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 Ulcerative Colitis (UC) Who Have Had an Inadequate Clinical Response and/or Intolerance to Medical Therapy
Overview
- Phase
- Phase 3
- Intervention
- abatacept (ABA)
- Conditions
- Ulcerative Colitis
- Sponsor
- Bristol-Myers Squibb
- Enrollment
- 591
- Locations
- 51
- Primary Endpoint
- Induction Period (IP); Number of Participants With Clinical Response (Per Mayo Score) at Week 12: IP Cohort 1 (IP1C)
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
The purpose of this clinical research study is to learn if abatacept can improve signs and symptoms of active ulcerative colitis in patients who have not had an adequate response to other therapies. The safety of this treatment will also be studied
Detailed Description
The Induction Period First Cohort (IP1C) arms (30/10 mg/kg and 10 mg/kg) were placebo-controlled arms that were used for the primary endpoint and its analysis. The Induction Period Second Cohort arms (IP2C 30/10 mg/kg and 10 mg/kg) were not placebo-controlled, their sole purpose being to provide sufficient numbers of participants for the maintenance phase. The first cohort (IP1C) was randomized to receive placebo or 1 of 3 doses of abatacept. Following completion of the IP1C randomization, a second cohort (IP2C) was randomized to receive 1 of 2 doses of abatacept. After all participants in the IP1C completed or discontinued, the data was locked and the formal analysis for the Induction Period primary endpoint was performed. Summary tables for the second cohort (IP2C) and the Maintenance and Open-label phases were generated from a second, subsequent data lock.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Men or women 18 years or older
- •Ulcerative colitis for at lease 3 months
- •Moderate to severe active ulcerative colitis
- •Inadequate response or intolerance to standard ulcerative colitis treatment
Exclusion Criteria
- Not provided
Arms & Interventions
Abatacept (ABA)
Induction Period; 3 arms for Cohort 1: ABA 30/\~10 mg/kg (ABA administered at 30 mg/kg followed by ABA at \~10 mg/kg), ABA \~10 mg/kg, ABA 3 mg/kg Induction Period; 2 arms for Cohort 2: ABA 30/\~10 mg/kg and Second Cohort ABA \~10 mg/kg 1 arm for maintenance period (ABA \~10 mg/kg)
Intervention: abatacept (ABA)
Placebo
1 arm for induction period 1 arm for maintenance period
Intervention: placebo
abatacept
1 arm for open-label extension phase (ABA \~10 mg/kg)
Intervention: abatacept
Outcomes
Primary Outcomes
Induction Period (IP); Number of Participants With Clinical Response (Per Mayo Score) at Week 12: IP Cohort 1 (IP1C)
Time Frame: Week 12 (Day IP-85)
The Mayo Scoring system ranges from 0 - 12 points and is a composite index consisting of 4 disease variables (stool frequency, rectal bleeding, endoscopy evaluation, and Physician's Global Assessment). Higher Mayo scores indicate greater severity of disease. A clinical response is defined as a reduction from baseline in the Mayo score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point.
Maintenance Period (MP); Number of Participants With Clinical Response (Per Mayo Score) at Month 12
Time Frame: Month 12 (Day MP-365)
The Mayo Scoring system ranges from 0 - 12 points and is a composite index consisting of 4 disease variables (stool frequency, rectal bleeding, endoscopy evaluation, and Physician's Global Assessment). Higher Mayo scores indicate greater severity of disease. A clinical response is defined as a reduction from baseline in the Mayo score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point.
Open-Label Extension Period (OL); Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and AEs Leading to Discontinuation
Time Frame: Day OL-1 through the end of the OL
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.
OL; Number of Participants With AEs of Special Interest
Time Frame: Day OL-1 through Day OL-729
AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, and opportunistic infections; autoimmune disorders; neoplasms; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion).
OL; Number of Participants With Physical Examination Findings
Time Frame: Day OL-1 through Day OL-729
Complete physical examination was obtained at the Screening Visit, Day MP-365, and OL Final Visit/Early Termination visits. Interim physical examinations were performed at other study visits. Interim physical exam were not as comprehensive as the initial full examination but did note any changes in the participant's condition since the last assessment and did not preclude examination of any of the body systems as clinically indicated. Participants were observed for AEs and vital signs (blood pressure, heart rate, and temperature).
OL; Number of Participants With Marked Hematology Laboratory Abnormalities
Time Frame: Day OL-1 through Day OL-729
High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Hemoglobin (HGB): \>3 g/dL decrease from Baseline (BL); Hematocrit: \<0.75 x BL; Erythrocytes: \<0.75 x BL; Platelets (PLT): \<0.67 x LLN/\>1.5 x ULN; Leukocytes: \<0.75 x LLN/ \>1.25 x ULN; neutrophils+bands: \<1.0 x 10\^3 c/uL; eosinophils: \>0.750 x 10\^3 c/uL; monocytes: \>2000 mm3; lymphocytes: \<0.750 x 10\^3 c/uL/ \>7.50 x 10\^3 c/uL.
OL; Number of Participants With Liver and Kidney Function and Electrolyte Laboratory Abnormalities
Time Frame: Day OL-1 through Day OL-729
Low=lower than LLN, High=greater than ULN. LLN/ULN= Alkaline phosphatase (ALP): \>2 x ULN; aspartate aminotransferase (AST): \>3 x ULN; alanine aminotransferase (ALT): \>3 x ULN; G-Glutamyl transferase (GGT): \>2 x ULN; Bilirubin: \>2 x ULN; blood urea nitrogen (BUN): \>2 x BL; creatinine: \>4 x BL; potassium (K): \<0.9 x LLN/ \>1.1 x ULN; calcium (Ca): \<0.8 x LLN/\>1.2 x ULN; phosphorous (P): \<0.75 x LLN/ \>1.2 5 x ULN
OL; Number of Participants With Chemistry and Urinalysis Laboratory Abnormalities
Time Frame: Day OL-1 through Day OL-729
Low=lower than LLN, High=greater than ULN. LLN/ULN= serum glucose (Glu): \<65 mg/dL/ \>220 mg/dL; fasting serum Glu: \<0.8 x LLN/ \>1.5 x ULN; total protein: \< 0.9 x LLN/ \>1.1 x ULN; albumin:\<0.9 x LLN; uric acid: \>1.5 x ULN. For Urinalysis (Urine protein, urine Glu, urine blood, leukocyte esterase, Red Blood Cells \[RBCs\], White Blood Cells \[WBCs\]): Use ≥2 when BL value missing or value ≥4, or when pre-dose=0 or 0.5. Use ≥3 when pre-dose=1. Use ≥4 when pre-dose=2 or 3
Secondary Outcomes
- IP; Number of Participants With AEs Of Special Interest: IP1C + IP2C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Physical Examination Findings: IP1C + IP2C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Marked Hematology Laboratory Abnormalities: IP1C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Marked Liver and Kidney Function and Electrolyte Laboratory Abnormalities: IP1C(Day IP-1 through Day IP-85)
- OL; Number of Participants With Clinical Remission Over Time(Day OL-1 through Day OL-729)
- OL; Number of Participants With Mayo Endoscopic Subscores Indicating Mucosal Healing (≤1 Point) During OL(Open-Label Period (Day OL-1 through Day OL-729))
- MP; Number of Participants With Abatacept-Induced Antibodies(For participants not entering OL: All measurements starting after Day MP-1 (including follow-up visits). For participants entering OL: From first measurement after Day MP-1 to Day MP-365 (Day OL-1).)
- MP; Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and AEs Leading to Discontinuation(Day MP-1 through Day MP-365)
- MP; Number of Participants With AEs of Special Interest(Day MP-1 through Day MP-365)
- MP; Number of Participants With Physical Examination Findings(Day IP-85 through Day MP-365)
- IP; Number of Participants With Marked Chemistry and Urinalysis Laboratory Abnormalities: IP1C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Marked Hematology, Liver and Kidney Function, and Electrolyte Laboratory Abnormalities: IP2C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Marked Chemistry and Urinalysis Laboratory Abnormalities: IP2C(Day IP-1 through Day IP-85)
- IP; Number of Participants With Abatacept-Induced Antibodies: IP1C + IP2C(For participants treated in MP: Day IP-1 (Baseline) to Day MP-1 (Day IP-85). For participants treated in OL directly after IP: Day IP-1 to Day OL-1. For participants treated only in IP: All measurements after Day IP-1 (including follow-up visits))
- MP; Number of Participants in Clinical Remission at Month 12(Month 12 (Day MP-365))
- MP; Number of Participants With Mayo Endoscopic Subscores Indicating Mucosal Healing (≤1 Point) at Month 12(Month 12 (Day MP-365))
- MP; Number of Participants With Marked Hematology Laboratory Abnormalities(Day IP-85 through Day MP-365)
- IP; Baseline Mayo Score: IP1C(Baseline)
- IP; Number of Participants in Clinical Remission (Per Mayo Score) at Week 12: IP1C(Week 12 (Day IP-85))
- IP; Number of Participants in Mucosal Healing (Per Mayo Score) at Week 12: IP1C(Week 12 (Day IP-85))
- IP; Number of Participants With Clinical Response (Per Mayo Score) at Week 12 Analyzed by Cochran-Armitage Trend Test for Dose-Response Relationship: IP1C(Week 12 (Day IP-85))
- IP; Baseline Inflammatory Bowel Disease Questionnaire (IBDQ) Score: IP1C(Baseline)
- IP; Mean Change From Baseline To Week 12 in Inflammatory Bowel Disease Questionnaire (IBDQ): IP1C(Baseline (Day IP-1), Day IP-85 (Week 12))
- IP; Number of Participants With Mayo Rectal Bleeding Subscores Indicating Mild Disease (≤1 Point) at Week 12: IP1C(Day IP-85 (Week 12))
- IP; Number of Participants With Mayo Stool Frequency Subscores Indicating Mild Disease (≤1 Point) at Week 12: IP1C(Day IP-85 (Week 12))
- IP; Number of Participants With Mayo Physician Global Assessment (PGA) Subscores Indicating Mild Disease (≤1 Point) at Week 12: IP1C(Day IP-85 (Week 12))
- IP; Number of Participants Who Are Anti-TNF-Inadequate Responders/Anti-TNF Intolerant With Clinical Response At Week 12 Analyzed by Cochran-Armitage Trend Test for Dose-Response Relationship: IP1C(Week 12 (Day IP-85))
- IP; Number of Participants With Clinical Response At Week 12 Among Participants With Anti-TNF (Infliximab) Failure/Intolerance: IP1C(Week 12 (Day IP-85))
- IP; Number of Participants in Clinical Remission at Week 12 Among Participants With Anti-TNF (Infliximab) Failure/Intolerance: IP1C(Week 12 (Day IP-85))
- MP; Number of Participants With Baseline Oral Corticosteroid Use Who Have Discontinued Corticosteroids and Achieved Clinical Remission by Month 12(Day MP-365 (Month 12))
- OL; Number of Participants With Clinical Response or Clinical Remission Upon Retreatment With Abatacept Among Those Who Received Abatacept in the IP or MP Period(Last Study Visit (Day OL-729))
- OL; Number of Participants With Abatacept-Induced Antibodies(For participants receiving OL medication, all measurements starting after Day OL-1 (including follow-up visits and at 56 and 85 days after last dose))
- OL; Number of Participants Using Corticosteroids During OL(Day OL-1 through Day OL-729)
- MP; Mean Change From Baseline to Month 12 in IBDQ(Day MP-365)
- MP; Mean Change From Baseline to Month 12 in Short Form-36 (SF-36)(Day MP-365)
- MP; Number of Participants With Baseline Oral Corticosteroid Use Who Have Discontinued Corticosteroids for 90 Consecutive Days and Achieved Clinical Remission by Month 12(Day MP-365 (Month 12))
- IP; Number of Participants in Mucosal Healing at Week 12 Among Participants With Anti-TNF (Infliximab) Failure/Intolerance: IP1C(Week 12 (Day IP-85))
- IP; Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and AEs Leading to Discontinuation: IP1C + IP2C(Day IP-1 through Day IP-85)
- MP; Number of Participants With Clinical Response at Month 12 Among Participants With Inadequate Response/Intolerance to Prior Anti-TNF Therapy (Infliximab)(Month 12 (Day MP-365))
- MP; Number of Participants With Clinical Remission at Month 12 Among Participants With Inadequate Response/Intolerance to Prior Anti-TNF Therapy (Infliximab)(Month 12 (Day MP-365))
- MP; Number of Participants With Clinical Mucosal Healing at Month 12 Among Participants With Inadequate Response/Intolerance to Prior Anti-TNF Therapy (Infliximab)(Month 12 (Day MP-365))
- MP; Number of Participants With Marked Chemistry and Urinalysis Laboratory Abnormalities(Day IP-85 through Day MP-365)
- MP; Number of Participants in Clinical Remission at Both Month 6 and Month 12(Month 6 (Day MP-169), Month 12 (Day MP-365))
- MP; Number of Participants With Mayo Rectal Bleeding Subscores Indicating Mild Disease (≤1 Point) at Month 12(Day MP-365 (Month 12))
- MP; Number of Participants With Mayo Stool Frequency Subscores Indicating Mild Disease (≤1 Point) at Month 12(Day MP-365 (Month 12))
- MP; Number of Participants With Mayo PGA Subscores Indicating Mild Disease (≤1 Point) at Month 12(Day MP-365 (Month 12))
- OL; Number of Participants With Clinical Response Over Time(Day OL-1 through Day OL-729)