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    Clinical Trial Results:
    Optimising Treatment With Tumour Necrosis Factor Inhibitors In Rheumatoid Arthritis: Is Dose Tapering Practical In Good Responders? A “Proof Of Principle” And Exploratory Trial. (OPTTIRA)

    Summary
    EudraCT number
    		 2010-020738-24
    Trial protocol
    		 GB  
    Global end of trial date
    07 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2019
    First version publication date
    15 Mar 2019
    Other versions
    Summary report(s)
    		 Summary Report

    Trial information

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    Trial identification
    Sponsor protocol code
    Version 1.2 (20/06/2011)
    Additional study identifiers
    ISRCTN number
    		 ISRCTN28955701
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor David Scott, King's College London, +44 02078485200, kch-tr.opttira@nhs.net
    Scientific contact
    Professor David Scott, King's College London, +44 02078485200, kch-tr.opttira@nhs.net
    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
    07 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study investigates whether in it is possible to reduce the dose of or even stop TNF-inhibitors without adversely affecting the control of this disease. This will be assessed by looking at: a. The risk of disease flares (using the disease activity score with a 28 tender and swollen joint count (DAS28). An increase of disease activity score (DAS28) of 0.6 or more represents adversely affecting disease control and is considered a flare) b. If flares are reversed by reverting to the original TNF inhibitor dosage c. If either tapering group show worse key RA assessments including disease activity (DAS28) and disability as measured by health assessment questionnaire (HAQ) scores d. Structural damage (plain hand and fe
    Protection of trial subjects
    Participants had their DMARD monitoring performed as part of the trial’s safety monitoring which has been designed to fit with routine clinical practice,
    Background therapy
    		 Patients will continue to receive the DMARDs prescribed prior to trial entry at standard doses . They will be taking either Etanercept OR Adalimumab
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 97
    Worldwide total number of subjects
    97
    EEA total number of subjects
    97
    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)
    97
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from multiple centers across the UK between 2011 and 2014

    Pre-assignment
    Screening details
    		 Patients already on TNF inhibitors (failure to respond to two DMARDs) and have a sustained good response. Patients must be taking Etanercept or Adalimumab at standard doses (50mg/week and 40mg/fortnight respectively) and at least one concomit

    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 applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 - TNF inhibitor tapered to 66% of initial dose
    Arm description
    		 Experimental group 1 – patients have their TNF inhibitor tapered to 66% of initial dose by reducing frequency of dosing. Month 1 to 6 - TNF inhibitor tapered to 66% of initial dose. Month 7 to 12 - Time between injections increased on each occasion until injections are stopped completely.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50mg subcutaneously reducing as detailed in trial protocol.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During the “Proof of Principle” phase (months 0 – 6) patients will self administer Adalimumab subcutaneously at a dose of 40mg according to the protocol regime. During the Exploratory Phase (months 7 - 12) patients in the experimental groups will increase the time between injections until injections are stopped completely

    Arm title
    		 Group 2 - TNF inhibitor tapered to 33%
    Arm description
    		 Experimental group 2 - patients have their TNF inhibitor tapered to 33% of initial dose. Months 1 to 6 - patients have their TNF inhibitor tapered to 33% of initial dose. Months 7 to 12 - During the Exploratory Phase (months 7 - 12) patients in the experimental groups will increase the time between injections on each occasion until injections are stopped completely.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50mg subcutaneously reducing as detailed in trial protocol. reducing to 33% of original dose.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During the “Proof of Principle” phase (months 0 – 6) patients will self administer Adalimumab subcutaneously at a dose of 40mg according to the protocol regime. During the Exploratory Phase (months 7 - 12) patients in the experimental groups will increase the time between injections until injections are stopped completely

    Arm title
    		 Group 3 Control Group
    Arm description
    		 Control group – patients continue on standard doses as prescribed prior to trial entry.
    Arm type
    		 Control

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50mg subcutaneously weekly as routine standard of care.

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab subcutaneously at a dose of 40mg as per routine standard of care.

    Number of subjects in period 1
    		Group 1 - TNF inhibitor tapered to 66% of initial dose Group 2 - TNF inhibitor tapered to 33% Group 3 Control Group
    Started
    21
    26
    50
    Completed
    21
    26
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 97 97
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 97 97
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 72 72
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    Group 1 - TNF inhibitor tapered to 66% of initial dose
    Reporting group description
    		 Experimental group 1 – patients have their TNF inhibitor tapered to 66% of initial dose by reducing frequency of dosing. Month 1 to 6 - TNF inhibitor tapered to 66% of initial dose. Month 7 to 12 - Time between injections increased on each occasion until injections are stopped completely.

    Reporting group title
    Group 2 - TNF inhibitor tapered to 33%
    Reporting group description
    		 Experimental group 2 - patients have their TNF inhibitor tapered to 33% of initial dose. Months 1 to 6 - patients have their TNF inhibitor tapered to 33% of initial dose. Months 7 to 12 - During the Exploratory Phase (months 7 - 12) patients in the experimental groups will increase the time between injections on each occasion until injections are stopped completely.

    Reporting group title
    Group 3 Control Group
    Reporting group description
    		 Control group – patients continue on standard doses as prescribed prior to trial entry.

    Primary: Development of flares

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    End point title
    		 Development of flares [1]
    End point description
    Development of flares, defined as an increase in DAS28 scores ≥ 0.6 [44].
    End point type
    Primary
    End point timeframe
    0 to 12 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See attached chart for results
    End point values
    		 Group 1 - TNF inhibitor tapered to 66% of initial dose Group 2 - TNF inhibitor tapered to 33% Group 3 Control Group
    Number of subjects analysed
    21
    26
    50
    Units: whole
    21
    26
    50
    Attachments
    		 Secondary Outcomes
    Flare Rates
    Adverse Event Data
    No statistical analyses for this end point

    Secondary: Secondary Outcome measures

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    End point title
    		 Secondary Outcome measures
    End point description
    DAS28 (tender and swollen joint counts, patient global (VAS), ESR) and Extended Joint Count 68/66 Simple disease activity score (SDAI) and clinical disease activity score (CDAI) [45] Health Assessment Questionnaire (HAQ) scores [46] Adverse events EuroQol scores [47] SF-36 Plain x-rays of the hands and feet scored by Larsen’s and van der Heijdi Sharpe Modified Scores (to provide preliminary data) Analysis of serum, immunological and gene expression profiles
    End point type
    Secondary
    End point timeframe
    0-12 months
    End point values
    		 Group 1 - TNF inhibitor tapered to 66% of initial dose Group 2 - TNF inhibitor tapered to 33% Group 3 Control Group
    Number of subjects analysed
    21
    26
    50
    Units: whole
    21
    26
    50
    Attachments
    		 Consort Flowchart
    Dosing Schedules
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    0-12 MONTHS
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Whole Trial
    Reporting group description
    		 All participants received either Etanacept or Adalimumab

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Please see uploaded Adverse Event chart.
    Serious adverse events
    		 Whole Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 97 (4.12%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Collapse - reason unidentified
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Otitis externa
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Whole Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 97 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2011
    Amendment to remove the requirementfor additional Clinical Trial labelling for the IMPs and NIMPs. Also to request return of excess TNF inhibitors at month 12 to patients (re-labelled with the routine dosing instructions) to avoid destruction and wastage of expensive IMPs.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28968858
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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