| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Behçet disease
STELABEC-1: patients with oral ulcers
STELABEC-2 : patients with active posterior uveitis or panuveitis |
Maladie de Behçet
STELABEC-1: patients avec atteinte cutanéo-muqueuse
STELABEC-2 : patients avec uvéite postérieure, panuvéite et/ou vascularite rétinienne
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| E.1.1.1 | Medical condition in easily understood language |
| Behçet Disease |
| Maldie de Behçet |
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| 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 | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004212 |
| E.1.2 | Term | Behcet's disease |
| E.1.2 | System Organ Class | 100000004866 |
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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 |
| Primary objective of the study are to evaluate the proof of concept of efficacy of ustekinumab in subjects with Behçet disease, including patients with oral ulcers (STELABEC-1) and patients with active posterior uveitis or panuveitis (STELABEC-2), and to evaluate the safety and tolerability of ustekinumab. |
| L'objectif principal est d'évaluer l'efficacité de l'ustekinumab chez les patients atteints de maladie de Behçet. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary goal is to evaluate the safety and tolerability of ustekinumab in subjects with Behçet disease. |
| Les objectifs secondaires sont d'évaluer l'efficacité et la tolérance de l'ustekinumab chez les patients atteints de maladie de Behçet. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Are at least 18 years of age.
2. Have a diagnosis of BD according to the International Classification Criteria (criteria from the International Study Group and/or the 2013 International Criteria for BD).
3. Have an active disease at screening, defined by the presence of:
- For the STELABEC-1 study: Recurrent oral and/or genital ulcers, defined as ?2 episodes within 3 months before study entry. Before study entry, patients should have at least 2 oral ulcers within the last 2 weeks before baseline visit.
- For the STELABEC-2 study: Active posterior uveitis and/or panuveitis and/or retinal vasculitis, defined by the presence of at least 1 or the following parameters in at least one eye :
i. Active, inflammatory, chorioretinal and/or inflammatory retinal vascular lesion
ii. >=2+ anterior chamber cells (Standardization of Uveitis Nomenclature [SUN] criteria)
iii. >=2+ vitreous haze (National Eye Institute [NEI]/SUN criteria)
Patients presenting with both muco-cutaneous and ocular manifestations will be included in the STELABEC-1 or STELABEC-2 trial according to the severity of each manifestation, based on the decision of the physician in charge of the patients. Patients with predominant muco-cutaneous manifestations will be included in STELABEC-1, whereas those with predominant ocular manifestations will be included in STELABEC-2.
4. Have previously received at least 1 non-biologic therapy:
- For the STELABEC-1 study: Colchicine ?1 mg/day for all patients
- For the STELABEC-2 study: Subjects must have active disease at the baseline visit despite at least 2 weeks of oral prednisone ? 10 mg/day to ?60 mg/day (or oral corticosteroid equivalent)
5. Are on a stable BD treatment regimen consisting of any of the following medications (alone or in combination):
- Corticosteroids for a period of at least 2 weeks prior to Day 0 (ie, day of 1st dose of study agent)
- Colchicine for a period of at least 30 days prior to Day 0
- Immunosuppressive or immunomodulatory agents for a period of at least 30 days prior to Day 0 (ie, day of 1st dose of study agent)
- Thalidomide for a period of at least 60 days prior to Day 0
6. A female subject is eligible to enter the study if she is:
- Not pregnant or breast-feeding
- Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed or have current documented tubal ligation); or
- Of childbearing potential (ie, women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea [even severe], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to 1 of the following:
Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 8 weeks after the last dose of study agent; or
Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent and 15 weeks after the last dose of study agent:
- Implants of levonorgestrel;
- Injectable progesterone;
- Any intrauterine device (IUD) with a documented failure rate of less than 1% per year;
- Oral contraceptives (either combined or progesterone only);
- Double barrier method: Condom, cervical cap or diaphragm with spermicidal agent;
- Transdermal contraceptive patch;
- Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subject.
7. Have the ability to understand the requirements of the study provide written informed consent (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits).
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1/ Age > 18 ans
2/ Diagnostic de maladie de Behçet selon les critères de classification internationaux (critères de l'International Study Group ou critères internationaux de 2013)
3/ Maladie active définie par :
- STELABEC-1 : Aphtes buccaux et/ou génitaux, lésions cutanées nodulaires et/ou lésions papulo-pustuleuses récidivants (définis par >=3 épisodes au cours du dernier mois)
- STELABEC-2: Uvéite postérieure, panuvéite ou vascularite rétinienne active, définie par la présence d'au moins 1 des critères suivants sur au moins un oeil:
- Lésion inflammatoire, choriorétinienne et/ou vasculaire rétinienne active
- >=2+ en chambre antérieure (critères de la Standardization of Uveitis Nomenclature [SUN])
- >=2+ dans le corps vitré (critères National Eye Institute [NEI]/SUN)
4/Patients résistants aux traitements conventionnels de première ligne:
- STELABEC-1 : Colchicine >=1 mg/j
- STELABEC-2 : les patients doivent avoir une maladie active à la visite d'inclusion malgré au moins 2 semaines de traitement par prednisone (ou équivalent) >=10 mg/j et <=60 mg/j
5/ Patients sous doses stables de traitement, depuis au moins 2 semaines pour les corticoïdes et 30 jours pour les immunosuppresseurs ou immunomodulateurs
6/ Femme en âge de procréer non enceinte et non allaitante, et ayant une contraception efficace
7/ Patients ayant les capacités de recevoir et comprendre les informations relatives au protocle et à donner un consentement éclairé, et ayant signé le formulaire d'information et consentement de participation à l'étude.
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| E.4 | Principal exclusion criteria |
1. Have required 3 or more courses of systemic corticosteroids for concomitant conditions (eg, asthma, atopic dermatitis) within 90 days of Day 0 (Topical or inhaled steroids are permitted)
2. Have received intravenous (IV) or oral cyclophosphamide within 180 days of Day 0.
3. Have received any of the following within 90 days of Day 0:
- Anti-TNF therapy (eg, adalimumab, etanercept, infliximab).
- Interleukin-1 receptor antagonist (anakinra).
- Abatacept
- Interleukin-6 receptor antagonist (tocilizumab)
- Intravenous immunoglobulin (IVIG).
- High dose prednisone (> 100 mg/day).
4. Have received any of the following within 60 days of Day 0:
- A non-biologic investigational agent.
- Any new immunosuppressive/immunomodulatory agent.
Note: New inhaled steroids and new topical immunosuppressive agents (eg, eye drops, topical creams) are allowed. Any NSAID use for < 1 week is allowed.
- Any steroid injection (intramuscular, intraarticular or intravenous).
5. Have received any of the following within 30 days of Day 0:
- A live vaccine within 30 days of Day 0.
- A change in dose of a corticosteroid within 2 weeks days of Day 0.
- A change in dose of other immunosuppressive/immunomodulatory agent within 30 days of Day 0.
6. Have very severe Behçet disease (defined by current severe complication of BD: digestive, cardiac, pulmonary or central nervous system involvement assessed as very severe by the referring clinician), requiring high dose prednisone (?1mg/kg) within 30 days of Day 0.
7. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
8. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to BD (ie, cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk.
9. Have a planned surgical procedure or a history of any other medical disease (eg, cardiopulmonary), laboratory abnormality, or condition (eg, poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
10. Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
11. Have required management of acute or chronic infections, as follows:
- Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
- Hospitalization for treatment of infection within 60 days of Day 0.
- Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days of Day 0.
12. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within 364 days prior to Day 0.
13. Have a historically positive test or test positive at screening for HIV-1 antibody, hepatitis C virus antibodies, hepatitis B surface antigen (HbsAg) (with or without positive serum HBV DNA), or antiHBcAg positivity (without HbsAg positivity), or positive for Hepatitis C antibody (confirmed on the same sample with a Hepatitis C RIBA® immunoblot assay). .
14. Have a Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed:
- Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.
- Stable Grade 3/4 proteinuria (? 6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed).
- Stable Grade 3 neutropenia or stable Grade 3 white blood cell count.
15. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies.
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1/ Patients ayant reçu >=3 cures de corticoïdes par voie systémique pour une pathologie associée au cours des 180 derniers jours avant l'inclusion.
2/ Patients ayant reçu du cyclophosphamide par voie orale ou intra-veineuse au cours des 180 derniers jours avant l'inclusion.
3/ Patients ayant reçu au cours des 90 derniers jours avant l'inclusion les molécules suivantes :
- Traitement anti-TNF (adalimumab, etanercept, infliximab)
- Antagoniste du récepteur de l'nterleukine-1 (anakinra)
- Abatacept
- Antagoniste du récepteur de l'nterleukine-6 (tocilizumab)
- Immunoglobulines intra-veineuses
- Prednisone à haute dose (> 100 mg/j)
4/ Patients ayant reçu au cours des 60 derniers jours avant l'inclusion les molécules suivantes :
- Agent expérimental non-biologique
- Nouvel agent immunosuppresseur et/ou immunomodulateur
- Injection de dérivés corticoïdes (intra-musculaire, intra-articulaire ou intra-veineuse).
5/ Patients ayant reçu au cours des 30 derniers jours avant l'inclusion les molécules suivantes :
- Vaccin vivant
- Changement de la dose de corticoïdes dans les 2 semaines précédant l'inclusion
- Changement de la dose d'un traitement immunosuppresseur ou immunomodulateur dans les 30 jours précédant l'inclusion
6/ Maladie de Behçet mettant en jeu le pronostic vital
7/ Antécédent de transplantation d'organe ou de greffe de cellules souches
8/ Patients ayant une pathologie chronique associée instable ou incontrôlée
9/ Patients ayant une intervention chirurgicale ou une pathologie associée contre-indiquant selon l'investigateur l'inclusion
10/ Patient ayant un antécédent de néoplasie dans les 5 années précédant l'inclusion, à l'exception des cancers cutanés traités de manière adéquate ou des carcinomes in situ du col de l'utérus
11/ Patients ayant une infection aigue ou chronique évolutive, incluant les infections par le VIH, le VHB et le VHC
12/ Patients ayant une dépendance à l'alcool ou à une drogue dans les 364 jours précédant l'inclusion
13/ Patients ayant des anomalies biologiques de grade 3
14/ Patients ayant un antécédent de réaction anaphylactique à l'administration de produits de contraste, de protéines recombinantes ou d'anticorps monoclonaux d'origine humaine ou murine.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary assessment criterion of this trial is the treatment efficacy at week 24.
For the STELABEC-1 study on oral ulcers, the primary efficacy endpoint is the change in the number of oral ulcers at week 24 compared to baseline.
The primay endpoint will distinguish complete response, defined as the absence of any oral and genital ulceration at week 24; and partial response, defined as a decrease ?50% in the number of oral ulcers. This primary endpoint was used in previous studies on oral ulcers in BD (for example, Hamuryudan et al., Ann Intern Med, 1998).
For the STELABEC-2 study on eye involvement, the primary efficacy endpoint is the achievement of uveitis or retinal vasculitis remission.
The secondary assessment criteria of this trial are:
- Mean change from baseline in the number of oral and genital ulcers at all evaluations.
- Mean change from baseline in oral or genital ulcer pain VAS at all evaluations.
- Ocular examination at all evaluations.
- Change from baseline in Behçet Syndrome Activity Score (BSAS) and Behçet Disease Current Activity Form (BDCAF) disease activity scores for BD at weeks 12, 24 and 52.
- Change from baseline in Behçet Diease Quality of Lise Measure, SF-36 and RAPID3 at weeks 12, 24 and 52.
- Safety evaluated by assessing adverse events (including headache, arthralgia, infection, depression, dizziness, diarrhea, pruritus, myalgia, asthenia) and routine hematologic and laboratory values (detailed in the table above).
The primary efficacy endpoint and the secondary efficacy endpoints will also be assessed at week 52 in patients continuing the treatment until week 40.
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Critère de jugement principal ;
Efficacité du traitement évaluée à la semaine 24 pour les 2 sous-études STELABEC-1 et STELABEC-2.
Pour l'étude STELABEC-1, le critère de jugement principal est le changement dans le nombre de lésions cutanéo-muqueuses. Une réponse complète est définie par l'absence de lésions cutanéo-muqueuses à la semaine 24. Une réponse partielle est définie par une diminution ?50% du nombre de lésions cutanéo-muqueuses.
Pour l'étude STELABEC-2, le critère de jugement principal est l'obtention d'une rémission de l'uvéite ou de la vascularite rétienne à la semaine 24 selon les critères internationaux en vigueur.
Critères de jugement secondaires:
- Changement du nombre de lésions cutanéo-muqueuses à chaque évaluation.
- Changement moyen de l'EVA douleur des aphtes buccaux et/ou génitaux à chaque évaluation.
- Changement de l'examen ophtalmologique à chaque évaluation.Changement moyen des scores d'activité BSAS et du BDCAF aux semaines 12, 24 et 52.
- Changement moyen des scores de qualité de vie Behçet Disease Quality of Life Measure, SF-36 et RAPID-3 aux semaines 12, 24 et 52.
- Tolérance du traitement.
Les critères de jugement principal et secondaires seront également évalués à la semaine 52 pour les patients poursuivant le traitement à l'étude.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary assessment criterion of this trial is the treatment efficacy at week 24.
The primary efficacy endpoint will also be assessed at week 52 in patients continuing the treatment until week 40. |
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| E.5.2 | Secondary end point(s) |
- Mean change from baseline in the number of oral and genital ulcers at all evaluations.
- Mean change from baseline in oral or genital ulcer pain VAS at all evaluations.
- Ocular examination at all evaluations.
- Change from baseline in Behçet Syndrome Activity Score (BSAS) and Behçet Disease Current Activity Form (BDCAF) disease activity scores for BD at weeks 12, 24 and 52.
- Change from baseline in Behçet Diease Quality of Lise Measure, SF-36 and RAPID3 at weeks 12, 24 and 52.
- Safety evaluated by assessing adverse events (including headache, arthralgia, infection, depression, dizziness, diarrhea, pruritus, myalgia, asthenia) and routine hematologic and laboratory values (detailed in the table above).
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- Changement du nombre de lésions cutanéo-muqueuses à chaque évaluation.
- Changement moyen de l'EVA douleur des aphtes buccaux et/ou génitaux à chaque évaluation.
- Changement de l'examen ophtalmologique à chaque évaluation.Changement moyen des scores d'activité BSAS et du BDCAF aux semaines 12, 24 et 52.
- Changement moyen des scores de qualité de vie Behçet Disease Quality of Life Measure, SF-36 et RAPID-3 aux semaines 12, 24 et 52.
- Tolérance du traitement.
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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 | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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