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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy of Tocilizumab as a Remission-Induction and Glucocorticoid-Sparing Regimen in Subjects with New-Onset Polymyalgia Rheumatica (PMR-SPARE)

    Summary
    EudraCT number
    		 2016-004990-42
    Trial protocol
    		 AT  
    Global end of trial date
    02 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2021
    First version publication date
    14 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PMR-SPARE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Vienna, Department of Internal Medicine III
    Sponsor organisation address
    Währinger Gürtel 18-20, Vienna, Austria, 1090
    Public contact
    Principal Investigator, Department of Medicine III, Division of Rheumatology, daniel.aletaha@meduniwien.ac.at
    Scientific contact
    Principal Investigator - Daniel Aletaha, Department of Medicine III, Division of Rheumatology, +43 4040043000, daniel.aletaha@meduniwien.ac.at
    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
    02 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Objectives: To assess the efficacy and safety of a tocilizumab-based regimen compared with placebo on top of rapidly tapered GC treatment in a double-blind, controlled fashion, focusing on GC-free remission of disease. Methodology: In this double-blind, parallel group study, 36 patients with PMR will be recruited from three rheumatology centres and will be randomized in a 1:1 ratio to tocilizumab or placebo over the course of 16 weeks, accompanied by a rapid tapering GC scheme over 11 weeks in both arms. The primary endpoint is GC-free remission at week 16, and follow-up will be performed until week 24 for safety and sustained efficacy. Patients will receive either the subcutaneous preparation of 162 mg tocilizumab weekly or matching placebo injections.
    Protection of trial subjects
    The investigator informed each subject comprehensively regarding the nature, significance, impact and risks of this clinical trial. During this instruction the subjects were made aware of the fact that they can withdraw their consent – without giving reasons – at any time without their further medical care being influenced in any way. In addition, subjects also received a written patient information sheet in comprehensible language, explaining the nature and purpose of the study and its progress. The patient information sheet was approved by ethics committee. The consent form was signed and dated by the subject and the physician who conducted the informed consent discussion before any study related procedure was performed. Additionally, the subjects were given a copy of the signed informed consent form. The subjects had agreed to the possibility of study-related data being passed on to relevant authorities. According to the stipulations of the Austrian Data Protection Law, confidentiality and pseudonymity of the volunteers were assured. After giving written consent the subject underwent the first screening investigations. During their participation in the clinical trial all subjects were insured as defined by legal requirements. The investigator of the clinical trial received a copy of the insurance conditions and filed the copy in the Investigator Site file for reference. The sponsor provided insurance to indemnify (legal and financial coverage) the investigator/center against claims arising from the study, except for claims that arise from malpractice and/or negligence. The compensation of the subject in the event of study-related injuries complied with the applicable regulations.
    Background therapy
    		 All patients will be treated openly with 20 mg/day of prednisone at randomization. A pre-specified taper regimen will be followed over 11 weeks (for details on the taper regimen see Table 2). In case of relapse (as defined by the investigators, who were all also blinded to CRP/ESR results), patients in either the tocilizumab or placebo group, should increase the prednisone dose by 5 mg for 1 week. Given remission is then re-achieved, the GC dose will be tapered within 4 weeks to the pre-relapse dose (within this 4-weeks period tapering is conducted at the discretion of the investigator). Subsequently, the pre-specified tapering protocol will be followed again. In case remission is not achieved by the dose increment of 5mg, or relapses occur on GC doses >5mg, the GC dose may be further increased at the discretion of the investigator. Subsequent tapering will also be at the discretion of the physician until the pre-relapse dose is achieved. Then, the pre-specified protocol will be followed.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2017
    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
    Austria: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    10
    From 65 to 84 years
    25
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Diagnosis of PMR (at, or up to 2 weeks before the screening visit) as confirmed by the investigator at screening and at baseline + fulfilment of the provisional 2012 ACR-EULAR classification criteria + GC naïve or on GC treatment for a maximum of 2 weeks at screening with an initial dose between 12.5 and 25 mg/day prednisone.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding was maintained throughout the 24-week treatment phase of this study by the provision of tocilizumab and matching placebo for tocilizumab in pre-filled syringes in a matching presentation for the first 16 weeks and maintenance of the blinding until week 24. The investigators involved in patient assessment remained blinded to the results of the fasting lipids, ALT/AST, CRP and ESR.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tocilizumab 162mg s.c. once weekly
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tocilizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    162mg of Tocilizumab were administered subcutaneously via self-injection for 16 weeks.

    Arm title
    		 Placebo s.c. once weekly
    Arm description
    		 Placebo injections were administered via self-injection every week.
    Arm type
    		 Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Started
    19
    17
    Completed
    16
    11
    Not completed
    3
    6
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    -
    4
         Lost to follow-up
    1
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tocilizumab 162mg s.c. once weekly
    Reporting group description
    		 -

    Reporting group title
    Placebo s.c. once weekly
    Reporting group description
    		 Placebo injections were administered via self-injection every week.

    Reporting group values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly Total
    Number of subjects
    		 19 17 36
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.8 ( 9.0 ) 71.1 ( 9.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 9 19
        Male
    		 9 8 17
    Disease duration at screening
    Units: day
        arithmetic mean (standard deviation)
    		 8 ( 5 ) 6 ( 3 ) -
    C-reactive protein
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 1.6 ( 2.4 ) 0.98 ( 1.5 ) -
    Patients assessment of pain
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    		 30.8 ( 26.0 ) 22.8 ( 16.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Tocilizumab 162mg s.c. once weekly
    Reporting group description
    		 -

    Reporting group title
    Placebo s.c. once weekly
    Reporting group description
    		 Placebo injections were administered via self-injection every week.

    Primary: Patients in glucocorticoid-free remission at wk 16

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    End point title
    		 Patients in glucocorticoid-free remission at wk 16
    End point description
    The primary efficacy endpoint was the achievement of glucocorticoid-free remission at week 16.
    End point type
    Primary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: Patients
        Glucocorticoid-free remission
    12
    2
    Statistical analysis title
    		 GC-free remission (wk 16)
    Statistical analysis description
    The primary and key secondary endpoints were tested between the groups using either Fisher’s exact tests for categorical variables, Kruskal-Wallis tests for non-normally distributed continuous data, or Kaplan-Meier estimator for time-to-event data. To control for type I error of the secondary endpoints, we applied a strategy of hierarchical testing, by which hypothesis testing continues until reaching the first non-significance.
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Patients in glucocorticoid-free remission at wk 12

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    End point title
    		 Patients in glucocorticoid-free remission at wk 12
    End point description
    To control for type I error of the secondary endpoints, we applied a strategy of hierarchical testing, by which hypothesis testing continues until reaching the first non-significance. The pre-determined hierarchy for testing secondary endpoints was: proportion of subjects in glucocorticoid-free remission at week 12  proportion of subjects in glucocorticoid-free remission at week 24 -> time to first relapse -> cumulative dose of prednisone at week 16 -> cumulative dose of prednisone at week 24 -> proportion of subjects with increased ESR >20mm/h, or increased CRP levels >5mg/L at week 24 -> patient pain (VAS) at week 16 -> patient global assessment of disease activity (VAS) at week 16 -> Evaluator global assessment (VAS) at week 16 -> SF-36 at week 16 -> HAQ at week 16.
    End point type
    Secondary
    End point timeframe
    at week 12
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: Patients
        Glucocorticoid-free remission at week 12
    11
    3
    Statistical analysis title
    		 Glucocorticoid-free remission at week 12
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Patients in glucocorticoid-free remission at wk 24

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    End point title
    		 Patients in glucocorticoid-free remission at wk 24
    End point description
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: Patients
        Glucocorticoid-free remission at week 24
    11
    3
    Statistical analysis title
    		 Glucocorticoid-free remission at week 24
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to first relapse (days)

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    End point title
    		 Time to first relapse (days)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: day
        arithmetic mean (standard error)
    130 ( 13 )
    82 ( 11 )
    Statistical analysis title
    		 Time to first relapse (days)
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Cumulative prednisone dose (wk 16)

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    End point title
    		 Cumulative prednisone dose (wk 16)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    727 (721 to 842)
    935 (861 to 1244)
    Statistical analysis title
    		 Cumulative prednisone dose at week 16
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Cumulative prednisone dose (wk 24)

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    End point title
    		 Cumulative prednisone dose (wk 24)
    End point description
    End point type
    Secondary
    End point timeframe
    baseline to week 24
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: milligram(s)
        median (inter-quartile range (Q1-Q3))
    781 (721 to 972)
    1290 (1106 to 1809)
    Statistical analysis title
    		 Cumulative prednisone dose at week 24
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: subjects with increased ESR or CRP at wk 24

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    End point title
    		 subjects with increased ESR or CRP at wk 24
    End point description
    subjects with increased ESR (>20mm/h) or increased CRP (> 5mg/L)
    End point type
    Secondary
    End point timeframe
    at week 24
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: Patients
        Increased ESR (>20mm/h) at week 24
    4
    8
        Increased CRP (>5mg/L) at week 24
    8
    9
    Statistical analysis title
    		 Subjects with increased ESR (>20mm/h) at wk 24
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - not significant
    Statistical analysis title
    		 subjects with increased CRP (> 5mg/L) at wk 24
    Comparison groups
    Tocilizumab 162mg s.c. once weekly v Placebo s.c. once weekly
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - not significant

    Secondary: Pain (VAS) at wk 16

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    End point title
    		 Pain (VAS) at wk 16
    End point description
    End point type
    Secondary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    12 (4 to 29)
    15 (1.5 to 45.5)
    No statistical analyses for this end point

    Secondary: Patient global assessement (VAS) at wk 16

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    End point title
    		 Patient global assessement (VAS) at wk 16
    End point description
    End point type
    Secondary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    8 (3 to 25)
    16 (3 to 50)
    No statistical analyses for this end point

    Secondary: Evaluator global assessment (VAS) at wk 16

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    End point title
    		 Evaluator global assessment (VAS) at wk 16
    End point description
    End point type
    Secondary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: millimeter(s)
        median (inter-quartile range (Q1-Q3))
    2 (0 to 6)
    5 (1 to 30)
    No statistical analyses for this end point

    Secondary: Short Form-36 (Physical Component Score) at wk 16

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    End point title
    		 Short Form-36 (Physical Component Score) at wk 16
    End point description
    End point type
    Secondary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: Physical Component Score
        median (inter-quartile range (Q1-Q3))
    56.3 (48.8 to 61.0)
    46.9 (42.2 to 49.8)
    No statistical analyses for this end point

    Secondary: Health Assessment Questionnaire (0-3) at wk 16

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    End point title
    		 Health Assessment Questionnaire (0-3) at wk 16
    End point description
    End point type
    Secondary
    End point timeframe
    at week 16
    End point values
    		 Tocilizumab 162mg s.c. once weekly Placebo s.c. once weekly
    Number of subjects analysed
    19
    17
    Units: HAQ-DI
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0.5)
    0.88 (0.13 to 1.13)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Adverse event reporting additional description
    In total, 19 patients were exposed to tocilizumab treatment (162mg s.c. every week) and 17 patients received placebo treatment in the course of this study. As shown in Table 7, the total in-trial duration was 8.2 patient years for the tocilizumab group and 6.3 patient years for the placebo group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Tocilizumab 162mg s.c. every week
    Reporting group description
    		 -

    Reporting group title
    Placebo s.c. every week
    Reporting group description
    		 -

    Serious adverse events
    		 Tocilizumab 162mg s.c. every week Placebo s.c. every week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    5 / 17 (29.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Giant cell arteritis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Heat stroke
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Tocilizumab 162mg s.c. every week Placebo s.c. every week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 19 (78.95%)
    14 / 17 (82.35%)
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    3 / 19 (15.79%)
    4 / 17 (23.53%)
         occurrences all number
    6
    6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
    Additional description: musculoskeletal complains not related to polymyalgia rheumatica disease activity by discretion of investigator
         subjects affected / exposed
    0 / 19 (0.00%)
    7 / 17 (41.18%)
         occurrences all number
    0
    7
    Infections and infestations
    Infection
         subjects affected / exposed
    12 / 19 (63.16%)
    6 / 17 (35.29%)
         occurrences all number
    17
    6

    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.
    None reported
    For support, Contact us.
    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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