| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BEH¿ET¿S DISEASE REFRACTORY TO STANDARD OF CARE THERAPIES |
| Malattia di Beh¿et refrattaria alle terapie standard |
|
| E.1.1.1 | Medical condition in easily understood language |
| BEH¿ET¿S DISEASE REFRACTORY TO STANDARD OF CARE THERAPIES |
| Malattia di Beh¿et refrattaria alle terapie standard |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| 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 | 10004215 |
| E.1.2 | Term | Behcets disease |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 |
Primary Efficacy Objective
The primary objective of the study is to evaluate the effectiveness of either 6-month infliximab-IFX or adalimumab-ADA course following an induction with systemic corticosteroids and defined by the time to response of ocular and/or neurological and/or muco-cutaneous manifestations of Behcet¿s disease that have been occurred despite at least 3-month immunosuppressive standard of care therapy with azathioprine or cyclosporine
Primary Safety Objective
The safety and tolerability profiles of anti TNF alpha agents will be evaluated as the frequency of adverse events (AEs) and serious adverse events (SAEs) during the course of study.
|
Obiettivo primario di efficacia
L'obiettivo primario dello studio ¿ quello di valutare l'efficacia del trattamento di 6 mesi con infliximab-IFX o adalimumab-ADA a seguito di una induzione con corticosteroidi sistemici e definito dal tempo di risposta di oculare e / o manifestazioni neurologiche e / o muco-cutanee della malattia di Behcet che si sono verificati nonostante almeno 3 mesi di terapia immunosoppressiva standard con azatioprina o ciclosporina
Obiettivo primario di sicurezza
I profili di sicurezza e tollerabilit¿ degli agenti anti-TNF alfa saranno valutate come la frequenza di eventi avversi (EA) e gli eventi avversi gravi (SAE) durante il corso dello studio. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives will be the evaluation during all the treatment period including the follow up time of:
- the proportion of BD subjects who will have a relapse of ocular, neurological or muco-cutaneous
manifestations while on anti TNF alpha agents;
- the adherence to the IMPs defined as the administration/intake >70% of anti TNF alpha agents in the
considered period;
- the retention on anti TNF alpha agents and reasons of withdrawal;
- their effects on quality of life measured by the NEI-VFQ25.
|
Obiettivi secondari
Gli obiettivi secondari saranno la valutazione durante tutto il periodo dello studio compreso il follow-up di:
- La proporzione di soggetti BD che avr¿ una ricaduta di manifestazioni oculari, neurologiche o muco-cutanee durante il trattamento con agenti anti-TNF alfa;
- L'adesione agli agenti anti-TNF alfa;
- La conservazione ad agenti anti TNF alfa;
- Effetti sulla qualit¿ della vita (QoL). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Subject’s written informed consent given before any study-related procedure not part of the subject’s
normal medical care, with the understanding that consent may be withdrawn by the subject at any time
without prejudice to his or her future medical care;
-Age >=18-<65 years;
-Males or females;
-Diagnosis of BD according to the 1990 ISG criteria;
-Presenting active ocular and/or neurologic and/or muco-cutaneous manifestations, that have been occurred while on IS SoC therapy with either Aza or CsA of at least 3-month duration prior to study entry;
-Records’ availability for Aza or CsA and other IS SoC treatments (at least 3-month immunosuppressive standard of care therapy with azathioprine or cyclosporine A);
-Patients who develop severe and life-threatening complications treated with IS SoC and/or CS therapies;
- Concerning tubercolosis (TB), patients who meet no evidence of active or latent TB could be enrolled in the study. At screening, in case of a negative Quantiferon, TB Gold in Tube Test should be performed. Moreover a chest radiograph taken at screening or within the 3 months prior to the screening without evidence of active or latent TB infection should be registered.
Patients previously treated for TB could be enrolled in the study. The subjects should be included if they have previously received an adequate course of therapy as per local standard of care for either latent TB (9 months of isoniazid in a location where rates of primary multi drug resistant TB infections are <5% or an acceptable alternative regimen) or active TB. In these patients TB Gold in Tube Test (or equivalent assay) need be obtained. A chest radiograph must be obtained if not done so within 3 months prior to screening;
-Subjects who are women of childbearing potential must agree to utilize a highly effective contraceptive measure throughout the course of the study for the entire duration of the trial and the subsequent follow-up (see section 4.3).
Section 4.3 Contraceptive methods
In accordance with the CTFG recommendations related to contraception and pregnancy testing in clinical trials, birth control methods which may be considered as highly effective include the following: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal or Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable o Intrauterine device (IUD) o Intrauterine hormone-releasing system (IUS) o Bilateral tubal occlusion o Vasectomised partner(s).
|
¿ Pazienti in grado di fornire un consenso informato
¿ Eta’: 18-65 anni
¿ Maschi o Femmine
¿ Diagnosi di Malattia di Behcet secondo i criteri del Gruppo Internazionale di Studio sulla Malattia di Behçet (1990)
¿ Manifestazioni attive oculari, neurologiche o mucocutanee incorse durante la terapia (standard of care) con Aza o CsA durate per almeno 3 mesi nel periodo precedente allo studio
¿ Aza o CsA e altre terapie immunosoppressive standard ( almeno 3 mesi di terapie immunosoppressive con Aza o CsA)
¿ Pazienti che sviluppano complicanze gravi e pericolose trattati con IS SoC e / o terapie CS (corticosteroidi);
¿ I pazienti che non hanno TB attiva o latente possono essere arruolati nello studio. Allo screening, in caso di Quantiferon negativo, dovrà comunque essere eseguito il QuantiFERON-TB Gold test. Inoltre sarà necessaria una radiografia del tronco effettuata allo screening o entro 3 mesi dallo screening in cui non si evidenza alcuna infezione per TB attiva o latente.
Pazienti precedentemente trattati per TB potranno entrare nello studio purchè abbiano ricevuto un adeguato trattamento sia per TB latente che per TB attiva. In questi pazienti 3
dovrà essere eseguito il QuantiFERON-TB Gold test (o un saggio equivalente). È necessaria una radiografia del tronco effettuata entro 3 mesi dallo screening.
¿ Donne potenzialmente fertili devono utilizzare metodi contraccettivi altamente efficaci per tutta la durata dello studio e fino alla visita di F.U. I metodi di controllo delle nascite, considerati altamente efficaci sono:
contraccezione ormonale combinata (estrogeno e progesterone) associata ad inibizione dell’ovulazione: orale, intravaginale, transdermica;
contraccezione con progesterone associata ad inibizione dell’ovulazione: orale, iniettabile, impiantabile;
dispositivo intrauterino (IUD);
dispositivo intrauterino a rilascio di progestinico (IUS);
chiusura delle tube;
vasectomia del partner.
|
|
| E.4 | Principal exclusion criteria |
-Actual “end-stage” BD, with severe retinal damage or central nervous system (CNS) irreversible damage;
-Visual acuity < 1/10 on Snellen chart in both eyes or bilateral permanent blindness;
-Other severe BD manifestations, i.e. arterial aneurysm, thrombosis of the caval, hepatic veins, or cerebral sinuses;
-Any infection at screening or frequent acute or chronic infections within 3 months prior to the study entry;
-Congestive heart failure;
-Multiple sclerosis or any other central demyelinating disorder;
-History of malignancy within previous 5 years (except curatively excised skin cancer);
-Transplanted organ (except cornea);
-Substance abuse within 3 years;
-Enrollment in other investigative clinical trial;
-Prior history of anti TNF alpha agents’ or other monoclonal antibody treatments, or known allergy to murine or chimeric proteins
- Hypersensitivity to the active substances or to any of the excipients
- History of HIV, HCV or HBV infections. At the screening a specific test to assess the seronegativity to the viruses should be performed.
- No subjects with current active TB may be enrolled in the study.
-Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin
(hCG) laboratory test;
-Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during the entire study;
-History of poor compliance.
|
¿ Stadio finale della malattia di Behcet, con danno severo della retina o danno irreversibile a carico del sistema nervoso centrale
¿ Acuità visiva secondo scala di Snellen < 1/10 in entrambi gli occhi o cecità bilaterale permanente
¿ Altre manifestazioni severe come aneurisma arterioso, trombosi delle vene cave, epatiche o dei seni cerebrali
¿ Qualsiasi infezione allo screening o frequenti infezioni acute o croniche nei tre mesi precedenti all’ingresso nello studio
¿ Insufficienza cardiaca congestizia;
¿ Sclerosi multipla o qualsiasi altro disordine di demielinizzazione centrale
¿ Storia di malignità nei 5 anni precedenti allo studio (eccetto cancro della cute opportunamente trattato)
¿ Trapianto d’organo (eccetto cornea)
¿ Sostanze d’abuso nei tre anni precedenti lo studio
¿ Partecipazione ad altri studi clinici
¿ Precedenti trattamenti con antiTNFalfa o anticorpi monoclonali o allergia nota a proteine murine o chimeriche
¿ Ipersensibilità alle sostanze attive e loro eccipienti
¿ Storia di infezioni da HIV, HCV o HBV. Al momento dello screening è necessario eseguire l’analisi per accertare la sieronegatività.
¿ Pazienti con TB attiva
¿ Donne in gravidanza e/o allattamento. La gravidanza è definita come periodo che va dal concepimento alla fine della gestazione e deve essere accertata con il saggio di laboratorio per hCG
¿ Donne potenzialmente fertili che non usano metodi contraccezionali efficaci durante l’intero studio.
¿ Storia di scarsa compliance. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary study endpoint will be the time to response of sight-threatening uveitis and/or neurological and/or muco-cutaneous manifestations over 6-month antiTNFalpha agents’ treatment. |
| Endpoint primario dello studio sarà il tempo di risposta oculare e / o neurologici e / o manifestazioni muco-cutanee rispetto al trattamento di 6 mesi agenti antiTNFalpha '. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary objectives will be the evaluation during all the treatment period including the follow up time of:
- the proportion of BD subjects who will have a relapse of ocular, neurological or muco-cutaneous
manifestations while on anti TNF alpha agents;
- the adherence to the IMPs defined as the administration/intake >70% of anti TNF alpha agents in the
considered period;
- the retention on anti TNF alpha agents and reasons of withdrawal;
- their effects on quality of life measured by the NEI-VFQ25.
|
Gli obiettivi secondari saranno la valutazione durante tutto il periodo di trattamento compreso il tempo di follow-up di:
- La proporzione di soggetti BD che avr¿ una ricaduta di manifestazioni oculari, neurologiche o muco-cutanea in trattamento con anti TNA alfa;
- Il rispetto degli IMP definiti come la somministrazione / assunzione> 70% di anti TNF alfa nel periodo considerato;
- La conservazione a agenti anti TNA alfa e motivi di ritiro ;
- Effetti sulla qualit¿ della vita, misurata con il NEI-VFQ25. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| VALUTATORE IN CIECO |
| EVALUATOR BLIND |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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