A Phase 3, Multi-Center, Randomized, Placebo-Controlled Study to Evaluate the Clinical Efficacy and Safety of Induction and Maintenance Therapy with Abatacept in Subjects with Active Crohn’s Disease (CD) who have had an Inadequate Clinical Response and/or Intolerance to Medical Therapy. Revised Protocol 01, incorporating Protocol Amendment 02 (Version 1.0, Date: 06-Dec-2006). And Pharmacogenetics Blood Sample Amendment 01 - Site Specific (Version 2.0, Date: 26-Oct-2006)

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-003371-13-NL
• Date of registration: 19/01/2007
• Prospective Registration: Yes
• Primary sponsor: Bristol-Myers Squibb International Corporation
• Public title: A Phase 3, Multi-Center, Randomized, Placebo-Controlled Study to Evaluate the Clinical Efficacy and Safety of Induction and Maintenance Therapy with Abatacept in Subjects with Active Crohn’s Disease (CD) who have had an Inadequate Clinical Response and/or Intolerance to Medical Therapy. Revised Protocol 01, incorporating Protocol Amendment 02 (Version 1.0, Date: 06-Dec-2006). And Pharmacogenetics Blood Sample Amendment 01 - Site Specific (Version 2.0, Date: 26-Oct-2006)
• Scientific title: A Phase 3, Multi-Center, Randomized, Placebo-Controlled Study to Evaluate the Clinical Efficacy and Safety of Induction and Maintenance Therapy with Abatacept in Subjects with Active Crohn’s Disease (CD) who have had an Inadequate Clinical Response and/or Intolerance to Medical Therapy. Revised Protocol 01, incorporating Protocol Amendment 02 (Version 1.0, Date: 06-Dec-2006). And Pharmacogenetics Blood Sample Amendment 01 - Site Specific (Version 2.0, Date: 26-Oct-2006)
• Date of first enrolment: 22/05/2007
• Target sample size: 906
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-003371-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Belgium, Czech Republic, Denmark, France, Germany, Ireland, Italy, Netherlands, Poland, United Kingdom

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years)
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years)
F.1.3.1 Number of subjects for this age range

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 s

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Crohn's disease, NOS
MedDRA version: 8.1 Level: LLT Classification code 10011401 Term: Crohn's disease

Intervention(s)

Product Name: Abatacept
Product Code: BMS-188667
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Abatacept
CAS Number: 332348-12-6
Current Sponsor code: BMS-188667
Other descriptive name: CTLA4Ig
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

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.

Secondary Objective: 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

Main Objective: * 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.

Secondary ID(s)

2006-003371-13-DE

IM101084