g. continuous positive airway pressure, non-invasive bi-level positive airway pressure or non-invasive volume ventilation) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
    16. Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal
    tract
    17. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever
    is longer, prior to dosing
    18. Any clinically significant laboratory abnormality
    19. Other concurrent investigational medications
    20. Active peptic ulcer
    21. Previous surgery or infections of small intestine
    22. Patients unable to easily swallow the treatment pills at time of enrolment
    23. Occurrence of frequent biliary colic, biliary infections, severe pancreatic abnormalities
    24. Subjects who weigh 88 lbs (40 kg) or less at screening
    25. Aspartate aminotransferase or alanine aminotransferase concentrations more than 3 times the upper limit of normal
    26. Creatinine clearance 50 ml/min or less
    27. Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neoplastic, renal, gastrointestinal, or other disorder that, in the Investigator's opinion, could interfere
    with the subject's participation in the study, place the subject at increased risk, or confound interpretation of study results
    28. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive TUDCA or that the subject is unable or unlikely to comply with the dosing schedule or study
    evaluations
    29. The patient of reproductive potential is sexually active and is not willing to use highly effective contraception during the study
    and up to 90 days after the day of last dose
    30. The patient is pregnant or breast feeding
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is measured through identification of the responder patients defined as those showing an improvement of at least 20% in the ALSFRS-R slope during the 18 months compared to the lead-in period. For each randomised patient, slope coefficients of ALSFRS-R are calculated by linear regression models separately during the lead-in period and during the 18 months of treatment period.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 3 months during the treatment period.
    E.5.2Secondary end point(s)
    - Survival time measured by death or respiratory insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days)
    - Difference in change from baseline in ALSFRS-R
    - ALSAQ-40 questionnaire
    - Forced Vital Capacity
    - EQ-5D scale
    - Muscle force assessed by the MRC sum-score
    - Safety is assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine labs (haematology, biochemistry)
    - Neurofilament levels in the CSF and serum; MMP-9 expression in serum
    - Plasma creatinine levels as indicators of muscle waste
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 3 months during the treatment period.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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. Sites will be closed once data cleaning is completed and the regulatory authority and ethics committee will be
    informed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 140
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 440
    F.4.2.2In the whole clinical trial 440
    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)
    We plan to offer each patient the possibility to continue taking active medication (TUDCA according to the same regimen of active treatment arm) without knowing whether they had been allocated to active or reference therapy. Participants in the extension study will receive TUDCA for up to an additional 18 months. We will seek funds in order to support the extension and the study will be submitted as a separate regulatory and ethics submission.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CRN: Yorkshire and Humber
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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