E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Definite or probable amyotrophic lateral sclerosis |
Sclerosi laterale amiotrofica definita o probabile |
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E.1.1.1 | Medical condition in easily understood language |
Definite or probable amyotrophic lateral sclerosis |
Sclerosi laterale amiotrofica definita o probabile |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052889 |
E.1.2 | Term | ALS |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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) |
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E.2.2 | Secondary 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
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- 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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)
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E.4 | Principal 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
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- 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
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E.5 End points |
E.5.1 | Primary 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 |
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E.5.1.1 | Timepoint(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 |
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E.5.2 | Secondary 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 |
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E.5.2.1 | Timepoint(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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |