E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011401 |
E.1.2 | Term | Crohn's disease |
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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 |
* Placebo-Controlled Induction Period: Compare the proportion of subjects who have a clinical response (as defined by a reduction in Crohn’s Disease Activity Index [CDAI] >= 100 or an absolute CDAI score < 150) at both Day IP-57 (Week 8) and Day IP-85 (Week 12) between the abatacept and placebo treatment regimens.
* Maintenance Period: Compare the proportion of subjects who are in clinical remission (CDAI < 150) at Day MP-365 (12 months) between the abatacept and placebo treatment regimens.
* Open-label Extension Phase: Assess the long-term clinical safety and tolerability of abatacept treatment. |
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E.2.2 | Secondary objectives of the trial |
Induction Period (IP): -Compare proportion of subjects in clinical remission at both Day IP-57 & IP-85 between abatacept & placebo treatment regimens -Evaluate dose-response relationship by comparing proportions of subjects with a clinical response at both Day IP-57 & IP-85 induced by placebo & abatacept in increasing doses -Assess improvements in quality of life at Day IP-85 using the IBD Questionnaire in abatacept vs. placebo treated subjects
Maintenance Period (MP): -Compare proportion of subjects between abatacept & placebo treatment regimens: • who have a clinical response at Day MP-365 • in clinical remission at both Day MP-169 & MP-365 -Assess in abatacept vs. placebo treated subjects improvements in quality of life using the SF-36 & IBD Questionnaire
*IP+MP: Assess tolerability & safety of abatacept in subjects with CD Assess immunogenicity of abatacept in subjects with CD
See Protocol Sections 2.1.2, 2.2.2, 2.3.2 for additional secondary objectives
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent 2) Subject must have had CD for at least 3 months from the time of initial diagnosis. Active CD must be confirmed by radiologic, endoscopic or histologic evidence within the previous 12 months. If previous confirmation of diagnosis is not available or if previous diagnosis is not deemed conclusive at time of screening, CD diagnosis should be confirmed by endoscopy, radiology or histology. 3) Subjects must satisfy at least one of the following criteria: a/ Having had an inadequate response to at least 1 of the following treatments (subjects may be currently receiving 1 of these medications or have received them previously): i) oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalizide) at or above the approved label dose for at least 8 weeks and/or ii) oral prednisone >= 30 mg/day (or equivalent) or budesonide >= 9 mg/day 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] or methotrexate >= 15 mg/week) 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 b/ Have been intolerant to one of the above mentioned treatments (e.g., unable to achieve doses or treatment durations because of dose limiting side effects [e.g., leukopenia]). Subjects currently receiving and tolerating the above mentioned treatments (with the exception of anti-TNF agents) should continue their treatment (see Drug Stabilization Requirements, 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 entry into the Induction Period. Acceptable documentation of inadequate response or intolerance in subjects include 1 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 CD therapy that is maintaining clinical remission, for the purpose of meeting eligibility requirements to enroll into this study. 4) Moderate to severe CD as measured by a CDAI score >= 220 and =< 450 5) hsCRP > Upper Limit of Normal (ULN) 6) Oral corticosteroid treatment must have been reduced to the equivalent of =< 30 mg prednisone or =< 9 mg budesonide daily at a stable dose for at least 2 weeks prior to entry into the Induction Period 7) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to entry into the Induction Period 8) Azathioprine, 6-mercaptopurine and methotrexate should be at a stable dose for at least 8 weeks prior to entry into the Induction Period 9) Men and women, ages >= 18 |
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E.4 | Principal exclusion criteria |
1)WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for entire study period & for up to 10 weeks after study 2)WOCBP using a prohibited contraceptive method 3)Women who are pregnant or breastfeeding 4)Women with positive pregnancy test on enrollment or prior to study drug administration 5)Diagnosis of Ulcerative or Indeterminate Colitis 6)CD isolated to stomach, duodenum, jejunum, or perianal region without colonic or ileal involvement 7)Suspected or diagnosed intra-abdominal or perianal abscess at screening 8)Known strictures or stenosis leading to symptoms or obstruction 9)Current evidence of fulminant colitis, toxic megacolon or bowel perforation 10)Current need for colostomy or ileostomy or use of seton for perianal disease 11)Previous total proctocolectomy or subtotal colectomy with ileorectal anastomosis 12)Surgical bowel resection < 6 months before screening 13)Extensive small bowel resection or known short bowel syndrome 14)Primary sclerosing cholangitis 15)Currently receiving total parenteral nutrition 16)Past/current evidence of definite low grade or high grade colonic dysplasia 17)Subjects who are scheduled or anticipate the need for surgery aside from dermatologic procedures 18)History of clinically significant drug or alcohol abuse 19)Concomitant illness, likely to require systemic glucocorticosteroid therapy during study (e.g. moderate to severe asthma) 20)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 21)History of cancer within last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to enrollment. Subjects with carcinoma in situ, treated with definitive surgical intervention, are allowed 22)Subjects at risk for tuberculosis 23)Subjects with any serious bacterial infection within last 3 months, unless treated & resolved with antibiotics, or any chronic bacterial infection 24)Female subjects who have had breast cancer screening that is suspicious for malignancy, & in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations (Protocol Section 7.3.2.4) 25)Subjects with evidence of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of HIV, Hepatitis B or Hepatitis C infection detected during screening 26)Subjects with herpes zoster or cytomegalovirus that resolved < 2 months before signing informed consent 27)Subject who have received any live vaccines within 3 months of the anticipated first dose of study medication or who will have need of a live vaccine at any time following entry in Induction Period 28)Subject with a clinically significant abnormal chest x-ray at screening 29)Positive stool culture for enteric pathogens 30)Stool positive for C. Difficile toxin 31)Any of the following lab values: • Hgb < 8.5 g/dL • WBC < 3,000/mm3 (3 x 109/L) • Platelets < 100,000/mm3 (100 x 109/L) • Serum creatinine > 2x upper limit of normal • Serum ALT or AST > 3x upper limit of normal • Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study 32)History of severe or anaphylactic infusion reaction after receiving a biologic agent, suspected to be associated with an immune response 33)CTLA4Ig or abatacept at any point in time before screening 34)Any marketed biologic used for CD (including infliximab) within 8 weeks before entry in Induction Period 35)Any biologic immunomodulators used for CD or other conditions within 8 weeks before entry in Induction Period 36)Rituximab within 1 year before screening 37)Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks before entry in Induction Period 38)Rectal administration of 5-ASA within 2 weeks before entry in Induction Period 39)Tacrolimus, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption columns (such as Prosorba columns), D Penicillamine, Leflunomide, Thalidomide, fish-oil preparations, probiotics, non-steroidal anti-inflammatory agents (NSAIDs), aspirin > 81mg/day within 2 weeks before entry in Induction Period 40)Subjects requiring Cholestyramine or other drugs interfering with enterohepatic circulation 41)Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks of entry in Induction Period. In Ireland, subjects who have received treatment with any investigational drug (including placebo) within 16 weeks of the Day IP-1 dose 42)Prisoners or subjects who are compulsorily detained
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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/~10mg/kg treatment regimen versus placebo and abatacept ~10mg/kg treatment regimen versus placebo who are in clinical response on Days IP-71 and 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 factors: 1) disease severity, and 2) concomitant use of immunosuppressants.
* The primary efficacy assessment of the Maintenance Period will test for treatment differences in the proportion of subjects who are in clinical remission 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) disease activity following Induction therapy, and 2) concomitant use of immunosuppressants.
* Safety Analysis: 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 Analysis: 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. |
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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 | Yes |
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 + health related Quality of Life: IBD Questionnaire and SF-36 questinonaire |
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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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |