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    Clinical Trial Results:
    The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis Study Comparing the cost-effectiveness and safety of additional low-dose glucocorticoid in treatment strategies for elderly patients with rheumatoid arthritis

    Summary
    EudraCT number
    		 2015-002729-21
    Trial protocol
    		 DE   HU   SK   FI   PT  
    Global end of trial date
    28 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Feb 2022
    First version publication date
    05 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VUMC-ARC-GLORIA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02585258
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VU University Medical Center
    Sponsor organisation address
    de Boelelaan 1117, Amsterdam, Netherlands, 1081 HV
    Public contact
    Project Coordinator, VU University Medical Center, leonie@middelinc.com
    Scientific contact
    Scientific Lead, VU University Medical Center, 31 204444474, m.boers@amsterdamumc.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
    29 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    a) To assess the effectiveness, safety and cost-effectiveness of 2 years of low-dose GC therapy (5 mg/day) compared to placebo as co-treatment for elderly RA patients in a pragmatic randomized trial b) Study medication adherence through a medication packaging solution, and test the effectiveness of smart device technology to improve adherence
    Protection of trial subjects
    Informed Consent Procedure, trial insurance and no additional assessments than standard of care.
    Background therapy
    		 Standard of care treatment.
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    29 Jun 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: 285
    Country: Number of subjects enrolled
    Portugal: 26
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 60
    Country: Number of subjects enrolled
    Romania: 56
    Worldwide total number of subjects
    451
    EEA total number of subjects
    451
    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)
    0
    From 65 to 84 years
    441
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 From June 2016 to December 2018, 451 patients were randomised in the Gloria trial in 7 European countries, the majority (285) in The Netherlands.

    Pre-assignment
    Screening details
    		 Patients of 65 years of age and older with RA according to the 2010 classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), requiring antirheumatic therapy because of inadequate disease control, as evidenced by a disease activity score (DAS28) ≥2.60.

    Period 1
    Period 1 title
    Study duration (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Everybody involved in the trial was blinded, except for the unblinded monitor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active
    Arm description
    		 1 prednisolone 5 mg capsule / day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prednisolon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    daily 1 capsule

    Arm title
    		 Placebo
    Arm description
    		 1 placebo capsule per day
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 placebo capsule per day

    Number of subjects in period 1 [1]
    		Active Placebo
    Started
    224
    225
    Subjects completed 2 years
    141
    137
    subjects included in safety population
    224
    225
    Completed
    141
    137
    Not completed
    83
    88
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    42
    48
         Adverse event, non-fatal
    28
    29
         Lost to follow-up
    3
    -
         Lack of efficacy
    7
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: the baseline characteristics are reported for the safety population (n=449). This excludes two patients in the prednisolone group who withdrew consent and did not start study medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active
    Reporting group description
    		 1 prednisolone 5 mg capsule / day

    Reporting group title
    Placebo
    Reporting group description
    		 1 placebo capsule per day

    Reporting group values
    		 Active Placebo Total
    Number of subjects
    		 224 225 449
    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)
    		 72.5 ( 5.3 ) 72.6 ( 5.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 160 156 316
        Male
    		 64 69 133
    prior glucocorticoid therapy
    Units: Subjects
        prior GC therapy
    		 105 104 209
        no prior GC therapy
    		 119 121 240
    current DMARD therapy
    Units: Subjects
        current DMARD therapy
    		 169 187 356
        no current DMARD therapy
    		 55 38 93
    RF/anti-CCP
    This system cannot create categories that are non-mutually exclusive.
    Units: Subjects
        both negative
    		 57 45 102
        RF pos/aCCP neg
    		 48 46 94
        RF neg/aCCP pos
    		 13 19 32
        both positive
    		 106 115 221
    BMI
    body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.2 ( 4.5 ) 27.2 ( 4.4 ) -
    disease duration
    Units: years
        arithmetic mean (standard deviation)
    		 10.8 ( 10.4 ) 10.4 ( 10.2 ) -
    DAS28
    The reported data refer to the safety population (n=449)
    Units: score
        arithmetic mean (standard deviation)
    		 4.43 ( 1.04 ) 4.60 ( 1.05 ) -
    joint damage score (Sharp van der Heijde)-mean
    Units: score
        arithmetic mean (standard deviation)
    		 20.0 ( 34.6 ) 17.2 ( 33.4 ) -
    joint damage score (Sharp van der Heijde)-median-Q1Q3
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 7 (2 to 20) 6 (2 to 15) -

    End points

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    End points reporting groups
    Reporting group title
    Active
    Reporting group description
    		 1 prednisolone 5 mg capsule / day

    Reporting group title
    Placebo
    Reporting group description
    		 1 placebo capsule per day

    Subject analysis set title
    study duration-safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    In the safety analyses, all patients who took at least one dose of study medication are included.

    Subject analysis set title
    study duration-efficacy-modified ITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    in the modified intention to treat analysis, all subjects from the safety population are included that returned for at least one follow up assessment

    Primary: primary safety endpoint

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    End point title
    		 primary safety endpoint
    End point description
    The number of patients with at least one adverse event of special interest (AESI), determined in the safety population. AESI define as either serious adverse event (SAE), or one of the following: any AE (except loss of efficacy, worsening of disease) that leads to the definite cessation of trial medication; • a cardiovascular event (myocardial infarction, cerebrovascular event, peripheral arterial vascular event) • newly occurring hypertension requiring drug treatment; • newly occurring diabetes mellitus requiring drug treatment; • symptomatic bone fracture requiring treatment; • infection requiring antibiotic treatment; • newly occurring cataract or glaucoma.
    End point type
    Primary
    End point timeframe
    study duration
    End point values
    		 Active Placebo
    Number of subjects analysed
    224
    225
    Units: patients
        endpoint met (at least one AESI)
    134
    111
        endpoint not met
    90
    114
    Statistical analysis title
    		 primary harm outcome analysis
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [1]
    Method
    		 GEE
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 1.04
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [1] - one-sided.

    Primary: mean DAS28 change post baseline

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    End point title
    		 mean DAS28 change post baseline
    End point description
    Placebo group is reference. The negative sign of the treatment effect indicates that disease activity was lower in the prednisolone group. This system does not allow reporting of intermediate timepoints. See figure. The longitudinal model estimated the overall treatment effect on the change, adjusted for time point and stratification factors. The statistical analysis of change is given at 24 months.
    End point type
    Primary
    End point timeframe
    Measured at month 3,6,12,18,24 (mITT population).
    End point values
    		 Active Placebo
    Number of subjects analysed
    221
    223
    Units: score
        arithmetic mean (standard error)
    -0.37 ( 0.14 )
    0 ( 0 )
    Attachments
    		 Change in DAS28 over time (primary model)
    Statistical analysis title
    		 primary efficacy analysis (DAS28)
    Statistical analysis description
    analysis performed on the mITT population. Negative sign indicates disease activity decreased more in prednisolone than in placebo patients.
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [2] - one-sided.

    Secondary: change in Sharp van der Heijde damage score

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    End point title
    		 change in Sharp van der Heijde damage score
    End point description
    Change expressed as score at end of trial minus score at baseline.
    End point type
    Secondary
    End point timeframe
    study duration
    End point values
    		 Active Placebo
    Number of subjects analysed
    221
    223
    Units: score
        arithmetic mean (standard deviation)
    0.3 ( 1.0 )
    1.9 ( 6.4 )
    Statistical analysis title
    		 difference in damage progression
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.003 [4]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 0.7
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Notes
    [3] - The positive difference indicates that prednisolone patients had less damage progression than placebo.
    [4] - there is no comment, but the system generates an error on this field.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the ICF untill month 27.
    Adverse event reporting additional description
    AEs, AESIs and SAEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Prednisolone-Active
    Reporting group description
    		 Active treatment group

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Serious adverse events
    		 Prednisolone-Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 224 (24.55%)
    46 / 225 (20.44%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    neoplasms
         subjects affected / exposed
    9 / 224 (4.02%)
    7 / 225 (3.11%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Injury, poisoning and procedural complications
    injuries
         subjects affected / exposed
    3 / 224 (1.34%)
    6 / 225 (2.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac disorders
         subjects affected / exposed
    5 / 224 (2.23%)
    8 / 225 (3.56%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nervous system disorders
    neurvous system disorders
         subjects affected / exposed
    6 / 224 (2.68%)
    7 / 225 (3.11%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    general discorders
         subjects affected / exposed
    15 / 224 (6.70%)
    10 / 225 (4.44%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorder
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    6 / 224 (2.68%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    respiratory
         subjects affected / exposed
    7 / 224 (3.13%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    infections
         subjects affected / exposed
    22 / 224 (9.82%)
    12 / 225 (5.33%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prednisolone-Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    173 / 224 (77.23%)
    167 / 225 (74.22%)
    Blood and lymphatic system disorders
    total nonserious events
    Additional description: Nonserious events are not reported by SOC, this will be reported in the main scientific publication. However, this system does not accept that (ERROR messages preventing successful validation). Therefore, totals repeated here.
         subjects affected / exposed
    173 / 224 (77.23%)
    167 / 225 (74.22%)
         occurrences all number
    906
    669

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2019
    - adjustment of eligibility criteria (lower disease activity, and less stringent requirements for stable conc antirheumatic therapy) - strongly reduced sample size based on blinded interim analysis of the incidence of the primary outcome for harm.

    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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