The purpose of this clinical research study is to learn if abatacept can improve signs and symptoms of active Crohn's Disease in patients who have not had an adequate response to other therapies. The safety of this treatment will also be studied.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
451
Dextrose 5% in water, intravenous (IV). Placebo on days Induction Period (IP)-1, IP-15,IP-29, IP-57; 3 mg/kg on days IP-1, IP-15,IP-29, IP-57; \~10 mg/kg on days IP-1, IP-15,IP-29, IP-57, or 30 mg/kg on days IP-1,IP-15 and \~10 mg/kg on days IP-29, IP-57. Induction Period 3 months Maintenance Period 12 months
Normal saline, IV, 0 mg/kg, every 28 days. Induction Period 3 months Maintenance Period 12 months
\~10 mg/kg, every 28 days. Open- Label Extension Period until the drug is marketed for Crohn's Disease (CD)or the CD development program for abatacept is discontinued
Induction Period (IP); Number of Participants With Crohn's Disease Activity Index (CDAI)-Defined Clinical Response at Both Day IP-57 and Day IP-85
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12).
Maintenance Period (MP); Number of Participants In CDAI-Defined Clinical Remission (CDAI <150) at Day MP-365 (12 Months)
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day MP-365 (12 months) of maintenance therapy
Open-Label Extension Period (OL); Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and Discontinuation Due to AEs
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.
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University Of Alabama Medical Center
Birmingham, Alabama, United States
Cedars-Sinai Medical Center
Los Angeles, California, United States
The Permanente Medical Group, Inc
Sacramento, California, United States
University Of Florida
Gainesville, Florida, United States
Borland-Groover Clinic
Jacksonville, Florida, United States
Shafran Gasteroenterology Center
Winter Park, Florida, United States
Atlanta Gastroenterology Associates
Atlanta, Georgia, United States
University Of Chicago Hospitals
Chicago, Illinois, United States
Health Science Center
Pratt, Kansas, United States
University Of Kentucky Medical Center
Lexington, Kentucky, United States
...and 91 more locations
Time frame: Between Day OL-1 and Day OL-617
OL; Number of Participants With Adverse Events (AEs) of Special Interest
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).
Time frame: Between Day OL-1 and Day OL-617
IP; Number of Participants in CDAI-defined Clinical Remission at Both Day IP-57 and Day IP-85 (Key Secondary Outcome)
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12) of induction therapy
IP; Number of Participants With CDAI-Defined Clinical Response at Both Day IP-57 and Day IP-85 Analyzed by Cochran-Armitage Trend Test for Dose-Response Relationship
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12) of induction therapy
IP; Change From Baseline to Day IP-85 In Inflammatory Bowel Disease Questionnaire (IBDQ)
The Inflammatory Bowel Disease Questionnaire (IBDQ) consists of a self-administered 32-item questionnaire evaluating quality of life across 4 dimensional scores: Bowel, Systemic, Social and Emotional. Responses to each question can range from 1 to 7, with 1 indicating severe problem and 7 indicating normal health. The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score ranges between 32 to 224 with higher scores indicating a better quality of life. Change from Baseline= post-Baseline - Baseline value.
Time frame: Baseline, Day IP-85
IP; Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and Discontinuation Due to AEs
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.
Time frame: Day IP-1 through Day IP-85
IP; Number of Participants With Adverse Events (AEs) of Special Interest
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).
Time frame: Day IP-1 through Day IP-85
IP; Number of Participants With Positive Antibody Response to Abatacept (ABA)
A electrochemiluminescent immunoassay screened sera for drug-specific antibodies, immunocompetition identified specific anti-ABA reactivity. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Possibly immunoglobulin (Ig) category= reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing.
Time frame: 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)
IP; Number of Participants With CDAI-Defined Clinical Response at Both Day IP-57 and Day IP-85 Among Participants With Inadequate Response and/or Intolerance to Anti-Tumor Necrosis Factor (TNF)
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12) of induction therapy
IP; Number of Participants in CDAI-Defined Clinical Remission at Both Day IP-57 and Day IP-85 Among Participants With Inadequate Response and/or Intolerance to Anti-TNF
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12) of induction therapy
IP; Number of Participants Who Are Anti-TNF-Inadequate Responders/Anti-TNF Intolerant With CDAI-Defined Clinical Response at Both Day IP-57 and Day IP-85 Analyzed by Cochran-Armitage Trend Test for Dose-Response Relationship
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: At both Day IP-57 (Wk 8) and Day IP-85 (Wk 12) of induction therapy
MP; Number of Participants With Adverse Events (AEs), Related AEs, Deaths, Serious AEs (SAEs), Related SAEs, and Discontinuation Due To AEs
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.
Time frame: Between Day IP-85 and Day MP-365
MP; Number of Participants With Adverse Events (AEs) of Special Interest:
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).
Time frame: Between Day IP-85 and Day MP-365
MP; Number of Participants With Positive Antibody Response to Abatacept
A electrochemiluminescent immunoassay screened sera for drug-specific antibodies, immunocompetition was used to identify specific anti-Abatacept reactivity. CTLA4 and Possibly Ig category= reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing.
Time frame: For participants not entering OL: All measurements 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 CDAI-defined Clinical Response at Day MP-365.
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day MP-365
MP; Number of Participants in CDAI-defined Clinical Remission at Both Day MP-169 and Day MP-365
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day MP-169
MP; Change From Baseline to Day MP-365 in Short Form-36 (SF-36)
The SF-36 is a validated instrument measuring health-related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores (1) physical component summary=physical functioning, role-physical, bodily pain, and general health; (2) mental component summary=vitality, social functioning, role-emotional, and mental health. There is no total overall score; scoring is done for both subscores and summary scores. For subscores and summary scores, 0 =worst score (or quality of life) and 100=best score. Change from Baseline= post-Baseline - Baseline value.
Time frame: Baseline, Day MP-365
MP; Change From Baseline to Day MP-365 in Inflammatory Bowel Disease Questionnaire (IBDQ)
The Inflammatory Bowel Disease Questionnaire (IBDQ) consists of a self-administered 32-item questionnaire evaluating quality of life across 4 dimensional scores: Bowel, Systemic, Social and Emotional. Responses to each question can range from 1 to 7, with 1 indicating severe problem and 7 indicating normal health. The total IBDQ is computed as the sum of the responses to the individual IBDQ questions. The total score ranges between 32 to 224 with higher scores indicating a better quality of life. Change from Baseline= post-baseline - Baseline value.
Time frame: Baseline, Day MP-365
MP; Number of Participants Who Were Not On Background Corticosteroid Therapy at Day MP-365 Among All Participants Who Received Baseline Corticosteroid Therapy
Participants who received corticosteroid therapy (e.g. prednisone or budesonide) were to maintain a stable dose until Day MP-1. On or after Day MP-1, a recommended tapering regimen of corticosteroid therapy was planned if the participant was in remission (i.e., CDAI score \< 150), or if the participant's condition had satisfactorily improved according to investigators clinical assessment. Other CD therapy was to remain at a stable dose throughout the Maintenance Period, with the exception of decreases due to drug-related toxicities.
Time frame: Day MP-365
MP; Number of Participants Who Were Not On Background Corticosteroid Therapy at Day MP-365 Among Participants Who Received Baseline Corticosteroid Therapy and Who Achieved CDAI-Defined Clinical Remission
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score is based partly on entries from participant's Diary (7 days before evaluation) which is kept while on study. CDAI scores range from 0 to \~600. Clinical response=CDAI reduction ≥100 or absolute CDAI \<150. Clinical remission=CDAI \<150. Moderate to severe disease=CDAI ≥220 and ≤450.
Time frame: Day MP-365
MP; Number of Participants With CDAI-Defined Clinical Response Among Participants With Inadequate Response and/or Intolerance to Anti-Tumor Necrosis Factor (TNF)
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day MP-365
MP; Number of Participants in CDAI-Defined Clinical Remission Among Participants With Inadequate Response and/or Intolerance to Anti-TNF
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day MP-365
OL; Number of Participants Who Were Not On Background Corticosteroid Therapy Among All Participants Who Received Baseline Corticosteroid Therapy
Background corticosteroid therapy included prednisone or budesonide.
Time frame: Between Day OL-1 and Day OL-617
OL; Number of Participants With CDAI-defined Clinical Response or Clinical Remission at Day OL-169
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day OL-169
OL; Number of Participants With CDAI-defined Clinical Response or Clinical Remission at Day OL-365
CDAI is a composite index consisting of a weighted scoring of 8 disease variables:number of liquid stools, extent of abdominal pain, general well-being, occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. CDAI score was based partly on entries (7 days before evaluation) from participant's Diary kept while on study. CDAI scores range from 0 to \~600 points. Clinical response=CDAI reduction ≥100 points or absolute CDAI \<150 points. Clinical remission=CDAI \<150 points. Moderate to severe disease=CDAI ≥220 and ≤450 points.
Time frame: Day OL-365
OL; Number of Participants With Positive Antibody Response to Abatacept
A electrochemiluminescent immunoassay screened sera for drug-specific antibodies, immunocompetition was used to identify specific anti-Abatacept reactivity. CTLA4 and Possibly Ig category= reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity was defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing.
Time frame: 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 With Pharmacogenomic Marker Activity
Changes in the expression of individual ribonucleic acid (RNA) transcripts were to be evaluated from whole blood using both microarray transcriptional profiling and quantitative polymerase chain reaction (PCR) methods. Peripheral RNA transcriptional profiling was to be used only to identify individual RNA transcripts that differ in expression with respect to time, treatment and outcome.
Time frame: Between Day OL-1 and Day OL-617