Placebo-Controlled Induction Period Primary Objective: Compare the proportion of subjects who have a clinical response at Week 12 between the abatacept and placebo treatment regimens.Maintenance Period Primary Objective: Compare the proportion of…
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Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Placebo-Controlled Induction Period:
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
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
Assess the long-term clinical safety and tolerability of abatacept treatment
during the Open-Label Extension Phase.
Secondary outcome
Placebo-Controlled Induction Period
1) Compare the proportion of subjects in clinical remission (defined as Mayo
score <= 2 points and no individual subscore exceeding 1 point) at Week 12
between the abatacept and placebo treatment regimens.
2) Compare the proportion of subjects with mucosal healing (defined as
endoscopic subscore <= 1 point) at Week 12 between the abatacept and placebo
treatment regimens.
3) Evaluate the dose-response relationship by comparing the proportions of
subjects in clinical response at Week 12 induced by placebo and abatacept in
increasing doses (3 mg/kg, ~10 mg/kg, 30/~10 mg/kg).
4) Assess in abatacept vs placebo treated subjects improvements in quality of
life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) score
at Week 12.
5) Assess the proportion of abatacept vs placebo treated subjects with Mayo
subscores (rectal bleeding, stool frequency, physician*s global assessment)
indicative of mild disease (individual subscore <= 1) at Week 12.
6) Evaluate in subjects who have had in inadequate response and/or intolerance
to anti TNF therapy, the dose-response relationship by comparing the
proportions of subjects in clinical response at Week 12 induced by placebo and
abatacept in increasing doses (3 mg/kg, ~10 mg/kg, 30/~10 mg/kg).
7) Assess in abatacept vs placebo treated subjects who have had an inadequate
response and/or intolerance to anti-TNF therapy, a) the proportion in clinical
response, b) the proportion in remission, and c) the proportion with mucosal
healing at Weeks 12.
8) Assess the immunogenicity of abatacept in subjects with UC
9) Assess the tolerability and safety of abatacept in subjects with UC.
For the Secondary Objectives for the Maintenance Period and Open-Label
Extension Phase, please refer to pages 26-28 of the protocol.
Background summary
UC is a severe disorder with significant morbidity and impact on quality of
life. Despite the availability of a range of medications, there still remains
a need for therapeutic alternatives because patients may not respond to
existing therapeutic choices, may not maintain a response, or may develop
treatment limiting toxicities. Current available therapies are sub-optimal.
Abatacept has the potential to be an effective and safe alternative to those
therapies. The intended application of the results from this study is to prove
that abatacept is effective and safe for the treatment of patients with UC with
a view to obtaining a marketing license for this indication.
Study objective
Placebo-Controlled Induction Period Primary Objective: Compare the proportion
of subjects who have a clinical response at Week 12 between the abatacept and
placebo treatment regimens.
Maintenance Period Primary Objective: Compare the proportion of subjects who
have a clinical response at Month 12 between the abatacept and placebo
treatment regimens.
Study design
The study consists of three periods (Screening, Induction, and Maintenance) and
an Open-Label Extension phase. Following the brief Screening Period, eligible
subjects will enter a 12 week placebo-controlled Induction Period. A first
cohort of 490 subjects will be randomized to the Induction Period in a 2:1:2:2
fashion to receive placebo (N = 140) or one of three dosing regimens of
abatacept [3 mg/kg (N = 70), ~10 mg/kg (N = 140), or 30/~10 mg/kg (N = 140)] in
a double-blind manner. Following the randomization of the initial 490 subjects,
a second cohort of 146 subjects will be randomized to the Induction Period in a
1:1 fashion to one of two dosing regimens of abatacept (~10 mg/kg or 30/~10
mg/kg) in a double-blind manner. A formal analysis of the Induction Period data
will be conducted after the first cohort of 490 subjects have completed the
12-week placebo-controlled Induction Period.
All responders from both cohorts will enter the 12-month, randomized,
double-blind, parallel dosing, placebo-controlled Maintenance Period (MP). It
is anticipated that approximately 356 responders from the Induction Period will
be randomized into the Maintenance Period in a 1:1 ratio to either ~10 mg/kg
abatacept (N = 178) or placebo (N = 178). Subjects who complete the MP or who
experience Disease Relapse during this period may enter an Open-label Extension
phase. All non-responders from both Induction Period cohorts will also have the
option to enroll into the Open-Label Extension phase. Approximately 170 sites
in North America, Europe, Latin America, South Africa, Australia and India will
participate.
Intervention
Abatacept will be administered intravenously. Induction Period: Days IP-1 and
IP-15, subjects will receive placebo or abatacept at 3 mg/kg
(non-weight-tiered), ~10 mg/kg dose (weight-tiered), or 30 mg/kg doses
(non-weight-tiered). On Days IP-29 and IP-57, subjects will receive placebo or
abatacept 3 mg/kg or ~10 mg/kg doses. After randomization to the Maintenance
Period, subjects will receive placebo or abatacept ~10 mg/kg every 4 weeks up
to and including Day MP-337. In the Open-Label Extension, subjects will
receive abatacept ~10 mg/kg every 4 weeks until marketed in local country or
study is discontinued.
Study burden and risks
The major identified risk of abatacept is an increased incidence of infection.
Consistent with its mechanism of action, the abatecept RA program identified
both non-serious and serious infections, mainly bacterial (urinary tract
infections, pneumonia) and viral (herpes simplex) occurring more frequently in
abatacept-treated subjects. Despite this identified risk, the majority of
infections presented typically, responded appropriately to treatment, and there
did not appear to be a major difference in outcome between abatacept and
placebo. The risk for serious infections did not increase in the open-label
periods with increasing exposure. Opportunistic infections and tuberculosis
were uncommon, although all subjects were screened for latent TB. The overall
reisk of malignancy for abatacept-treated subjects was comparabale with
placebo-treated subjects during the double-bllind periods. The incidence of
malignancy did not appear to be greater with increased exposure. An important
caution is that the clinical studies contain neither sufficient numbers of
subjects nor follow up of sufficient duration to assess long term treatment or
to rule out increases in the risk of adverse events with long latency, such as
malignancy. Treatment with abatacept was associated with an excellent
peri-infusional safety profile, and abatacept was associated with a low level
of immunogenicity.
Vijzelmolenlaan 9
3447 GX Woerden
NL
Vijzelmolenlaan 9
3447 GX Woerden
NL
Listed location countries
Age
Inclusion criteria
1) Subject is willing to participate in the study and has signed the 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, unable to 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.
4) Subjects must have a Mayo score >= 6 and an endoscopic subscore of >= 2
5) Men and women, ages >= 18
Exclusion criteria
1) Diagnosis of Crohn*s Disease or Indeterminate Colitis or clinical findings suggestive of Crohn*s disease (i.e., fistula or granulomas on biopsy)
2) Diagnosis of ulcerative colitis that is limited to the rectum (ulcerative proctitis).
3) Current evidence of fulminant colitis, toxic megacolon or bowel perforation
4) Current need for colostomy or ileostomy
5) Previous total proctocolectomy or subtotal colectomy with ileorectal anastomosis, any surgical resection for UC
6) Surgical bowel resection within 6 months before screening for reasons other than UC
7) Primary sclerosing cholangitis (PSC)
8) Currently receiving total parenteral nutrition (TPN)
9) Required intravenous corticosteroids for UC two weeks before screening.
10) Past or current evidence of definite colonic dysplasia
11) Subjects who are scheduled or anticipate the need for surgery, aside from dermatologic procedures
12) Subjects who have a history of clinically significant drug or alcohol abuse
13) Concomitant illness that in the opinion of the Investigator, is likely to require systemic glucocorticosteroid therapy during the study (e.g. moderate to severe asthma)
14) Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease. Concomitant medical conditions that in the opinion of the Investigator might place the subject at unacceptable risk for participation in this study
15) Subjects with a history of cancer within the 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
16) Subjects at risk for tuberculosis (TB).
17) Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis and bronchiectasis)
18) Female subjects who have had a breast cancer screening that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations
19) A history of severe or anaphylactic infusion reaction after receiving a biologic agent, suspected to be associated with an immune response
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-003604-19-NL |
| CCMO | NL15938.058.07 |