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    Clinical Trial Results:
    A Cluster Randomized Controlled Trial of an Enhanced Treatment Algorithm for the Management of Crohn's Disease

    Summary
    EudraCT number
    		 2014-001050-41
    Trial protocol
    		 DE  
    Global end of trial date
    16 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Apr 2022
    First version publication date
    29 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RP1202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01698307
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alimentiv Inc (formerly Robarts Clinical Trials Inc)
    Sponsor organisation address
    100 Dundas Street Suite 200, London, Canada, N6A-5B6
    Public contact
    Joan Morris, Project Director, Alimentiv Inc (formerly Robarts Clinical Trials Inc), 01 226-270-7652, joan.morris@alimentiv.com
    Scientific contact
    Vipul Jairath, Chief Medical Officer, Alimentiv Inc (formerly Robarts Clinical Trials Inc), 01 226-270-7652, vipul.jairath@alimentiv.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the Randomized Evaluation of an Algorithm for Crohn's Treatment Study-2 (REACT-2) cluster-randomized trial was to compare the efficacy of enhanced care (early combination therapy with treatment intensification to a target of absence of ulcers [>5mm in size], or deep remission) and step-care (treatment intensification to a target of clinical remission [Harvey Bradshaw Index (HBI) score ≤4]) for the treatment of Crohn's disease (CD). The primary outcome compared the risk of the first chronological CD-related complication (defined as a composite of CD-related surgeries, non-surgical events, and hospitalizations, and complications, hospitalizations and surgeries related to CD medications or procedures) at 24 months between the 2 treatment approaches.
    Protection of trial subjects
    All investigative sites obtained and maintained Ethics committee/Institutional Review Board approval. While investigators were asked to adhere to the treatment algorithms to the extent possible, treatment modification was allowed to ensure patient safety (e.g., avoiding use of a product contraindicated due to previous intolerance, or childbearing potential).
    Background therapy
    		 -
    Evidence for comparator
    		 Clinical management of active Crohn's disease (CD) includes sequential introduction of corticosteroids, immunosuppressants and biological therapy (e.g, step-care). Advanced therapies are typically reserved for more refractory patients to balance the perceived risks of these agents compared to first line drugs. Societal guidelines recommend the introduction of monoclonal antibodies for patients with moderate-to-severe CD with inadequate response or intolerance to conventional therapy. However this approach can risk prolonged corticosteroid exposure and inadequate management of underlying inflammatory disease and associated complications. Treatment to an objective target of endoscopic healing (absence of ulcers) in addition to symptomatic improvement is also favored in contemporary guidelines. Deep (clinical and endoscopic) remission has been associated with significantly lower risk of new fistulas, abscesses, hospitalization, or surgery. Early aggressive treatment, including earlier initiation of biologic therapy, is recognized as a potential approach to improve outcomes for patients with CD. The REACT-1 randomized trial found a lower composite rate of major adverse outcomes (defined as occurrence of surgery, hospital admission, or serious disease-related complications) at 2 years with early combined treatment with a tumor necrosis factor agent and antimetabolite to conventional step-care however the trial design did not reflect current recommended treatment targets and ileocolonoscopy was not performed to assess disease activity.
    Actual start date of recruitment
    17 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 330
    Country: Number of subjects enrolled
    United Kingdom: 282
    Country: Number of subjects enrolled
    Germany: 103
    Country: Number of subjects enrolled
    United States: 379
    Worldwide total number of subjects
    1094
    EEA total number of subjects
    103
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    982
    From 65 to 84 years
    110
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Trial recruitment began in March 2014. Enrollment per territory: Canada: first patient 28-Mar-2014; last patient 02-Mar-2018 United States: first patient 13-Aug-2014; last patient 13-Sep-2017 Germany: first patient 23-Jul-2015; last patient 27-Feb-2018 United Kingdom: first patient 20-May-2015; last patient 11-Apr-2018

    Pre-assignment
    Screening details
    		 Eligible practices could: implement EC or SC; provide data for 40 patients; perform ileocolonoscopy; transfer ileocolonoscopy videos. Eligible patients: ≥18 years of age with CD and able to receive adalimumab; no condition preventing compliance; no prior failure of all anti-TNFs; no investigational trial within 24 months; no short bowel syndrome.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enhanced care
    Arm description
    		 Patients with one large (>5 mm) ulcer. Combination therapy with adalimumab and azathioprine or methotrexate +/- glucocorticosteroids (GCS) as required with tapering. Ileocolonoscopy at 16 weeks to assess for remission (no large ulcer or GCS); if yes, continue current combination treatment; if no, increase to weekly adalimumab +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch anti-metabolite +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.
    Arm type
    		 Early combination therapy

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Indicated dose for Crohn's disease with dose escalation as needed for inadequate response

    Arm title
    		 Step-care
    Arm description
    		 Patients with Harvey Bradshaw Index (HBI) score >4 + glucocorticosteroids (GCS) with tapering. Evaluate in 16 weeks; if remission (HBI≤4), no maintenance therapy; if no remission, add azathioprine or methotrexate +/- GCS with tapering. Evaluate in 16 weeks for patients not in remission at prior assessment; if remission, continue antimetabolite; if no remission, add adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, increase to weekly adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch anti-metabolite +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.
    Arm type
    		 Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Enhanced care Step-care
    Started
    525
    569
    Completed
    415
    397
    Not completed
    110
    172
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    27
    17
         Relocation/travel
    12
    18
         Not Crohn's disease
    1
    2
         Eligibility criteria violation
    2
    4
         Other health condition
    3
    3
         Pregnancy
    2
    -
         Poor patient compliance
    21
    8
         Changed or left practitioner
    3
    5
         Lost to follow-up
    38
    50
         Site closure
    -
    63

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enhanced care
    Reporting group description
    		 Patients with one large (>5 mm) ulcer. Combination therapy with adalimumab and azathioprine or methotrexate +/- glucocorticosteroids (GCS) as required with tapering. Ileocolonoscopy at 16 weeks to assess for remission (no large ulcer or GCS); if yes, continue current combination treatment; if no, increase to weekly adalimumab +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch anti-metabolite +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Reporting group title
    Step-care
    Reporting group description
    		 Patients with Harvey Bradshaw Index (HBI) score >4 + glucocorticosteroids (GCS) with tapering. Evaluate in 16 weeks; if remission (HBI≤4), no maintenance therapy; if no remission, add azathioprine or methotrexate +/- GCS with tapering. Evaluate in 16 weeks for patients not in remission at prior assessment; if remission, continue antimetabolite; if no remission, add adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, increase to weekly adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch anti-metabolite +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Reporting group values
    		 Enhanced care Step-care Total
    Number of subjects
    		 525 569 1094
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 489 493 982
        From 65-84 years
    		 36 74 110
        85 years and over
    		 0 2 2
    Gender categorical
    Units: Subjects
        Female
    		 310 324 634
        Male
    		 215 245 460
    Number of patients per practice
    Units: Number
        arithmetic mean (standard deviation)
    		 37.5 ( 12.1 ) 37.9 ( 9.8 ) -
    CD duration
    These are practice level summaries
    Units: Months
        arithmetic mean (standard deviation)
    		 138.8 ( 43.8 ) 153.4 ( 37.0 ) -
    Current smoker
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 19.4 ( 9.6 ) 15.3 ( 10.3 ) -
    5-ASA use
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 12.6 ( 7.4 ) 21.8 ( 18.6 ) -
    Corticosteroid use
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 6.3 ( 4.0 ) 7.0 ( 5.5 ) -
    Any immunosuppressant use
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 31.6 ( 9.3 ) 34.8 ( 14.0 ) -
    Anti-TNF use
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 23.0 ( 15.9 ) 29.1 ( 18.8 ) -
    Combination therapy use
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 14.3 ( 14.6 ) 19.8 ( 14.3 ) -
    Prior surgery for CD
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 41.7 ( 14.1 ) 48.4 ( 11.9 ) -
    CD location: ileum
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 34.0 ( 17.9 ) 29.9 ( 12.5 ) -
    CD location: colon
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 23.1 ( 12.8 ) 24.0 ( 8.4 ) -
    CD location: ileocolonic
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 40.0 ( 19.4 ) 44.0 ( 15.3 ) -
    Active fistula
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 6.1 ( 5.2 ) 8.8 ( 6.0 ) -
    Harvery Bradshaw Index score
    These are practice level summaries
    Units: Score
        arithmetic mean (standard deviation)
    		 4.2 ( 1.1 ) 3.4 ( 1.3 ) -
    Harvey Bradshaw Index score ≤ 4
    These are practice level summaries
    Units: percent
        arithmetic mean (standard deviation)
    		 62.7 ( 11.3 ) 70.3 ( 14.2 ) -
    EQ-5D index score
    These are practice level summaries
    Units: Score
        arithmetic mean (standard deviation)
    		 0.73 ( 0.03 ) 0.74 ( 0.04 ) -
    EQ-5D visual analogue score
    These are practice level summaries
    Units: Score
        arithmetic mean (standard deviation)
    		 71.9 ( 3.8 ) 75.4 ( 5.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Enhanced care
    Reporting group description
    		 Patients with one large (>5 mm) ulcer. Combination therapy with adalimumab and azathioprine or methotrexate +/- glucocorticosteroids (GCS) as required with tapering. Ileocolonoscopy at 16 weeks to assess for remission (no large ulcer or GCS); if yes, continue current combination treatment; if no, increase to weekly adalimumab +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch anti-metabolite +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Reporting group title
    Step-care
    Reporting group description
    		 Patients with Harvey Bradshaw Index (HBI) score >4 + glucocorticosteroids (GCS) with tapering. Evaluate in 16 weeks; if remission (HBI≤4), no maintenance therapy; if no remission, add azathioprine or methotrexate +/- GCS with tapering. Evaluate in 16 weeks for patients not in remission at prior assessment; if remission, continue antimetabolite; if no remission, add adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, increase to weekly adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch anti-metabolite +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Primary: Patient-level risk of CD-related complications: 24 months

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    End point title
    		 Patient-level risk of CD-related complications: 24 months
    End point description
    Risk of the first chronological CD-related complication (defined as a composite of CD-related surgeries, non-surgical events, and hospitalizations, and complications, hospitalizations and surgeries related to CD medications or procedures) at 24 months
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    40.9 (33.3 to 50.1)
    43.1 (35.3 to 52.5)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.15
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 7.2

    Secondary: Patient-level risk of CD-related complications: 12 months

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    End point title
    		 Patient-level risk of CD-related complications: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    29.7 (22.3 to 39.5)
    31.3 (23.6 to 41.5)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Step-care v Enhanced care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.19
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 7.2

    Secondary: Patient-level risk of CD-related complications: 6 months

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    End point title
    		 Patient-level risk of CD-related complications: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    18.0 (12.3 to 26.4)
    21.0 (14.6 to 30.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.25
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 6

    Secondary: Patient-level risk of CD-related surgery: 24 months

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    End point title
    		 Patient-level risk of CD-related surgery: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    7.0 (3.8 to 12.8)
    6.4 (3.8 to 10.6)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.06
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 6.1

    Secondary: Patient-level risk of CD-related surgery: 12 months

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    End point title
    		 Patient-level risk of CD-related surgery: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    5.2 (2.6 to 10.3)
    3.9 (2.1 to 7.0)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 3.1
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 5.9

    Secondary: Patient-level risk of CD-related surgery: 6 months

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    End point title
    		 Patient-level risk of CD-related surgery: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    2.4 (1.1 to 5.0)
    2.0 (1.0 to 3.7)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 2.82
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 2.7

    Secondary: Patient-level risk of all-cause surgery: 24 months

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    End point title
    		 Patient-level risk of all-cause surgery: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    7.6 (4.6 to 12.5)
    7.3 (4.6 to 11.6)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.82
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 5.4

    Secondary: Patient-level risk of all-cause surgery: 12 months

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    End point title
    		 Patient-level risk of all-cause surgery: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    5.4 (2.9 to 10.1)
    4.2 (2.4 to 7.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 2.66
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 5.3

    Secondary: Patient-level risk of all-cause surgery: 6 months

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    End point title
    		 Patient-level risk of all-cause surgery: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    1.8 (0.6 to 4.9)
    1.7 (0.7 to 4.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 2.3
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 2.7

    Secondary: Patient-level risk of CD-related hospitalization: 24 months

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    End point title
    		 Patient-level risk of CD-related hospitalization: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    14.4 (10.1 to 20.6)
    11.4 (7.8 to 16.9)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.99
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 9.4

    Secondary: Clinical remission: 24 months

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    End point title
    		 Clinical remission: 24 months
    End point description
    Harvey Bradshaw Index score ≤ 4
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    32.3 (25.5 to 41.0)
    30.7 (21.9 to 42.9)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.46

    Secondary: Clinical remission: 12 months

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    End point title
    		 Clinical remission: 12 months
    End point description
    Harvey Bradshaw Index score ≤ 4
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    45.2 (38.2 to 53.5)
    47.6 (38.6 to 58.8)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.22

    Secondary: Deep remission: 24 months

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    End point title
    		 Deep remission: 24 months
    End point description
    Deep remission defined as Harvey Bradshaw Index score ≤ 4, no corticosteroids for the treatment of Crohn's disease, and normal C-reactive protein
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    15.9 (10.3 to 24.5)
    13.5 (8.6 to 21.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.99

    Secondary: Deep remission: 12 months

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    End point title
    		 Deep remission: 12 months
    End point description
    Deep remission defined as Harvey Bradshaw Index score ≤ 4, no corticosteroids for the treatment of Crohn's disease, and normal C-reactive protein
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    24.1 (17.8 to 32.7)
    24.7 (18.1 to 33.7)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.5

    Secondary: Progression-free deep remission: 24 months

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    End point title
    		 Progression-free deep remission: 24 months
    End point description
    Deep remission without disease progression, where disease progression is defined as the de novo development of strictures, fistula, the occurrence of an intra-abdominal abscess, or surgery for Crohn's disease (resection, bypass, stricturoplasty)
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    15.5 (10.0 to 24.0)
    13.2 (8.4 to 20.6)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2

    Secondary: Progression-free deep remission: 12 months

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    End point title
    		 Progression-free deep remission: 12 months
    End point description
    Deep remission without disease progression, where disease progression is defined as the de novo development of strictures, fistula, the occurrence of an intra-abdominal abscess, or surgery for Crohn's disease (resection, bypass, stricturoplasty)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    24.4 (18.0 to 33.0)
    23.8 (17.5 to 32.5)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    The risk ratio is estimated from individual-level data using a modified Poisson model for clustered binomial data adjusted for design elements. The proportions in each treatment algorithm are the associated least-squares means from this model. The comparisons are in reference to the step-care algorithm.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Modified Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.57

    Secondary: Difference in change from baseline in C-reactive protein concentration between treatment groups at month 24

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    End point title
    		 Difference in change from baseline in C-reactive protein concentration between treatment groups at month 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    327
    323
    Units: mg/L
        arithmetic mean (standard error)
    8.3 ( 1.2 )
    5.0 ( 0.6 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline C-Reactive Protein [mg/L].
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    650
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 6.6

    Secondary: Differerence in change from baseline in C-reactive protein concentration between treatment groups at month 12

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    End point title
    		 Differerence in change from baseline in C-reactive protein concentration between treatment groups at month 12
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    339
    363
    Units: mg/L
        arithmetic mean (standard error)
    8.7 ( 2.1 )
    6.5 ( 0.8 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline C-Reactive Protein [mg/L].
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    702
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 11.1

    Secondary: Difference in change from baseline in C-reactive protein concentration between treatment groups at month 6

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    End point title
    		 Difference in change from baseline in C-reactive protein concentration between treatment groups at month 6
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    262
    212
    Units: mg/L
        arithmetic mean (standard error)
    6.4 ( 0.9 )
    6.1 ( 1.0 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline C-Reactive Protein [mg/L].
    Comparison groups
    Step-care v Enhanced care
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 6.5

    Secondary: Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 24

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    End point title
    		 Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    419
    384
    Units: score
        arithmetic mean (standard error)
    2.4 ( 0.1 )
    2.4 ( 0.2 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change from baseline was performed at the patient-level using a linear mixed-model, modeling the change from baseline value, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    803
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 -0.2

    Secondary: Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 12

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    End point title
    		 Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 12
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    427
    456
    Units: score
        arithmetic mean (standard error)
    2.8 ( 0.2 )
    2.7 ( 0.2 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change from baseline was performed at the patient-level using a linear mixed-model, modeling the change from baseline value, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    883
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 0.2

    Secondary: Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 6

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    End point title
    		 Difference in change from baseline in Harvey Bradshaw Index score between treatment groups at month 6
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    424
    483
    Units: score
        arithmetic mean (standard error)
    2.7 ( 0.1 )
    2.8 ( 0.2 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change from baseline was performed at the patient-level using a linear mixed-model, modeling the change from baseline value, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    907
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 -0.2

    Secondary: Difference in change from baseline in EQ-5D score between treatment groups at month 24

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    End point title
    		 Difference in change from baseline in EQ-5D score between treatment groups at month 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    416
    381
    Units: score
        arithmetic mean (standard error)
    0.77 ( 0.01 )
    0.77 ( 0.01 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline EQ-5D single index.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    797
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.02

    Secondary: Difference in change from baseline in EQ-5D score between treatment groups at month 12

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    End point title
    		 Difference in change from baseline in EQ-5D score between treatment groups at month 12
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    428
    453
    Units: score
        arithmetic mean (standard error)
    0.76 ( 0.01 )
    0.76 ( 0.01 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline EQ-5D single index.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    881
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.02

    Secondary: Difference in change from baseline in EQ-5D score between treatment groups at month 6

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    End point title
    		 Difference in change from baseline in EQ-5D score between treatment groups at month 6
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    408
    472
    Units: score
        arithmetic mean (standard error)
    0.75 ( 0.01 )
    0.76 ( 0.01 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis of change within visit was performed at the patient-level using linear mixed-model accounting for clusters and adjusting for design elements and baseline EQ-5D single index.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.01

    Secondary: Patient-level risk of CD-related hospitalization: 12 months

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    End point title
    		 Patient-level risk of CD-related hospitalization: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    12.4 (8.8 to 17.5)
    8.2 (5.6 to 12.1)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.35
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 8.4

    Secondary: Patient-level risk of CD-related hospitalization: 6 months

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    End point title
    		 Patient-level risk of CD-related hospitalization: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    7.3 (4.5 to 11.9)
    4.8 (2.7 to 8.5)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 3.05
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 6.1

    Secondary: Patient satisfaction

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    End point title
    		 Patient satisfaction
    End point description
    How satisfied are you with the management of your Crohn's Disease during the course of participation in the study?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    412
    408
    Units: none
        arithmetic mean (standard deviation)
    9.3 ( 1.3 )
    9.2 ( 1.5 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    820
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.758
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Patient-level time to first CD-related complication

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    End point title
    		 Patient-level time to first CD-related complication
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to end of study
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    18.7 (5 to 24.4)
    12.5 (4.5 to 24.3)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.23

    Secondary: Patient-level risk of all cause hospitalization: 24 months

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    End point title
    		 Patient-level risk of all cause hospitalization: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    22.2 (18.0 to 27.3)
    22.6 (19.1 to 26.8)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.31
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 6.6

    Secondary: Patient-level risk of all cause hospitalization: 12 months

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    End point title
    		 Patient-level risk of all cause hospitalization: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    18.1 (14.5 to 22.5)
    15.1 (12.7 to 17.9)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.62
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 7.7

    Secondary: Patient-level risk of all cause hospitalization: 6 months

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    End point title
    		 Patient-level risk of all cause hospitalization: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    11.7 (8.2 to 16.5)
    7.9 (5.9 to 10.5)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.47
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 7.8

    Secondary: Patient-level risk of non-surgical CD-related complications: 24 months

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    End point title
    		 Patient-level risk of non-surgical CD-related complications: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    37.9 (30.4 to 47.3)
    41.8 (33.9 to 51.6)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.11
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 5.4

    Secondary: Patient-level risk of non-surgical CD-related complications: 12 months

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    End point title
    		 Patient-level risk of non-surgical CD-related complications: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    26.4 (19.0 to 36.7)
    29.3 (21.7 to 39.4)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.17
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 6.3

    Secondary: Patient-level risk of non-surgical CD-related complications: 6 months

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    End point title
    		 Patient-level risk of non-surgical CD-related complications: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    14.9 (9.7 to 22.9)
    19.1 (13.1 to 28.0)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.17
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 4.3

    Secondary: Patient-level risk of CD medication-related complications: 24 months

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    End point title
    		 Patient-level risk of CD medication-related complications: 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    18.8 (11.8 to 29.8)
    20.3 (12.4 to 33.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.37
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 7.6

    Secondary: Patient-level risk of CD medication-related complications: 12 months

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    End point title
    		 Patient-level risk of CD medication-related complications: 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    13.1 (8.3 to 20.9)
    13.0 (7.6 to 22.1)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.53
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 7.1

    Secondary: Patient-level risk of CD medication-related complications: 6 months

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    End point title
    		 Patient-level risk of CD medication-related complications: 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: percent
        number (confidence interval 95%)
    7.5 (3.8 to 14.8)
    8.9 (4.6 to 17.2)
    Statistical analysis title
    		 Risk ratio
    Statistical analysis description
    Risk estimates from a GEE marginal risk model for clustered time-to-event data with censoring, adjusted for clustering, design elements and treatment allocation. Treatment effect is estimated both in terms of the risk ratio and risk difference estimated from a GEE model. All analyses conducted at level of the individual.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.55
    Statistical analysis title
    		 Risk difference
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 GEE
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 4.9

    Secondary: Physician satisfaction (1)

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    End point title
    		 Physician satisfaction (1)
    End point description
    How effective do you feel the treatment algorithm is in managing your patients with Crohn’s Disease?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    14
    11
    Units: none
        arithmetic mean (standard deviation)
    7.1 ( 1.9 )
    6.0 ( 2.6 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.213
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Confidence interval

    Secondary: Physician satisfaction (2)

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    End point title
    		 Physician satisfaction (2)
    End point description
    How feasible do you think it is to sustain the treatment algorithm within your practice setting?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    14
    11
    Units: none
        arithmetic mean (standard deviation)
    7.6 ( 1.8 )
    6.0 ( 2.9 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.057
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Physician satisfaction (3)

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    End point title
    		 Physician satisfaction (3)
    End point description
    How satisfied are you with the information given to you regarding the use of the treatment algorithm in your practice setting?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    14
    11
    Units: none
        arithmetic mean (standard deviation)
    8.1 ( 1.3 )
    6.8 ( 2.8 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.095
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Physician satisfaction (4)

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    End point title
    		 Physician satisfaction (4)
    End point description
    How likely would you be to recommend the treatment algorithm to a colleague?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    14
    11
    Units: none
        arithmetic mean (standard deviation)
    7.6 ( 2.2 )
    6.2 ( 3.0 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.174
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Physician satisfaction (5)

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    End point title
    		 Physician satisfaction (5)
    End point description
    Overall how satisfied are you with the treatment algorithm to Crohn’s Disease management?
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    14
    11
    Units: none
        arithmetic mean (standard deviation)
    7.1 ( 2.4 )
    6.2 ( 3.3 )
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Linear-mixed model adjusted for stratification factors, caseload, and region.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.385
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Patient-level time to first CD-related surgery

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    End point title
    		 Patient-level time to first CD-related surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    24.3 (18.6 to 24.7)
    24.1 (12.2 to 24.6)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2.64

    Secondary: Patient-level time to first CD-related hospitalization

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    End point title
    		 Patient-level time to first CD-related hospitalization
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    24.2 (12.4 to 24.7)
    24.1 (11.0 to 24.5)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.09

    Secondary: Patient level time to first non-surgical CD-related complication

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    End point title
    		 Patient level time to first non-surgical CD-related complication
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    20.2 (6.1 to 24.4)
    12.8 (4.7 to 24.3)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.17

    Secondary: Patient-level time to first CD medication-related complication

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    End point title
    		 Patient-level time to first CD medication-related complication
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    24.1 (11.7 to 24.6)
    22.9 (8.2 to 24.5)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.4

    Secondary: Patient-level time to first all-cause surgery

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    End point title
    		 Patient-level time to first all-cause surgery
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    24.3 (18.6 to 24.8)
    24.1 (12.2 to 24.6)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 2.2

    Secondary: Patient-level time to first all-cause hospitalization

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    End point title
    		 Patient-level time to first all-cause hospitalization
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to study end
    End point values
    		 Enhanced care Step-care
    Number of subjects analysed
    525
    569
    Units: months
        median (inter-quartile range (Q1-Q3))
    24.1 (9.8 to 24.6)
    23.0 (9.1 to 24.5)
    Statistical analysis title
    		 Treatment effect
    Statistical analysis description
    Individual-level data were analyzed by a Cox proportional hazards regression, adjusting for design elements and clustering.
    Comparison groups
    Enhanced care v Step-care
    Number of subjects included in analysis
    1094
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.46

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months
    Adverse event reporting additional description
    Adverse events (serious and non-serious) reflect those occurring in >5% of patients
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Enhanced care
    Reporting group description
    		 Patients with one large (>5 mm) ulcer. Combination therapy with adalimumab and azathioprine or methotrexate +/- glucocorticosteroids (GCS) as required with tapering. Ileocolonoscopy at 16 weeks to assess for remission (no large ulcer or GCS); if yes, continue current combination treatment; if no, increase to weekly adalimumab +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch anti-metabolite +/- GCS with tapering. Ileocolonoscopy at 16 weeks for those not in remission at prior assessment; if remission, continue combination treatment; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Reporting group title
    Step-care
    Reporting group description
    		 Patients with Harvey Bradshaw Index (HBI) score >4 + glucocorticosteroids (GCS) with tapering. Evaluate in 16 weeks; if remission (HBI≤4), no maintenance therapy; if no remission, add azathioprine or methotrexate +/- GCS with tapering. Evaluate in 16 weeks for patients not in remission at prior assessment; if remission, continue antimetabolite; if no remission, add adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, increase to weekly adalimumab +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch anti-metabolite +/- GCS with tapering. Evaluate at 16 weeks for those not in remission at prior assessment; if remission, continue combination therapy; if no remission, switch tumor necrosis factor antagonist +/- GCS with tapering.

    Serious adverse events
    		 Enhanced care Step-care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 530 (6.98%)
    31 / 572 (5.42%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Crohn's disease
         subjects affected / exposed
    36 / 530 (6.79%)
    28 / 572 (4.90%)
         occurrences causally related to treatment / all
    0 / 41
    0 / 34
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enhanced care Step-care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    276 / 530 (52.08%)
    236 / 572 (41.26%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 530 (6.42%)
    35 / 572 (6.12%)
         occurrences all number
    35
    38
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    62 / 530 (11.70%)
    37 / 572 (6.47%)
         occurrences all number
    73
    41
    Crohn's disease
         subjects affected / exposed
    87 / 530 (16.42%)
    111 / 572 (19.41%)
         occurrences all number
    102
    133
    Diarrhoea
         subjects affected / exposed
    49 / 530 (9.25%)
    32 / 572 (5.59%)
         occurrences all number
    55
    32
    Nausea
         subjects affected / exposed
    43 / 530 (8.11%)
    28 / 572 (4.90%)
         occurrences all number
    47
    29
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    27 / 530 (5.09%)
    15 / 572 (2.62%)
         occurrences all number
    30
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    112 / 530 (21.13%)
    71 / 572 (12.41%)
         occurrences all number
    125
    73
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    45 / 530 (8.49%)
    22 / 572 (3.85%)
         occurrences all number
    53
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2019
    The study was extended from 1 to 2 years of follow-up. An extended follow up period was implemented in response to regulatory (FDA) recommendations and to enhance the scientific merit of the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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