Factors that led to termination: recruitment challenges and a lower incidence of flares than estimated, causing a high risk of the study being underpowered.

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.

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

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final\_Updated%20July\_9\_2014.pdf

http://engagezone.msd.com/ds\_documentation.php

Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.

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.