| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
|
| 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. |
|
| 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 |
|
| 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 |
|
| 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
-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
-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
-Subjects at risk for tuberculosis. Specifically, subjects with:
a)history of active TB within last 3 years even if it was treated
b)history of active TB >3 years ago unless there is documentation that prior anti-TB treatment was appropriate in duration & type
c)Current clinical, radiographic or laboratory evidence of active TB
d)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 for
malignancy, & 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 at screening
-Positive stool culture for enteric pathogens
-Stool positive for c. difficile toxin
Any of following lab values:
a)Hgb< 8.5 g/dL
b)WBC< 3,000/mm³ (3 x 109/L)
c)Platelets< 100,000/mm³ (100 x 109/L)
d)Serum creatinine> 2x upper limit of normal
e)Serum ALT or AST> 3x upper limit of normal
f)Any other laboratory test results that might place subject at unacceptable risk for participation in study
-History of severe or anaphylactic infusion reaction after receiving a biologic agent, suspected to be associated with an immune response
-CTLA4Ig or abatacept at any time prior to screening
-Any marketed biologic used for UC (including infliximab) within 8 weeks before
entry in IP
-Any biologic immunomodulators used for UC or other conditions within 8 weeks
before entry in IP
-Rituximab within 1 year before screening
-Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks before entry in IP
-Rectal administration of 5-aminosalycylates within 2 weeks prior to entry in IP
-Tacrolimus, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption
columns, D Penicillamine, Leflunomide, Methotrexate, Budesonide, Thalidomide, fish-oil preparations, probiotics, non-steroidal anti-inflammatory agents (NSAIDs), aspirin >81 mg/day within 2 weeks before entry in IP
-Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks of entry in IP. In Ireland, subjects who have received treatment with any investigational drug (incl. placebo) within 16 weeks of the Day IP-1 dose
-Prisoners or subjects who are compulsorily detained |
|
| 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. |
|
| 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 Questionnaire |
|
| 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 | 45 |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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