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    Clinical Trial Results:
    Tight control dose reductions of biologics in psoriasis patients with low disease activity: a randomized pragmatic trial.

    Summary
    EudraCT number
    		 2015-000943-17
    Trial protocol
    		 NL  
    Global end of trial date
    01 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jan 2021
    First version publication date
    09 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NL54557.091.15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02602925
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    René Descartesdreef 1, Nijmegen, Netherlands, 6526GL
    Public contact
    Elke de Jong, Radboud University Nijmegen Medical Centre, +31 243613342, Elke.deJong@radboudumc.nl
    Scientific contact
    Elke de Jong, Radboud University Nijmegen Medical Centre, +31 243613342, Elke.deJong@radboudumc.nl
    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 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We aim to investigate whether we could taper the biologics dose in psoriasis patietns with stable disease-activity and good quality of life. The primary research question for this proposal is: Is a biologics dose tapering strategy non-inferior to usual care with respect to disease activity?
    Protection of trial subjects
    All patients who are eligible for this study will be asked by their dermatologist and they will receive oral and written information from the local investigator. The investigator will obtain written informed consent and the patient will be randomized. The schedule of their biological will be explained depending on which biologic the patient uses. Subjects can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. When subjects are withdrawn from the study, they will not be replaced.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2016
    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
    Netherlands: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    86
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients who are eligible for this study will be asked by their dermatologist and they will receive oral and written information from the local investigator. The investigator will obtain written informed consent and the patient will be randomized.

    Pre-assignment
    Screening details
    		 Patients 18 years or older with plaque psoriasis and stable low disease activity using standard doses of adalimumab, etanercept, or ustekinumab for at least 6 months were included. Low disease activity is described as a PASI score of 5 or lower at 2 subsequent visits in the past 6 months and a DLQI score of 5 or lower at study inclusion.

    Pre-assignment period milestones
    Number of subjects started
    		 120
    Number of subjects completed
    		 120

    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
    Not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Randomized to usual care
    Arm description
    		 Patients continued to receive usual care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Randomized to dose reduction
    Arm description
    		 The doses of etanercept, adalimumab or ustekinumab are lowered according to a predefined schedule
    Arm type
    		 Active comparator

    Investigational medicinal product name
    adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose will be decreased to 66–70% of the normal dose of the biologic (by interval prolongation with a factor 1.5). After 3 months, if the patients remain in a state of low disease activity, the dose will be further reduced to 50% of the original dose (by doubling the original interval). The interval will be prolonged from 14 to 21 to 28 days.

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose will be decreased to 66–70% of the normal dose of the biologic (by interval prolongation with a factor 1.5). After 3 months, if the patients remain in a state of low disease activity, the dose will be further reduced to 50% of the original dose (by doubling the original interval). The interval will be prolonged stepwise from 7 days to 10 days to 14 days.

    Investigational medicinal product name
    ustekinumab
    Investigational medicinal product code
    Other name
    Stelara
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dose will be decreased to 66–70% of the normal dose of the biologic (by interval prolongation with a factor 1.5). After 3 months, if the patients remain in a state of low disease activity, the dose will be further reduced to 50% of the original dose (by doubling the original interval). The interval will be stepwise increased from 12 to 18 to 24 weeks

    Number of subjects in period 1
    		Randomized to usual care Randomized to dose reduction
    Started
    60
    60
    Completed
    58
    53
    Not completed
    2
    7
         Protocol violation
    1
    1
         Lost to follow-up
    1
    1
         Protocol deviation
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomized to usual care
    Reporting group description
    		 Patients continued to receive usual care

    Reporting group title
    Randomized to dose reduction
    Reporting group description
    		 The doses of etanercept, adalimumab or ustekinumab are lowered according to a predefined schedule

    Reporting group values
    		 Randomized to usual care Randomized to dose reduction Total
    Number of subjects
    		 60 60 120
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 50 100
        From 65-84 years
    		 10 10 20
    Age continuous
    54.0 [13.2]
    Units: years
        arithmetic mean (standard deviation)
    		 57 ± 13.3 53 ± 12.9 -
    Gender categorical
    82 (68%) males
    Units: Subjects
        Female
    		 18 20 38
        Male
    		 42 40 82

    End points

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    End points reporting groups
    Reporting group title
    Randomized to usual care
    Reporting group description
    		 Patients continued to receive usual care

    Reporting group title
    Randomized to dose reduction
    Reporting group description
    		 The doses of etanercept, adalimumab or ustekinumab are lowered according to a predefined schedule

    Primary: PASI score (disease activity) at month 12

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    End point title
    		 PASI score (disease activity) at month 12
    End point description
    End point type
    Primary
    End point timeframe
    PASI score at month 12
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: PASI number
        median (inter-quartile range (Q1-Q3))
    2.1 (0.6 to 3.6)
    3.4 (2.2 to 4.5)
    Statistical analysis title
    		 Noninferiority analysis
    Comparison groups
    Randomized to usual care v Randomized to dose reduction
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: DLQI (Dermatology Life Quality Index) at month 12

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    End point title
    		 DLQI (Dermatology Life Quality Index) at month 12
    End point description
    End point type
    Secondary
    End point timeframe
    DLQI (Dermatology Life Quality Index) at month 12
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: DLQI number
        median (inter-quartile range (Q1-Q3))
    0.0 (0.0 to 2.0)
    1.0 (0.0 to 2.0)
    Statistical analysis title
    		 Noninferiority analysis
    Comparison groups
    Randomized to usual care v Randomized to dose reduction
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Disease-activity scores (PASI) at each time point (month 3/6/9/12)

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    End point title
    		 Disease-activity scores (PASI) at each time point (month 3/6/9/12)
    End point description
    Reported result is significant difference at month 9
    End point type
    Secondary
    End point timeframe
    Month 3/6/9/12
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: PASI score
        arithmetic mean (confidence interval 95%)
    2.3 (1.8 to 2.9)
    3.4 (2.8 to 3.9)
    Statistical analysis title
    		 Noninferiority analysis
    Comparison groups
    Randomized to usual care v Randomized to dose reduction
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Proportion of patients with successful dose tapering

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    End point title
    		 Proportion of patients with successful dose tapering [1]
    End point description
    End point type
    Secondary
    End point timeframe
    After 12 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: End point reports on number of patients that succesfully tapered their dose. This is not applicable to patients that continued to receive usual care.
    End point values
    		 Randomized to dose reduction
    Number of subjects analysed
    53
    Units: Patients
    28
    No statistical analyses for this end point

    Secondary: Proportion of patients with short and persistent flares

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    End point title
    		 Proportion of patients with short and persistent flares
    End point description
    End point type
    Secondary
    End point timeframe
    During study period
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: Patients
        Short
    8
    19
        Persistent
    5
    5
    No statistical analyses for this end point

    Secondary: Topical corticosteroid use

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    End point title
    		 Topical corticosteroid use
    End point description
    End point type
    Secondary
    End point timeframe
    During study period (12 months)
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: Patients
    21
    44
    No statistical analyses for this end point

    Secondary: Additional methotrexate or acitretin use

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    End point title
    		 Additional methotrexate or acitretin use
    End point description
    End point type
    Secondary
    End point timeframe
    During study period (12 months)
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: Percentage
    12
    13
    No statistical analyses for this end point

    Secondary: Number of severe adverse events (SAEs)

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    End point title
    		 Number of severe adverse events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    During study period (12 months)
    End point values
    		 Randomized to usual care Randomized to dose reduction
    Number of subjects analysed
    58
    53
    Units: Events
    6
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Over the total study period (12 months)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Randomized to usual care
    Reporting group description
    		 Patients continued to receive usual care

    Reporting group title
    Randomized to dose reduction
    Reporting group description
    		 The doses of etanercept, adalimumab or ustekinumab are lowered according to a predefined schedule

    Serious adverse events
    		 Randomized to usual care Randomized to dose reduction
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 59 (10.17%)
    6 / 59 (10.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    grawitz tumor
    Additional description: grawitz tumor right kidney
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
    Additional description: Collum fracture
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Fasciotomy
    Additional description: 4 loge fasciotomie left leg clinically suspected for compartiment syndrome
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Percutane intentional extraluminal recanalisation a femorali
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
    Additional description: ischaemic CVA brainstem ischaemic CVA left hemisphere
         subjects affected / exposed
    1 / 59 (1.69%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Meniscus operation
    Additional description: partial medial menisectomy
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Total knee prothesis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotis desobstruction
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilatation vascular
    Additional description: ballondilatation distale anastomosis fem-fem crossover
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: motility disorder (pre-existent)
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
    Additional description: cholangitis
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Open wound
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
    Additional description: after hospitalisation
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis bacterial
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized to usual care Randomized to dose reduction
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 59 (77.97%)
    51 / 59 (86.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant tumor
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Nonmelanoma skin cancer
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 59 (5.08%)
         occurrences all number
    3
    3
    Surgical and medical procedures
    Elective surgery
         subjects affected / exposed [1]
    4 / 58 (6.90%)
    6 / 53 (11.32%)
         occurrences all number
    4
    6
    Blood and lymphatic system disorders
    Infection
         subjects affected / exposed
    37 / 59 (62.71%)
    40 / 59 (67.80%)
         occurrences all number
    73
    70
    Skin and subcutaneous tissue disorders
    Psoriatic arthritis
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Skin event
         subjects affected / exposed
    7 / 59 (11.86%)
    4 / 59 (6.78%)
         occurrences all number
    10
    4
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    4 / 59 (6.78%)
    13 / 59 (22.03%)
         occurrences all number
    4
    13
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: not all elective surgery cases were considered SAEs

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    1) Open-label design, 2) an absolute PASI score instead of a relative PASI score, 3) dose reduction led to higher topical treatment use and more visits, 4) for per-dsrug conclusions, study was underpowered, 5) no general flare criterion for psorias

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32049319
    http://www.ncbi.nlm.nih.gov/pubmed/33196101
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