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    Summary
    EudraCT Number:2017-004459-21
    Sponsor's Protocol Code Number:Co-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:2018-11-07
    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 number2017-004459-21
    A.3Full title of the trial
    Colchicine for Amyotrophic Lateral Sclerosis: a phase II, randomized, double blind, placebo controlled, multicenter clinical trial
    Trattamento con colchicina per la Sclerosi Laterale Amiotrofica: un trial clinico multicentrico, randomizzato, in doppio cieco, controllato con placebo, di fase II
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study evaluating the treatment with colchicine for the amyotrophic lateral sclerosis
    Studio sul trattamento con la colchicina per la sclerosi laterale amiotrofica
    A.3.2Name or abbreviated title of the trial where available
    Co-ALS
    Co-ALS
    A.4.1Sponsor's protocol code numberCo-ALS
    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 SponsorAZIENDA OSPEDALIERO-UNIVERSITARIA POLICLINICO DI MODENA
    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 support
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOspedale Civile S. Agostino Estense
    B.5.2Functional name of contact pointCentro coordinatore
    B.5.3 Address:
    B.5.3.1Street AddressVia P. Giardini 1355
    B.5.3.2Town/ cityModena
    B.5.3.3Post code41126
    B.5.3.4CountryItaly
    B.5.4Telephone number0593961640
    B.5.5Fax number0593963775
    B.5.6E-mailj.mandrioli@ausl.mo.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 COLCHICINA LIRCA - 1 MG COMPRESSE 60 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderACARPIA - SERVICOS FARMACEUTICOS LDA
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColchicina
    D.3.2Product code Colchicina
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOLCHICINA
    D.3.9.1CAS number 64-86-8
    D.3.9.2Current sponsor codeColchicina
    D.3.9.3Other descriptive nameCOLCHICINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Definite or probable amyotrophic lateral sclerosis
    Sclerosi laterale amiotrofica definita o probabile
    E.1.1.1Medical condition in easily understood language
    Definite or probable amyotrophic lateral sclerosis
    Sclerosi laterale amiotrofica definita o probabile
    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 20.0
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052889
    E.1.2Term ALS
    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
    The primary objective is to assess whether different colchicine doses decrease disease progression, measured through ALSFRS-R (ALS Functional Rating Scale-Revised), in ALS patients compared to the control arm.
    Valutare la capacità di colchicina nel determinare nel braccio in trattamento rispetto a quello di controllo un rallentamento nella progressione della SLA misurata con la scala ALSFRS-R (ALS Functional Rating Scale-Revised)
    E.2.2Secondary objectives of the trial
    - To evaluate colchicin safety and tolerability in ALS patients;
    - To analyse colchicine efficacy in enhancing autophagy quantifying mRNA and protein levels of p62, LC3, TFEB, ATGs, HSPB8, BAG3, BAG1, HSP70, and HSF1, also in muscle biopsy of patients (optional);
    - To identify changes in stress granules response and composition;
    - Measure of the overall levels and the relative ratio between soluble and insoluble species of TDP-43, TDP-43 fragments, SQSTM1/p62, UBQLN, OPTN in fibroblasts and lymphoblasts;
    - To study colchicine effects on extracellular vesicles secretion of TDP-43, hyperphosphorylated TDP-43, SQSTM1/p62, UBQLN and OPTN;
    - To study colchicine effects on peripheral and CSF biomarkers: creatinine, albumin, CK, and vitamin D, phosphorylated neurofilaments heavy chain, IL18 and its endogenous inhibitor IL-18BP, MCP1 and IL17;
    - To evaluate colchicine efficacy in terms of survival and forced vital capacity (FVC) progression
    - Valutare la sicurezza e la tollerabilità di colchicina in pazienti affetti da SLA;
    - Studiare i cambiamenti nella cascata di segnali correlata all’autofagia nella SLA (i livelli di m-RNA e l’espressione proteica di p62, LC3, TFEB, ATGs, HSPB8, BAG3, BAG1, HSP70 e HSF1) anche mediante biopsie muscolari (opzionale per i pazienti);
    - Valutare i cambiamenti nella localizzazione sub-cellulare di TDP-43 e la risposta dei granuli di stress in linfoblasti e fibroblasti;
    - Valutare i cambiamenti nella formazione di aggregati cellulari misurando i livelli e la solubilità di TDP-43, TDP-43, SQSTM1/p62, Ubiquilina 2 e Optineurina in linfoblasti e fibroblasti;
    - Valutare gli effetti sulla secrezione di esosomi contenenti TDP43, pTDP-43, SQSTM1/p62, Ubiquilina e Optineurina;
    - Analizzare i biomarker correlati alla progressione della SLA: creatinina, albumina, CK e vitamina D, pNfH, IL18 ed i suoi inibitori endogeni IL-18BP, MCP1 e IL17;
    - Studiare l’effetto della colchicina su colture di MN-iPSCs
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients diagnosed with a laboratory supported , clinically “probable” or “definite” amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000)
    - Sporadic ALS
    - ALS phenotypes: classic or bulbar
    - Female or male patients aged between 18 and 80 years old
    - Disease duration from symptoms onset no longer than 18 months at the screening visit
    - Patients treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening
    - Patients with a weight > 50 kg and a BMI ≥18
    - Patients with a FVC (Forced Vital Capacity) equal or more than 65 % predicted normal value for gender, height, and age at the screening visit
    - Patients able and willing to comply with study procedures as per protocol
    - Patients able to understand, and capable of providing informed consent at screening visit prior to any protocol-specific procedures
    - Use of highly effective contraception both for males and females
    - Pazienti con diagnosi di SLA definita, clinicamente probabile o probabile con supporto di laboratorio secondo i criteri di El Escorial - Revised (Brooks, 2000
    - SLA sporadica
    - Fenotipi di SLA: classico o bulbare
    - Età: 18-80 anni
    - Esordio di malattia ≤18 mesi dalla visita di screening
    - Pazienti in trattamento stabile con Riluzolo (100 mg/die) da almeno 30 giorni al momento dello screening
    - FVC ≥ 65% al momento dello screening
    - Peso > 50 Kg e BMI ≥ 18 al momento dello screening
    - Capacità di comprendere e aderire a quanto richiesto dal protocollo dello studio
    - Capacità di fornire il consenso Informato
    - Utilizzo di metodi contraccettivi altamente efficaci (donne e uomini in età fertile)

    E.4Principal exclusion criteria
    - Prior use of colchicine
    - Prior allergy/sensitivity to colchicine
    - Receiving colchicine or other anti-inflammatory drugs (such as corticosteroids, methotrexate, anti-neoplastic, Interleukin 1-1b antagonist, Tumor necrosis factor-alpha inhibitor)
    - Receiving food or co-medications such as strong-moderate cytochrome P450 3A4 inhibitors that will result in elevated plasma level of colchicine
    - Inflammatory disorders (SLE, Rheumatoid arthritis, connective tissue disorder) or chronic infections (HIV, hepatitis B or C infection) or significant history of malignancy
    - Severe renal (eGFR< 30ml/min/1.73m2), or liver failure or liver aminotransferase (ALT/AST > 2x Upper limit of normal)
    - Existing blood dyscrasia (e.g., myelodysplasia)
    - White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%
    - Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease
    - Patients who underwent non invasive ventilation, tracheotomy and /or gastrostomy
    - Women who are pregnant or breastfeeding
    - Participation in pharmacological studies within the last 30 days before screening
    - Patients with known pathogenic mutations (SOD1, TARDBP, FUS, C9ORF72)
    - Patients with familial ALS defined as presence of at least one first degree family member (parents/son/daughter/brother/sister) affected by ALS
    - Patients with the following ALS phenotypes: flail arm, flail leg, UMN-p, respiratory, PLS, progressive muscular atrophy
    - Pregresso uso di colchicina
    - Pregressa allergia o ipersensibilità a colchicina
    - Concomitante utilizzo di colchicina o di altri farmaci anti-infiammatori (quali corticosteroidi, metotrexato, farmaci anti-neoplastici, antagonisti di Interleuchina 1-1b, inibitori di TNF- alfa)
    - Assunzione contemporanea di alimenti o altri farmaci riconosciti come inibitori moderato-forti del citocromo P450-3A4 che possano provocare un aumento della concentrazione plasmatica di colchicina
    - Disordini disimmuni (es. LES, Artrite Reumatoide, altre Connettiviti), infezioni croniche (HIV, TBC, epatite B o C), anamnesi significativa di neoplasia
    - Grave insufficienza renale (eGFR<30 ml/min/1.73m2), o insufficienza epatica o incremento della transaminasi sieriche (ALT/AST > 2 volte il limite di normalità)
    - Discrasie ematologiche (per esempio mielodisplasie)
    - Conta leucocitaria < 4.000/mm³, Piastrinopenia < 100.000/mm³, Ematocrito < 30%
    - Comorbilità severe (insufficienza cardiaca, renale, epatica), malattie autoimmuni, patologie respiratorie interstiziali
    - Presenza di PEG o Ventilazione Non Invasiva o VMI
    - Gravidanza o allattamento
    - Partecipazione a qualsiasi trial farmacologico nei 30 giorni precedenti lo screening
    - Pazienti portatori con note mutazioni patogenetiche per la SLA (SOD1, TARDBP, FUS, C9ORF72)
    - Pazienti con SLA-familiare definita dalla presenza di almeno un altro caso di patologia nel primo grado di parentela (genitori, figli, fratelli o serelle)
    - Pazienti con i seguenti fenotipi di SLA: flail arm, flail leg, UMN-p, respiratorio, SLP, atrofia muscolare progressiva
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients exhibiting a positive response (considered as a decrease in ALS progression) comparing baseline and treatment end (week 30) between colchicine and placebo arm, using ALS Functional Rating Scale—Revised (ALSFRS-R)
    Proporzione di pazienti che presentano una risposta al trattamento (definita come un rallentamento nella progressione di malattia di almeno 4 punti del ALS Functional Rating Scale-Revised (ALSFRS-R)) misurata alla settimana 30 rispetto al basale nel gruppo di pazienti trattati con colchicina rispetto al gruppo di pazienti trattati con placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be assessed after 30 weeks from the start of treatment with colchicine or placebo
    L 'endpoint primario sarà valutato dopo 30 settimane dall'inizio del trattamento con colchicina o placebo
    E.5.2Secondary end point(s)
    Absolute and relative change from baseline of the score of ALSAQ-40 (Amyotrophic Lateral Sclerosis Specific Assessment Questionnnaire) at weeks 8, 30 and 54
    Variazione assoluta e relativa rispetto al basale del punteggio del ALSAQ-40 (Amyotrophic Lateral Sclerosis Specific Assessment Questionnnaire) alla settimana 8, 30 e 54
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoint will be evaluated at weeks 8, 30 and 54 after the start of treatment with colchicine or placebo
    L'endpoint sarà valutato alla settimana 8, 30 e 54 dopo l'inizio del trattamento con colchicina o placebo
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 trial3
    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 concerned9
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA9
    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 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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 Yes
    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 state54
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 54
    F.4.2.2In the whole clinical trial 54
    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 will be monitored and treated according to local clinical practice
    I pazienti saranno seguiti e trattati in accordo alla pratica clinica locale
    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 Decision2018-08-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-11
    P. End of Trial
    P.End of Trial StatusOngoing
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