Efficacy and Safety of Two Treatment Algorithms in Adults With Moderate to Severe Crohn's Disease

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

252 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-02-11

Study Completion Date

2017-01-03

Brief Summary

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The primary objective of this study was to demonstrate that tight control of disease activity, using stringent criteria based on Crohn's disease activity Index (CDAI), biomarkers (high sensitivity C-reactive protein \[hs-CRP\] and fecal calprotectin), and corticosteroid use, improves the rate of mucosal healing 48 weeks after randomization compared with management using less stringent criteria based only on CDAI and corticosteroid use.

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Detailed Description

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The study included a 1- to 3-week screening period, up to 8 weeks of prednisone run-in treatment, a 48-week post-randomization treatment period, and a 70 day follow-up phone call or clinic visit, for a total duration of up to 69 weeks.

Participants who met entry criteria were enrolled and initiated an oral prednisone regimen at Baseline (Week 0). At the first key visit, participants were randomized into 1 of 2 groups (Tight Control group or Clinically Driven group), with stratification according to screening smoking status, weight, and disease duration.

The first key visit was the randomization visit; subsequent key visits occurred every 12 weeks following the first key visit. Randomization normally took place 9 weeks after Baseline. However, participants who fulfilled the early randomization criteria may have been randomized as early as the Baseline (Week 0) visit. Therapeutic option changes, if appropriate, occurred at key visits based on results from previous success criteria visits.

Conditions

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Crohn's Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Tight Control Management

Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI), high sensitivity C-reactive protein (hs-CRP), fecal calprotectin, and corticosteroid use.

Participants received customized therapy that could include prednisone, adalimumab, and azathioprine. Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.

Therapy was escalated according to pre-specified tight control criteria: At Key Visit 1 the success criteria were CDAI \< 150, hs-CRP, \< 5 mg/L, fecal calprotectin \< 250 μg/g, and absence of prednisone use. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria were CDAI \< 150, hs-CRP \< 5 mg/L, fecal calprotectin \< 250 μg/g, and absence of prednisone during the preceding week.

Group Type EXPERIMENTAL

Adalimumab

Intervention Type BIOLOGICAL

If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.

Prednisone

Intervention Type DRUG

The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.

Azathioprine

Intervention Type DRUG

Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase \[ALT\], aspartate transaminase \[AST\], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.

Clinically Driven Management

Participants randomized to receive management of disease activity using criteria based on Crohn's Disease Activity Index (CDAI) and corticosteroid use.

Participants received customized therapy that could include prednisone, adalimumab, and azathioprine.

Participants who randomized at Week 9 meeting success criteria started with no therapy; participants who randomized prior to Week 9 or who randomized at Week 9 but did not meet the success criteria began treatment with adalimumab.

Therapy was escalated according to pre-specified failure criteria using less stringent criteria:

At Key Visit 1 the criteria for management of disease activity were a CDAI decrease ≥ 70 (CR-70) compared to Baseline or CDAI \< 200 at 1 week prior to the visit. At Key Visits 3, 4, and 5 (every 12 weeks after Key visit 1), the criteria for a change in treatment were a CDAI decrease of ≥ 100 (CR-100) compared to Baseline or CDAI \< 200, and absence of prednisone during the preceding week.

Group Type ACTIVE_COMPARATOR

Adalimumab

Intervention Type BIOLOGICAL

If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.

Prednisone

Intervention Type DRUG

The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.

Azathioprine

Intervention Type DRUG

Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase \[ALT\], aspartate transaminase \[AST\], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.

Interventions

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Adalimumab

If adalimumab was initiated, it was administered subcutaneously as a 160 mg induction dose the first week, followed by 80 mg 2 weeks later, followed by 40 mg every other week as a maintenance dose. The dose of adalimumab was increased from 40 mg eow to 40 mg every week in participants with an inadequate response and de-escalated to 40 mg eow in participants who met success criteria.

Intervention Type BIOLOGICAL

Prednisone

The suggested regimen for participants initiating prednisone consisted of a maximum dose of prednisone 40 mg/day for 2 weeks, followed by a fixed taper for 6 weeks.

Intervention Type DRUG

Azathioprine

Participants with normal thiopurine methyltransferase (TPMT) enzyme activity could receive oral azathioprine 2.5 mg/kg/day. In participants with intermediate TPMT enzyme activity azathioprine was initiated at a dose of 1.25 mg/kg/day. The dose of azathioprine was adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase \[ALT\], aspartate transaminase \[AST\], alkaline phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine.

Intervention Type DRUG

Other Intervention Names

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ABT-D2E7 Humira

Eligibility Criteria

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Inclusion Criteria

* Diagnosis of ileal, colonic (including rectal), or ileocolonic Crohn's disease (CD) confirmed using imaging technology or endoscopy not more than 6 years prior to Baseline.
* CDAI score of greater than or equal to 220 and less than or equal to 450 at the Baseline visit in participants not receiving prednisone or equivalent at Baseline. CDAI score of greater than or equal to 200 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone less than or equal to 20 mg or equivalent for at least 7 days before Baseline. CDAI score of greater than 150 and less than or equal to 450 at the Baseline visit if the participant is receiving prednisone higher than 20 mg or equivalent for greater than or equal to 7 days before Baseline
* Participant or his/her legal representative have voluntarily signed and dated an informed consent approved by and compliant with the requirements of this study protocol which has been approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
* Adequate cardiac, renal and hepatic function as determined by the Principal Investigator and demonstrated by Screening laboratory evaluations, questionnaires and physical examination results that do not indicate an abnormal clinical condition which would place the participant at undue risk and thus preclude participation in the study.
* Participant must be able to self-inject and orally administer study medication or have a designee or Healthcare Professional who can assist

Exclusion Criteria

* Previous or current biologic use for Crohn's disease or participation in a biologic study
* Previous or current use of immunomodulators (e.g., methotrexate, azathioprine, 6-mercaptopurine, JAK inhibitor, alpha-integrin) for Crohn's disease or participation in a Crohn's disease study with immunomodulator(s). Current use of immunomodulators for non-Crohn's disease at Baseline.
* Greater than two previous courses of corticosteroid (systemic corticosteroid) or budesonide) for Crohn's Disease. A course is defined as 1) total duration for burst and taper ≥ 4 weeks and 2) prednisone or equivalent ≥ 40 mg (or budesonide ≥ 9 mg) for at least 2 weeks.
* Participants with a poorly controlled medical condition such as: uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, moderate to severe congestive heart failure (New York Heart Association \[NYHA\] class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator or the sponsor, would put the participant at risk by participation in the protocol
* Participants with positive C. difficile stool assay at Screening.

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No