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    Summary
    EudraCT Number:2018-002722-22
    Sponsor's Protocol Code Number:TUDCA-ALS
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-18
    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 ConcernedItaly - Italian Medicines Agency
    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)
    Sicurezza ed efficacia dell’acido tauroursodeossicolico (TUDCA) come trattamento aggiuntivo nei pazienti affetti da sclerosi laterale amiotro-fica (SLA)
    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)
    Sicurezza ed efficacia dell’acido tauroursodeossicolico (TUDCA) come trattamento aggiuntivo nei pazienti affetti da sclerosi laterale amiotro-fica (SLA)
    A.3.2Name or abbreviated title of the trial where available
    TUDCA-ALS
    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 supportCommissione Europea
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto Clinico Humanitas
    B.5.2Functional name of contact pointUfficio Sperimentazioni Cliniche
    B.5.3 Address:
    B.5.3.1Street AddressVia A. Manzoni 56
    B.5.3.2Town/ cityRozzano - MI
    B.5.3.3Post code20089
    B.5.3.4CountryItaly
    B.5.4Telephone number0282244056
    B.5.6E-mailpaola.maisola@humanitas.it
    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 TUDCABIL
    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 nameTUDCABIL
    D.3.2Product code [TUDCA]
    D.3.4Pharmaceutical form Capsule, hard
    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 INNACIDO TAUROURSODESOSSICOLICO
    D.3.9.1CAS number 128-13-2
    D.3.9.2Current sponsor codeTUDCA
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 (ALS)
    sclerosi laterale amiotrofica (SLA)
    E.1.1.1Medical condition in easily understood language
    amyotrophic lateral sclerosis (ALS)
    sclerosi laterale amiotrofica (SLA)
    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 asses the efficacy of TUDCA in slowing disease prograssion in patients with ALS during the treatment period compared to the lead-in phase.
    Valutare l'efficacia di TUDCA nel rallentare la progressione della malattia in pazienti con SLA durante il periodo di trattamento rispetto alla fase di osservazione iniziale
    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 the survival time, the ALSAQ-40 questionnaire, 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: CSF and serum neurofilament levels, serum MMP-9 expression, and plasma creatinine levels.
    - Valutare l'efficacia di TUDCA nel rallentamento della progressione del-la malattia e della compromissione funzionale in pazienti con SLA, come misurato da: tempo di sopravvivenza, questionario ALSAQ-40, FVC, EQ-5D e forza muscolare
    -Valutare la sicurezza a lungo termine e la tollerabilità di TUDCA fino a 18 mesi nei pazienti con SLA

    Gli obiettivi esplorativi di questo studio sono:
    - valutare l’effetto di TUDCA sui possibili biomarcatori: valori liquorali o sierici di neurofilamenti, espressione MMP-9 nel siero, dosaggio creatinina plasmatica
    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 diag-nostic criteria 38
    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
    7. Signed informed consent.
    1. Diagnosi di SLA probabile supportata da laboratorio, probabile o definita, secondo i criteri diagnostici ALS El Escorial Revised
    2. Durata della malattia = 18 mesi
    3. Nessuna difficoltà di deglutizione (4 in subitem della deglutizione della ALSFRS-R)
    4. In grado di eseguire test di funzionalità polmonare riproducibili
    5. Capacità vitale forzata =70% del normale
    6. Terapia con riluzolo stabile nei 3 mesi nel periodo di lead-in
    7. Consenso informato firmato
    E.4Principal exclusion criteria
    8. Treatment with edaravone or other unaccepted concomitant therapy (as per Section 8)
    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 pres-sure, non-invasive bi-level positive airway pressure or non-invasive volume ventilation) for any por-tion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementa-tion
    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 up-per limit of normal
    26. Creatinine clearance 50 ml/min or less
    27. Any clinically significant neurological, haematological, autoimmune, endocrine, cardiovascular, neo-plastic, 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 inter-pretation of study results
    28. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to re-ceive TUDCA or that the subject is unable or unlikely to comply with the dosing schedule or study evaluations
    29. The patient 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 (see Contraceptive Guidance in Appendix A).
    8. Trattamento con edaravone o altra terapia concomitante non accettata (come da Sezione 8)
    9. Altre cause di debolezza neuromuscolare
    10. Presenza di altre malattie neurodegenerative
    11. Compromissione cognitiva significativa, demenza clinica o ma-lattia psichiatrica
    12. Grave malattia cardiaca o polmonare
    13. Altre malattie che precludono le valutazioni funzionali
    14. Altre malattie potenzialmente letali
    15. Al momento dello screening, qualsiasi utilizzo di ventilazione non invasiva per qualsiasi parte della giornata o ventilazione mec-canica tramite tracheotomia o su qualsiasi forma di integrazione di ossigeno
    16. Disturbi gastrointestinali che possono compromettere l'assor-bimento del farmaco in studio
    17. assunzione del farmaco in sperimentazione nei 30 giorni prece-denti l’arruolamento
    18. Qualsiasi anormalità di laboratorio clinicamente significativa
    19. Altri farmaci sperimentali concomitanti
    20. Ulcera peptica attiva
    21. Precedente intervento chirurgico o infezioni dell'intestino tenue
    22. Pazienti incapaci di deglutire facilmente le pillole del trattamen-to al momento dell'arruolamento
    23. Presenza di colica biliare frequente, infezioni delle vie biliari, anomalie pancreatiche gravi
    24. Soggetti che pesano 40 kg o meno allo screening
    25. Concentrazioni di aspartato aminotransferasi o alanina amino-transferasi maggiori di 3 volte il limite superiore del normale
    26. clearance della creatinina 50 ml / min o meno
    27. Qualsiasi disturbo neurologico, ematologico, autoimmune, en-docrino, cardiovascolare, neoplastico, renale, gastrointestinale o al-tro clinicamente significativo che, a giudizio del Ricercatore, po-trebbe interferire con la partecipazione del soggetto allo studio, pone il soggetto a maggior rischio, o potrebbe causare una inter-pretazione errata dei risultati dello studio
    28. Considerazione che il un candidato sia inadatto a ricevere TUD-CA o che non sia in grado di rispettare il programma dello studio
    29. Il paziente è sessualmente attivo e non è disposto a utilizzare metodi contraccettivi altamente efficaci durante lo studio e fino a 90 giorni dopo l'ultima dose
    E.5 End points
    E.5.1Primary end point(s)
    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 sep-arately during the lead-in period and during the 18 months of treatment period.
    L'endpoint primario viene misurato attraverso l'identificazione dei pazienti responder definiti come quelli che mostrano un miglioramento di almeno il 20% nella pendenza di ALSFRS-R durante i 18 mesi rispetto al periodo di lead-in. Per ciascun paziente randomizzato, i coefficienti di pendenza di ALSFRS-R sono calcolati da modelli di regressione lineare separatamente durante il periodo di lead-in e durante i 18 mesi del periodo di trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint will be evaluate during the initial observation period and during the 18 months of the treatment period.
    Questo endpoint sarà rilevato durante il periodo di osservazione iniziale e durante i 18 mesi del periodo di trattamento.
    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 disease progression and functional impairment between TUDCA and placebo over 18 months (as measured by ALSFRS-R, ALSAQ-40 questionnaire 33, Forced Vital Capacity 34, EQ-5D scale 35 and MRC sum-score 36).
    • Long-term safety and tolerability of TUDCA treatment in patients with ALS for up to 18 months (as assessed through adverse reaction, concomitant treatment, physical examination, vital signs and routine haematology and biochemistry analyses).
    • Effect of TUDCA on biomarkers of disease progression (such as CSF and serum Neurofilament levels, serum MMP-9 expression and plasma creatinine levels 37) over 18 months in comparison to placebo.
    • Tempo di sopravvivenza misurato tramite decesso o insufficienza respiratoria (DRI; definita come tracheotomia o ricorso a ventilazione non invasiva per un tempo =22 ore al giorno per un numero di giorni consecutivi =10).
    • Differenza rispetto alla fase di osservazione iniziale nella progressione della malattia e nella compromissione funzionale tra TUDCA e placebo in 18 mesi (come misurato da ALSFRS-R, questionario ALSAQ-40, capacità vitale forzata, scala EQ-5D e MRC sum-score).
    • Sicurezza e tollerabilità a lungo termine del trattamento con TUDCA in pazienti affetti da SLA fino a 18 mesi (come misurato attraverso reazioni avverse, terapia concomitante, esame fisico, segni vitali e analisi ematologiche e biochimiche di routine).
    • Effetto di TUDCA su biomarcatori di progressione della malattia (come i livelli liquorali o sierici di neurofilamenti, l’espressione di MMP-9 nel siero e il livelli di creatinina nel plasma) per 18 mesi in confronto a placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All efficacy and safety endpoints will be compared between the two randomization groups at the end of the study
    Tutti gli endpoint di efficacia e sicurezza saranno confrontati tra i due gruppi di randomizzazione al termine dello studio
    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 EEA25
    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 Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 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 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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    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)
    Riluzole at a dose of 50 mg twice a day (100 mg per day).
    Riluzolo alla dose di 50 mg due volte al giorno (100 mg al giorno).
    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 Decision2018-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
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