| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ulcerative colitis, NOS |
| colite ulcerosa, NOS |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009900 |
| E.1.2 | Term | Colitis ulcerative |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 |
| *Induction Period (IP): Compare the proportion of subjects in clinical response (defined as a reduction from baseline in Mayo score of >= 3 points and >= 30%, with an accompanying decrease from baseline in rectal bleeding subscore of >= 1 point or an absolute rectal bleeding subscore of =< 1 point) at Week 12 (Day IP-85) between the abatacept and placebo treatment regimens. *Maintenance Period (MP): Compare the proportion of subjects who have a clinical response (defined as a reduction from baseline in Mayo score of >= 3 points and >= 30%, with an accompanying decrease from baseline in rectal bleeding subscore of >= 1 point or an absolute rectal bleeding subscore of =< 1) at Month 12 (Day MP-365) between the abatacept and placebo treatment regimens. Open-Label Extension Phase (OL): Assess the long-term clinical safety and tolerability of abatacept treatment during the Open-Label Extension Phase. |
| Periodo di Induzione placebo-controllato: confrontare la proporzione di pazienti che hanno una risposta clinica alla 12a settimana tra i due regimi di trattamento: abatacept e placebo. Periodo di Mantenimento - confrontare la proporzione di pazienti che mostrano una risposta clinica al mese 12 tra i due regimi di trattamento: abatacept e placebo. |
|
| E.2.2 | Secondary objectives of the trial |
| IP: -Compare proportion of subjects between abatacept & placebo treatment regimens •in clinical remission at Week 12 •with mucosal healing at Week 12 -Evaluate dose-response relationship by comparing proportions of subjects in clinical response at Week 12 induced by placebo & abatacept in increasing doses -Assess in abatacept vs placebo treated subjects improvements in QoL as measured by IBDQ score at Week 12 MP: -Compare proportion of subjects between abatacept & placebo treatment regimens: •in clinical remission at Month 12 / at both Month 6 & 12 •with mucosal healing at Month 12 •using oral corticosteroids at baseline who discontinued corticosteroids & are in remission at Month 12 -Assess in abatacept vs placebo treated subjects improvements in QoL as measured by IBDQ score & SF-36 at Month 12 IP + MP: -Assess immunogenicity, tolerability & safety of abatacept in subjects with UC See Protocol Sections 2.1.2, 2.2.2, 2.3.2 for additional secondary objectives |
| Periodo di Induzione(IP):Confr.la proporzione di paz in remissione clinica(definita con un punteggio Mayo<=2 punti con nessun sottopunteggio superiore a uno)alla 12° sett.tra i due regimi di tratt.:abatacept e placebo;Valut.il rapporto dose-risposta in relazione alla proporzione di paz che hanno una risposta clinica alla 12° sett.indotta dall'incremento della dose di placebo e abatacept.Valut.il miglioramento nella qualita' di vita alla 12° sett.utilizzando il questionario IBDQ nei paz trattati con abatacept vs placebo.Periodo di Mantenimento(MP):Confr.la proporzione di paz in remissione clinica(definita con un punteggio Mayo<=2 punti con nessun sottopunteggio superiore a uno)al 12° mese tra i due regimi di tratt.:abatacept e placebo;Valut.la proporzione di paz che sono in clinica remissione al 6° mese(DAY MP-169)e 12° mese tra i due regimi di tratt.:abatacept e placebo;Valut.il miglioramento nella qualita' di vita al 12° mese utilizzando il punteggio IBDQ e il SF-36; |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1) Signed written informed consent 2) Subject must have had ulcerative colitis (UC) for at least 3 months from the time of initial diagnosis.The diagnosis of UC must have been confirmed by endoscopic and histologic evidence.If no previous confirmation of diagnosis is available or if previous diagnosis is not deemed conclusive, at time of screening endoscopy, histology should be performed to confirm diagnosis of UC 3) Subjects must satisfy one of the following criteria: a) In the past, had an inadequate response to one or more of the following treatments: i) Oral aminosalicylates (e.g.mesalamine, sulfasalazine, olsalazine, balsalizide) at or above the approved label dose for at least 6 weeks, and/or ii) Prednisone >= 40 mg/day (or equivalent) for at least 2 weeks, and/or iii) Immunosuppressants [azathioprine >= 2 mg/kg/day or 6-mercaptopurine >= 1.0 mg/kg/day, (or documentation of a therapeutic concentration of 6-thioguanine nucleotide)] for at least 12 weeks, and/or iv) An approved anti-TNF agent at an approved labeled dose for at least 8 weeks and/or v) Intravenous hydrocortisone >= 400 mg/day (or equivalent) for at least 1 week. AND/OR b) had been intolerant to one or more of the above mentioned treatments [e.g, unableto achieve doses or treatment durations because of dose limiting side effects (e.g.leukopenia, psychosis, uncontrolled diabetes, elevated liver enzymes)] AND/OR c) Currently receiving one or more of the following treatments: i) Oral aminosalicylates (e.g.mesalamine, sulfasalazine, olsalazine, balsalizide) at or above the approved label dose for at least 6 weeks and/or ii) Prednisone >= 20 mg/day (or equivalent) for at least 4 weeks and/or iii) Immunosuppressants [azathioprine >= 2 mg/kg/day or 6-mercaptopurine >= 1.0 mg/kg/day, (or documentation of a therapeutic concentration of 6-thioguanine nucleotide)] for at least 12 weeks. Subjects currently receiving oral corticosteroids, oral aminosalicylates, azathioprine, or 6-mercaptopurine should continue their treatment (see Protocol Section 6.4.2.1).Subjects who had an inadequate response and/or intolerance to anti-TNF treatment must have had their last dose at least 8 weeks prior to the entry into the Induction Period.Subjects who had an inadequate response and/or intolerance to intravenous corticosteroid treatment must have had their last dose at least 4 weeks prior to entry into the Induction Period. Inadequate response and/or intolerance in the past (as defined above) will be assessed by the treating physician. Acceptable documentation of inadequate response or intolerance in subjects include one or more of the following: medical records; letters provided by the referring physician; other referral documents (e.g., insurance authorization forms), provided they contain the relevant information to support the subject's ‘inadequate response' and/or ‘intolerance' to the designated therapy. In all circumstances, it should be established that discontinuation of the designated treatments was primarily due to lack of efficacy or intolerance (e.g., not due to unavailability of the drug). Subjects in clinical remission should not discontinue UC therapy that is maintaining clinical remission, for the purpose of meeting eligibility requirements to enroll into this study. 4) Subjects must have a Mayo score >= 6 and an endoscopic subscore of >= 2 5) Oral corticosteroid treatment must have been the equivalent of =< 30 mg prednisone daily at a stable dose for at least 2 weeks prior to entry into the Induction Period 6) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to entry into the Induction Period 7) Azathioprine or 6-mercaptopurine should be at a stable dose for at least 8 weeks prior to entry into the Induction Period 8) Men and women, ages >= 18 |
| consenso informato scritto; i pazienti devono avere una diagnosi di colite ulcerosa (UC) da almeno tre mesi. La UC deve essere confermata da prove endoscopiche e istologiche; i pazienti devono soddisfare uno dei seguenti criteri: i pazienti devono avere un'inadeguata risposta ad almeno uno dei seguenti trattamenti: 1.aminosalicilati orali (es:mesalazina, sulfasalazina, olsalazina, balsalazide) per almeno 6 settimane e/o 2.prednisone orale >= 40 mg/giorno (o equivalente) per almeno 2 settimane e/o 3. immunosoppressori (azatioprina >= 2 mg/kg/giorno o 6-mercaptopurina >= 1.0 mg/kg/giorno ( o la documentazione di una concentrazione terapeutica di 6-tioguanina nucleotide) per almeno 12 settimane e/o 4. un anti-TNF per almeno 8 settimane e/o 5.idrocortisone IV >= 400 mg/giorno (o equivalente) per almeno 1 settimana. e/o essere stati intolleranti ad uno o piu' dei sopracitati trattamenti e/o ricevere attualmente uno o piu' dei seguenti trattamenti: aminosalicilati orali (es:mesalazina, sulfasalazina, olsalazina, balsalazide) per almeno 6 settimane e/o prednisone orale >= 20 mg/giorno (o equivalente) per almeno 4 settimane e/o immunosoppressori (azatioprina >= 2 mg/kg/giorno o 6 -mercaptopurina >= 1.0 mg/kg/giorno (o la documentazione di una concentrazione terapeutica di 6-tioguanina nucleotide) per almeno 12 settimane e/o |
|
| E.4 | Principal exclusion criteria |
| -WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for entire study period & for up to 10 weeks after study (14 weeks for the European countries in which the European SmPC for Orencia¿ IV is applicable)-WOCBP using prohibited contraceptive method -Pregnant or breastfeeding women-Women with positive pregnancy test on enrollment or prior to study drug administration-Diagnosis of Crohn¿s Disease(CD), or Indeterminate Colitis or clinical findings suggestive of CD-Diagnosis of UC limited to rectum (ulcerative proctitis)-Current evidence of fulminant colitis, toxic megacolon or bowel perforation-Current need for colostomy or ileostomy-Previous total proctocolectomy or subtotal colectomy with ileorectal anastomosis, any surgical resection for UC-Surgical bowel resection within 6 months before screening for reasons other than UC-Primary sclerosing cholangitis(PSC)-Currently receiving total parenteral nutrition(TPN)-Required IV corticosteroids for UC 2 weeks before screening-Past or current evidence of definite colonic dysplasia-Subjects who are scheduled or anticipate need for surgery, aside from dermatologic procedures-Subjects with history of clinically significant drug or alcohol abuse-Concomitant illness likely to require systemic glucocorticosteroid therapy during study-Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease Concomitant medical conditions that might place subject at unacceptable risk for participation in study-Subjects with a history or current evidence of malignancies; specifically, subjects with: a) a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection), or b) evidence of malignancies (including that detected by screening procedures), or c) signs of possible malignancies detected by screening procedures for which the workup to exclude malignancy has not been completed.The following subjects may be enrolled; those with: a) existing non-melanoma skin cell cancers which have been entirely removed prior to randomization, or b) carcinoma in situ, treated with definitive surgical intervention c) no evidence of malignancy upon completion of evaluation prompted bysuspicious screening procedure-Subjects at risk for tuberculosis.Specifically, subjects with:a)history of active TB within last 3 years even if it was treatedb)history of active TB >3 years ago unless there is documentation that prior anti-TB treatment was appropriate in duration & typec)Current clinical, radiographic or laboratory evidence of active TBd)Latent TB which was not successfully treated.Positive TB screening test indicative of latent TB would not be eligible unless active TB infection has been ruled out & they have initiated treatment for latent TB with isoniazid(INH) for at least 2 weeks prior to entry in Induction Period (IP) & they have negative chest x-ray at enrollment.Such subjects must complete 9 months of INH treatment-Subjects with any serious bacterial infection within last 3 months, unless treated & resolved with antibiotics, or any chronic bacterial infection-Female subjects who have had breast cancer screening suspicious formalignancy, & in whom possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations -Evidence of active or latent bacterial or viral infections at time of potential enrollment, incl.subjects with evidence of HIV, Hepatitis B or HPC infection detected during screening -Subjects with herpes zoster or CMV that resolved< 2 months prior to signing ICF-Subject who received any live vaccines within 3 months of anticipated 1st dose of study medication or who will have need of a live vaccine at any time following entry in IP-Clinically significant abnormal chest x-ray |
|  Donne potenzialmente fertili che utilizzano un metodo contraccettivo proibito;  Donne con test di gravidanza positivo al momento dell¿arruolamento o prima della somministrazione del farmaco in studio;  Donne in stato di gravidanza o in allattamento;  Donne potenzialmente fertili che non vogliono o incapaci di usare un metodo contraccettivo accettato durante lo studio e nelle 10 settimane successive all¿ultima dose di farmaco in studio (14 settimane per i Paesi europei nei quali il riassunto delle caratteristiche di prodotto per Orencia IV e` applicabile);  Diagnosi di malattia di Crohn, colite di origine sconosciuta o qualsiasi ritrovamento clinico che possa suggerire la malattia di Crohn (fistula o granuloma);  Diagnosi di Colite ulcerosa limitata al retto;  Prove evidenti di colite fulminante, megacolon tossico o perforazione intestinale;  Necessita` di effettuare una colonstomia o ileostomia;  Pregressa proctocolectomia totale o colectomia subtotale con anastomosi ileorettale;  Resezione chirurgica intestinale a meno di 6 mesi dallo screening per ragioni diverse dalla colite ulcerosa;  Colangite sclerosante primaria;  Totale nutrizione parenterale;  Necessita` di corticosteroidi IV per colite ulcerosa per due settimane prima dello screening;  Precedente o attuale prova di displasia al colon;  Storia di abuso di farmaci o alcol;  Malattia concomitante che necessita di terapia con corticosteroidi durante lo studio  Sintomi di malattie severe, progressive o incontrollate renali, epatiche, ematologiche, polmonari, cardiologiche, neurologiche, oftalmologiche o cerebrali;  Pazienti con storia o corrente prova di cancro;  Pazienti a rischio per tubercolosi;  Pazienti con qualsiasi infezione batterica grave negli ultimi tre mesi a meno che non siano stati trattati e curati con antibiotici;  Donne con tumore maligno alla mammella o nelle quali la possibilita` che sia maligno non possa diagnosticato con certezza;  Pazienti con evidenza di infezioni batteriche o virali attive o latenti al momento dell¿arruolamento inclusi pazienti con evidenza di HIV, epatite B,C diagnosticate durante lo screening ;  Pazienti con Herpes zoster o citomegalovirus guariti meno di due mesi prima della firma del consenso informato;  Pazienti che hanno ricevuto vaccini vivi entro tre mesi dalla prima dose programmata del farmaco in studio o che avranno necessita` di un vaccino vivo durante il periodo di induzione dello studio;  Pazienti con alterazioni clinicamente significative al¿RX torace;  Coprocoltura positiva per patogeni intestinali;  Feci positive per Clostridium.  Qualsiasi dei seguenti valori di laboratorio: 1. emoglobina < 8.5 g/dL 2. conta leucocitaria< 3000/mm3 3. Piastrine < 100000/ mm3 4. Creatinina sierica > 2 volte il limite normale superiore; 5. ALT o AST > 3 volte il limite normale superiore; qualsiasi valore di laboratorio che a giudizio dello sperimentatore potrebbe esporre il paziente ad un rischio inaccettabile;  Somministrazione CTL4Ig o Abatacept in qualsiasi momento prima dello screening;  Qualsiasi immunomodulatore biologico utilizzato per la colite ulcerosa o altre condizioni nelle 8 settimane precedenti l¿ingresso del paziente nel periodo di induzione;  Rituximab nell¿anno precedente lo screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| * The Induction Period's primary efficacy assessment will test for differences in the proportion of subjects in the Induction Period abatacept 30/~10 mg/kg treatment regimen versus placebo and abatacept ~10 mg/kg treatment regimen versus placebo in clinical response on Day IP-85. The Induction Period's two primary comparisons will be tested using the Cochran-Mantel-Haenszel (CMH) Chi-square test at the 5% level of significance with stratification according to the Induction Period stratification factor of having had an inadequate response and/or intolerance to anti-TNF therapy. * The primary efficacy assessment of the Maintenance Period will test for treatment differences in the proportion of subjects in clinical response at Day MP-365. The CMH Chi-square test will be used to compare the two treatment groups at the 5% level of significance, with stratification according to the Maintenance Period stratification factors: 1) concomitant use of oral corticosteroids; 2) clinical remission status at Day IP-85; 3) having had an inadequate response and/or intolerance to anti-TNF therapy. * Safety Assessments Significant physical examination findings, and clinical and laboratory test results will be listed. Summary statistics will be tabulated. Frequency distributions and individual listings of all adverse events will be generated. Changes from baseline in clinical laboratory test results will be listed. * PK Assesments Summary statistics will be tabulated for PK parameters by dose groups. Geometric means and coefficients of variation will be presented for Cmax, Cmin and AUC (TAU). Medians and ranges (minimum and maximum) will be presented for Tmax. |
| Non disponibile |
|
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 33 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 33 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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