Treatment With Infliximab in a Medical Setting (Study P05587)

Study Overview
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Brief Summary
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This is an open-label, interventional study where a subset of participants will be randomized to one of two treatment-optimization strategies. Participants with moderate to severe Crohn's disease (CD) will receive induction treatment comprised of 3 infusions of infliximab at Weeks 0, 2, and 6. The participants will be evaluated at Week 10. Participants who are in clinical response will enter the observational phase of the study where they will receive standard of care treatment, as per the infliximab product monograph. Participants who lose response, may qualify for entry into the interventional phase of the study, where they will be randomized to one of the following treatment-optimization arms: 1) dose increase: infliximab 7 mg/kg, every 8 weeks or 2) shortened interval: infliximab 5 mg/kg every 6 weeks. Note: Due to early study termination, no statistical analysis was performed for the interventional part of this study, therefore, endpoints dedicated to this phase of the study have not been analyzed.

Official Title
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Optimization of Treatment With Infliximab in a Medical Setting

Conditions
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Crohn's Disease

Intervention / Treatment
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* Biological: Infliximab 5 mg/kg
* Biological: Infliximab 5 mg/kg every 6 weeks
* Biological: Infliximab 7 mg/kg every 8 weeks


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women >=18 years of age Moderate to severe CD (Crohn's Disease Activity Index [CDAI] >= 220 and <= 450) CD of at least 3 months duration confirmed within the past 2 years by radiography and/or endoscopy Biologic-naïve If using 5-Aminosalicylic Acid (5-ASA), there must be at least 4 weeks of stable dosage prior to screening If using azathioprine or 6-mercaptopurine, the start date must be at least 3 months prior to screening and the dose must be stable for at least 6 weeks prior to screening If using methotrexate, the participant must have been using methotrexate with a stable dosage of at least 6 weeks prior to screening Participants must be off corticosteroids or on a stable dose of corticosteroids for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroids at baseline must not exceed 30 mg of prednisone equivalent Participants are considered eligible according to the following tuberculosis (TB) screening criteria: Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study medication Within 3 months prior to the first administration of study medication, either have negative OR have a newly identified positive diagnostic TB test result (defined as at least 1 positive tuberculin skin test) during screening in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study medication Participants must have had a chest X-ray within 3 months prior to screening with no evidence of current or old active TB Participants' screening and baseline clinical laboratory tests (complete blood count [CBC], blood chemistries, and urinalysis) must be within the following parameters: Hemoglobin >=10 g/dL (100 g/L) White blood cells (WBCs) >=3.5 x 109/L Neutrophils >=1.5 x 10^9/L Platelets >=100 x 10^9/L Serum creatinine <1.5 mg/dL (or <133 μmol/L) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gammaglutamyltransferase <=1.5 x upper limit of normal (ULN); Total bilirubin <=1 x ULN Antibiotics for the treatment of CD (e.g., ciprofloxacin and metronidazole) must have been discontinued at least 3 weeks prior to screening Participants must be free of any clinically significant condition or situation, other than CD that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study Participants are willing and able to adhere to the study visit schedule and other protocol requirements Participants are capable of providing written informed consent, which must be obtained prior to conducting any protocol-specified procedures Sexually-active women of child-bearing potential must agree to use a medically accepted method of contraception prior to screening, while receiving protocol specified medication, and for 6 months after stopping the medication Women of child-bearing potential who are not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study Female participants of childbearing potential must have a negative serum pregnancy test (beta-hCG) at screening have an increased Harvey-Bradshaw Index (HBI) score >=3 points over the week 10 evaluation score and a CDAI score >=175 have received regular infusions of Infliximab (IFX) every 8 weeks during the observational phase with a maximum interval of no more than 10 weeks between each infusions having previous doses of IFX of >= 4.7 mg/kg Exclusion Criteria: Are pregnant or plan to become pregnant during the study period; participants who are breast feeding Have been treated with excluded drugs prior to entry: any biological or anti- Tumor necrosis factor (anti-TNF) agent such as infliximab, adalimumab, certolizumab, etanercept, pentoxifylline, or thalidomide Have had a serious infectious disease in the 8 weeks prior to entry Have active perianal fistulas and a Perianal disease activity index (PDAI) score >10 Have presumed fibro-stenotic stricture or acute bowel obstruction Have had live vaccination in the 6 weeks prior to entry Have known intolerance to study drug Have a history of myocardial infarction, congestive heart failure, coronary artery disease, or arrhythmias in the last 6 months Have a history of malignancy (within the past 5 years) with the exception of carcinoma in situ of the cervix or localized basal cell skin cancer that have been adequately treated Have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease Have a history of demyelinating disease such as multiple sclerosis Have a positive test for human immunodeficiency virus (HIV), hepatitis B virus (HBV) surface antigen, or hepatitis C virus (HCV) antibody Have renal, hepatic, hematological, cardiovascular, pulmonary, neurological, psychiatric, immunologic, gastrointestinal, endocrine, or other diseases if they are clinically significant. (A clinically significant disease is defined as one which in the opinion of the investigator can put the participants at risk because of participation in the study or a disease which can influence the participant's ability to participate in the study or affect the results of the study) Have clinically significant abnormal laboratory test results, unless regarded by the investigator as related to CD Have a history of alcohol or drug abuse Are unable to comply with the protocol Have any clinically significant findings in the physical examination that, in the investigator's judgment, may interfere with the study evaluation or affect participant safety Are in a situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study Are participating in any other clinical study(ies) except for registries Are on the staff, affiliated with, or a family member of the staff personnel directly involved with this study Are allergic to or have sensitivity to the study drug or any of its excipients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Shortened interval<br>Infliximab 5 mg/kg, then Infliximab 5 mg/kg every 6 weeks | Biological: Infliximab 5 mg/kg<br>* Participants received Infliximab 5 mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase. At Week 10, those who were in clinical response received further treatment every 8 weeks during the observational phase<br>* Other names: SCH 215596;Biological: Infliximab 5 mg/kg every 6 weeks<br>* Participants with loss of response in the observational phase were randomized at entry into the interventional phase received 5 mg/kg IV every 6 weeks (shortened interval group)<br>|
| Experimental: Increased dose<br>Infliximab 5 mg/kg, then Infliximab 7 mg/kg every 8 weeks | Biological: Infliximab 5 mg/kg<br>* Participants received Infliximab 5 mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase. At Week 10, those who were in clinical response received further treatment every 8 weeks during the observational phase<br>* Other names: SCH 215596;Biological: Infliximab 7 mg/kg every 8 weeks<br>* Participants with loss of response in the observational phase were randomized at entry into the interventional phase received 7 mg/kg IV every 8 weeks (increased dose group)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had a Clinical Response Using the Crohn's Disease Activity Index (CDAI) at Week 24 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to  600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Participants provided completed CDAI diary cards and were considered as responders in the interventional phase if their CDAI score at week 24 was decreased by 70 points or greater over their CDAI score at randomization into the interventional phase, or if their week 24 CDAI score is <= 150. Baseline is value at randomization. | Baseline and Week 24 of the Interventional phase | 
| Mean Change From Baseline in Harvey-Bradshaw Index (HBI) | Mean change in HBI score from Baseline to Week 10, 30, and 54. HBI score consists of clinical parameters: general well-being (0-4), abdominal pain (0-3), number of liquid stools per day, abdominal mass (0-3), and complications (score 1 per item). Total score is the sum of individual parameters. Minimum score is 0 and no pre-specified maximum score as it depends on the number of liquid stools. Lower scores indicate better well being. Clinical response/ long-term response is defined as a decrease by 3 or more points from baseline value. Loss of response is defined as an increase of >= 3 points. | Baseline and Evaluation Week 10, Week 30 and Week 54 of the Observational Phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Required Treatment Optimization in the Observational Phase | Participants required treatment-optimization if: Disease progression/lack of response after entering observational phase; or Participant was successfully randomized into the interventional phase The definition of loss of response was as follows: - An increased HBI score >= 3 points over the week 10 evaluation score and a CDAI score >= 175. Despite: having received regular infusions of infliximab every 8 weeks during the observational phase with a maximum interval of no > 10 weeks between each infusion, and having received previous doses of infliximab of >= 4.7 mg/kg. | Week 54 in the Observational Phase | 
| Number of Participants Who Had a Clinical Response Using the CDAI at Weeks 14-16 and 48 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to  600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 70-point reduction in CDAI score from randomization into the interventional phase or CDAI < 150 at week 14-16 and 48 in the Interventional Phase. Baseline is value at randomization. | Baseline and Weeks 14-16 and 48 in the Interventional Phase | 
| Number of Participants Who Had a Clinical Response Using the CDAI-100 at Weeks 14-16, 24 and 48 in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to  600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 100-point reduction in CDAI score from randomization into the interventional phase or CDAI < 150 at weeks 14-16, 24 and 48 in the Interventional Phase. Baseline is value at randomization. | Baseline and Weeks 14-16, 24 and 48 in the Interventional Phase | 
| Number of Participants Who Had Clinical Remission in the Interventional Phase | The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to  600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI < 150 at weeks 14-16, 24 and 48 in the Interventional Phase. | Weeks 14-16, 24 and 48 in the Interventional Phase | 
| Number of Participants Who Had Clinical Remission Off Steroids in the Interventional Phase | Number of participants who were in clinical remission and off systemic corticosteroids at visit. The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to  600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI < 150 at weeks 14-16, 24 and 48 in the Interventional Phase. | Weeks 14-16, 24 and 48 in the Interventional Phase |