E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active Ulcerative Colitis (UC) |
Colite ulcerosa da moderatamente a gravemente attiva |
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E.1.1.1 | Medical condition in easily understood language |
Moderately to severely active Ulcerative Colitis. UC is a long-term condition that results in inflammation and ulcers of the colon and rectum |
Moderately to severely active Ulcerative Colitis. UC is a long-term condition that results in inflammation and ulcers of the colon and rectum |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066678 |
E.1.2 | Term | Acute ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of 2 different dose regimens of vedolizumab IV in pediatric subjects with moderately to severely active UC during maintenance therapy, based on clinical remission at Week 54. |
valutare l’efficacia di 2 diversi regimi di dosaggio di vedolizumab per via endovenosa in soggetti pediatrici con CU da moderatamente a gravemente attiva durante la terapia di mantenimento, in base alla remissione clinica alla Settimana 54. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of high and low doses of vedolizumab IV as measured by sustained clinical and endoscopic remission at Weeks 14 and 54. • To evaluate the effect of high and low doses of vedolizumab IV in each weight group on achieving corticosteroid-free remission at Week 54. • To evaluate the effect of vedolizumab IV in each weight group on clinical response and clinical remission over time up to Week 54. • To characterize the exposure of 2 different regimens of vedolizumab in pediatric subjects with moderately to severely active UC after IV administration. • To evaluate safety in pediatric subjects on maintenance therapy up to Week 54. • To evaluate the immunogenicity of vedolizumab in pediatric subjects with moderately to severely active UC treated with vedolizumab IV. • To evaluate the effect of vedolizumab on patterns of growth and pubertal development in pediatric subjects with moderately to severely active UC during their participation in the study. |
Fare riferimento alla sinossi in Italiano |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects male or female aged 2 to 17 years, inclusive, who weigh =10 kg at the time of screening and enrollment into the study. 2. Subjects with moderately to severely active UC diagnosed at least 1 month before screening, defined by a modified Mayo score of 5 to 9 (sum of Mayo endoscopic subscore, stool frequency subscore, and rectal bleeding subscore) with a Mayo endoscopic subscore of =2 (mucosal friability indicates an endoscopic subscore of at least 2). 3. Subjects who have failed, lost response to, or been intolerant to treatment with at least 1 of the following agents: corticosteroids, immunomodulators (eg, azathioprine, 6-mercaptopurine, methotrexate), and/or TNF-a antagonist therapy (eg, infliximab, adalimumab). This includes subjects who are dependent on corticosteroids to control symptoms and who are experiencing worsening of disease when attempting to wean off corticosteroids. 4. Subjects with evidence of UC extending proximal to the rectum (ie, not limited to proctitis), at a minimum. 5. Subjects with extensive colitis or pancolitis of >8 years' duration or left-sided colitis of >12 years' duration must have documented evidence of a negative surveillance colonoscopy within 12 months before screening. 6. Subjects with vaccinations that are up-to-date based on the countrywide, accepted schedule of childhood vaccines. |
Soggetti ambosesso di età compresa tra 2 e 17 anni, inclusi, che pesano =10 kg al momento dello screening e dell’arruolamento nello studio. Soggetti con CU da moderatamente a gravemente attiva diagnosticata almeno 1 mese prima dello screening, definita da un punteggio Mayo modificato da 5 a 9 (somma del sottopunteggio Mayo endoscopico, sottopunteggio di frequenza delle evacuazioni e sottopunteggio di sanguinamento rettale) con un sottopunteggio endoscopico Mayo =2 (la friabilità mucosale indica un sottopunteggio endoscopico di almeno 2). Soggetti che non hanno risposto, hanno perso la risposta o sono risultati intolleranti al trattamento con almeno 1 dei seguenti agenti: corticosteroidi, immunomodulatori (per es. azatioprina, 6-mercaptopurina, metotrexato) e/o terapia con antagonisti del TNF-a (per es. infliximab, adalimumab). Ciò include i soggetti che sono dipendenti dai corticosteroidi per il controllo dei sintomi e che manifestano un peggioramento della malattia quando tentano di sospendere i corticosteroidi. Soggetti con evidenza di CU che, come minimo, si estende prossimalmente fino al retto (ovvero, non limitata alla proctite). I soggetti con colite estensiva o pancolite di durata >8 anni o colite al lato sinistro di durata >12 anni devono presentare evidenza documentata di una colonscopia di sorveglianza negativa entro 12 mesi prima dello screening. Soggetti con vaccinazioni che risultano aggiornate in base al programma vaccinale dell’infanzia accettato a livello nazionale. |
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E.4 | Principal exclusion criteria |
1. Subjects who have had previous exposure to approved or investigational anti-integrins including, but not limited to natalizumab, efalizumab, etrolizumab, or AMG 181, or mucosal addressin cell adhesion molecule-1 antagonists or rituximab. 2. Subjects who have had prior exposure to vedolizumab. 3. Subjects with hypersensitivity or allergies to any of the vedolizumab excipients. 4. Subjects who have received either (1) an investigational biologic (other than those listed in Exclusion Criterion #1) within 60 days or 5 half-lives before screening (whichever is longer); or (2) an approved biologic or biosimilar agent within 2 weeks before the first dose of study drug or at any time during the screening period. 5. Subjects with active cerebral/meningeal disease, signs/symptoms or history of progressive multifocal leukoencephalopathy (PML) or any other major neurological disorders including stroke, multiple sclerosis, brain tumor or neurodegenerative disease. 6. Subjects who currently require surgical intervention or are anticipated to require surgical intervention for UC during this study. 7. Subjects who have had subtotal or total colectomy or have a jejunostomy, ileostomy, colostomy, ileo-anal pouch, or known fixed stenosis of the intestine. 8. Subjects with a current diagnosis of indeterminate colitis. 9. Subjects with clinical features suggesting monogenic very early onset inflammatory bowel disease. |
Soggetti che hanno avuto una precedente esposizione ad anti-integrine approvate o sperimentali, tra cui, a titolo esemplificativo ma non esaustivo, natalizumab, efalizumab, etrolizumab o AMG 181, o antagonisti della molecola di adesione cellulare addressina mucosale 1 o rituximab. Soggetti che sono stati precedentemente esposti a vedolizumab. Soggetti con ipersensibilità o allergie a uno qualsiasi degli eccipienti di vedolizumab. Soggetti che hanno ricevuto (1) un farmaco biologico sperimentale (diverso da quelli elencati nel Criterio di esclusione n. 1) entro 60 giorni o 5 emivite prima dello screening (a seconda di quale periodo sia più lungo); o (2) un agente biologico o biosimilare approvato nelle 2 settimane che precedono la prima dose del farmaco dello studio o in qualsiasi momento durante il periodo di screening. Soggetti con malattia cerebrale/meningea attiva, segni/sintomi o anamnesi di leucoencefalopatia multifocale progressiva (LMP) o eventuali altri disturbi neurologici maggiori, tra cui ictus, sclerosi multipla, tumore cerebrale o malattia neurodegenerativa. Soggetti con necessità attuale o prevista di ricorrere a un intervento chirurgico per la CU durante questo studio. Soggetti che si sono sottoposti a colectomia subtotale o totale, si sottopongono a digiunostomia, ileostomia, colostomia o sono portatori di tasca ileo-anale o stenosi fissa nota dell’intestino. Soggetti con diagnosi attuale di colite indeterminata. Soggetti con caratteristiche cliniche che suggeriscono la presenza di una malattia infiammatoria intestinale monogenica a insorgenza molto precoce. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is clinical remission at Week 54, where clinical remission based on the modified Mayo score is defined as: • stool frequency subscore 0 to 1 and a decrease of 1 or more from baseline; • rectal bleeding subscore of 0; • endoscopy subscore 0 to 1 (modified so that a score of 1 does not include friability). |
L’endpoint primario è la remissione clinica alla Settimana 54, dove la remissione clinica basata sul punteggio Mayo modificato è definita come: • sottopunteggio di frequenza delle evacuazioni da 0 a 1 e una diminuzione di 1 o più rispetto al basale; • sottopunteggio di sanguinamento rettale pari a 0; e • sottopunteggio endoscopico da 0 a 1 (modificato in modo tale che un punteggio pari a 1 non includa la friabilità). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The end of study is defined as the Week 54 study visit. |
The end of study is defined as the Week 54 study visit. |
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E.5.2 | Secondary end point(s) |
• Clinical remission at Week 14, where a subject achieves clinical remission if he or she meets the definition described in the primary endpoint. • Sustained clinical remission at Week 54, where a subject achieves sustained clinical remission if he or she achieved clinical remission (as defined by primary endpoint) at Week 14 and at Week 54. • Corticosteroid-free clinical remission at Week 54, where a subject achieves corticosteroid-free clinical remission at Week 54 if he or she meets the definition described in the primary endpoint and was off corticosteroids at least 12 weeks prior to Week 54. • Clinical remission based on complete Mayo score at Week 54, where a subject achieves clinical remission if he or she achieved a complete Mayo score =2 points with no individual subscore >1 at Week 54. • Clinical remission based on PUCAI score at Week 54, where a subject achieves clinical remission if he or she has a PUCAI of =10 at Week 54. • Serum trough concentrations of vedolizumab over time. • Positive antivedolizumab antibodies (AVA) and positive neutralizing AVA during the study. • Sustained clinical response of subjects at Weeks 14 and 54, where a subject meets clinical response if he or she has a reduction in complete Mayo score (see Appendix G) of =3 points and =30% from baseline with an accompanying decrease in rectal bleeding subscore of =1 point or absolute rectal bleeding subscore of =1 point. • Clinical response at Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54 where a subject achieves clinical response if he or she meets the following definition: • Maintenance of a reduction of =2 points and =25% from the baseline partial Mayo score, including a =1-point decrease in the Mayo stool frequency subscore and a =1-point reduction in the rectal bleeding subscore or absolute rectal bleeding subscore of =1 point; and a =20point decrease from baseline in the PUCAI score for Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54. • Safety assessments: descriptions of adverse events (AEs); serious adverse events (SAEs); and adverse events of special interest (AESIs), including evaluation of opportunistic infection, such as PML, liver injury, malignancies, infusion-related reactions, and hypersensitivity. • Change from baseline in weight gain and linear growth z-score during the course of dosing with vedolizumab. • Tanner Stage V at Week 54, where a subject achieves Tanner Stage V at Week 54 based on progression of pubertal changes from baseline. |
• Remissione clinica alla Settimana 14, dove un soggetto raggiunge la remissione clinica se soddisfa la definizione descritta nell’endpoint primario. • Remissione clinica sostenuta alla Settimana 54, dove un soggetto raggiunge la remissione clinica sostenuta se ha raggiunto la remissione clinica (come definito dall’endpoint primario) alla Settimana 14 e alla Settimana 54. • Remissione clinica libera da corticosteroidi alla Settimana 54, dove un soggetto raggiunge la remissione clinica libera da corticosteroidi alla Settimana 54 se soddisfa la definizione descritta nell’endpoint primario e non ha assunto corticosteroidi per almeno 12 settimane prima della Settimana 54. • Remissione clinica basata sul punteggio Mayo completo alla Settimana 54, dove un soggetto raggiunge la remissione clinica se ha raggiunto un punteggio Mayo completo =2 punti senza alcun sottopunteggio individuale >1 alla Settimana 54. • Remissione clinica basata sul punteggio PUCAI alla Settimana 54, dove un soggetto raggiunge la remissione clinica se presenta un PUCAI =10 alla Settimana 54. • Concentrazioni sieriche di valle di vedolizumab nel tempo. • Anticorpi anti-vedolizumab (Anti-Vedolizumab Antibody, [AVA]) positivi e AVA neutralizzanti positivi durante lo studio. • Risposta clinica sostenuta dei soggetti alle Settimane 14 e 54, dove un soggetto soddisfa la risposta clinica se presenta una riduzione del punteggio Mayo completo (vedere Appendice G) =3 punti e =30% rispetto al basale con una concomitante diminuzione del sottopunteggio di sanguinamento rettale =1 punto o sottopunteggio di sanguinamento rettale assoluto =1 punto. • Risposta clinica alle Settimane 2, 6, 10, 14, 22, 30, 38, 46 e 54, dove un soggetto raggiunge la risposta clinica se soddisfa la seguente definizione: Mantenimento di una riduzione =2 punti e =25% rispetto al punteggio Mayo parziale al basale, che comprende una riduzione =1 punto nel sottopunteggio Mayo di frequenza delle evacuazioni e una riduzione =1 punto nel sottopunteggio di sanguinamento rettale o sottopunteggio di sanguinamento rettale assoluto =1 punto; e una riduzione =20 punti rispetto al basale nel punteggio PUCAI per le Settimane 2, 6, 10, 14, 22, 30, 38, 46 e 54. • Valutazioni di sicurezza: descrizioni di eventi avversi (EA), eventi avversi seri (Serious Adverse Event, [SAE]) ed eventi avversi di particolare interesse (Adverse Event of Special Interest, [AESI]), compresa la valutazione delle infezioni opportunistiche, come LMP, lesione epatica, neoplasie maligne, reazioni correlate all’infusione e ipersensibilità. • Variazione rispetto al basale nell’aumento di peso e nel punteggio z della crescita lineare nel corso della somministrazione di vedolizumab. • Stadio V di Tanner alla Settimana 54, dove un soggetto raggiunge lo Stadio V di Tanner alla Settimana 54 in base alla progressione delle variazioni puberali rispetto al basale. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity |
Immunogenicity |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Different doses of IMP are used in treatment arms |
Different doses of IMP are used in treatment arms |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bosnia and Herzegovina |
Canada |
China |
Israel |
Japan |
New Zealand |
Russian Federation |
Ukraine |
United States |
Austria |
Belgium |
Croatia |
France |
Germany |
Hungary |
Italy |
Lithuania |
Poland |
Romania |
Slovakia |
Spain |
United Kingdom |
Czechia |
Greece |
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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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The end of study is defined as the Week 54 study visit. |
The end of study is defined as the Week 54 study visit. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 17 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 17 |