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    Clinical Trial Results:
    A Phase 2a, Randomised, Double-blind, Parallel Study to Assess the Efficacy, Safety and Tolerability of AZD9567 compared to Prednisolone 20 mg in patients with active Rheumatoid Arthritis (RA)

    Summary
    EudraCT number
    		 2017-000838-64
    Trial protocol
    		 NL   DK  
    Global end of trial date
    12 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2020
    First version publication date
    27 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D6470C00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03368235
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, SE-151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.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
    Interim
    Date of interim/final analysis
    06 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of AZD9567 40 milligram (mg), compared to prednisolone 20 mg in participants with active rheumatoid arthritis (RA) in spite of stable treatment with conventional and/or subcutaneous or intravenous biological disease-modifying anti-rheumatic drugs (DMARDs).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jan 2018
    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: 16
    Country: Number of subjects enrolled
    Sweden: 5
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    15
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase 2a study conducted in participants with active RA in spite of stable treatment with conventional DMARDs at 5 investigational sites across Sweden and The Netherlands between 18 January 2018 and 12 November 2019.

    Pre-assignment
    Screening details
    		 A total of 21 participants were randomized in a 1:1 ratio to take either AZD9567 or prednisolone in a 2-week double-blind, double-dummy treatment period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZD9567
    Arm description
    		 Participants received AZD9567 40 mg oral suspension and placebo capsules matching with prednisolone, orally once daily, for 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matching with prednisolone orally once daily for 2 weeks.

    Investigational medicinal product name
    AZD9567
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    AZD9567 40 mg oral suspension once daily for 2 weeks.

    Arm title
    		 Prednisolone
    Arm description
    		 Participants received prednisolone 20 mg oral capsules and placebo oral suspension matching with AZD9567, once daily for 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisolone 20 mg capsule orally once daily for 2 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching with AZD9567 oral suspension once daily for 2 weeks.

    Number of subjects in period 1
    		AZD9567 Prednisolone
    Started
    11
    10
    Completed
    11
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZD9567
    Reporting group description
    		 Participants received AZD9567 40 mg oral suspension and placebo capsules matching with prednisolone, orally once daily, for 2 weeks.

    Reporting group title
    Prednisolone
    Reporting group description
    		 Participants received prednisolone 20 mg oral capsules and placebo oral suspension matching with AZD9567, once daily for 2 weeks.

    Reporting group values
    		 AZD9567 Prednisolone Total
    Number of subjects
    		 11 10 21
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 7 8 15
        From 65-84 years
    		 4 2 6
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 8.41 ) 55.5 ( 13.58 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 8 5 13
        Male
    		 3 5 8
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 11 10 21
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 11 10 21
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    AZD9567
    Reporting group description
    		 Participants received AZD9567 40 mg oral suspension and placebo capsules matching with prednisolone, orally once daily, for 2 weeks.

    Reporting group title
    Prednisolone
    Reporting group description
    		 Participants received prednisolone 20 mg oral capsules and placebo oral suspension matching with AZD9567, once daily for 2 weeks.

    Primary: Least Square (LS) Mean Change From Baseline in 28 Joint Disease Activity Score Using C-Reactive Protein (DAS28-CRP) at Day 15

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    End point title
    		 Least Square (LS) Mean Change From Baseline in 28 Joint Disease Activity Score Using C-Reactive Protein (DAS28-CRP) at Day 15
    End point description
    The DAS28-CRP is a measure of disease activity in RA. The score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment (PGA) of health (ranging from very well to very poor). The DAS28-CRP was derived as follows: 0.56 x √[tender joint count 28 (TJC28)] + 0.28 x √[swollen joint count 28 (SJC28)] + 0.014 x global health (GH) + 0.36 x Ln(CRP+1) + 0.96 to produce the overall DAS28-CRP score on a scale ranged from 0-10 with higher score indicating worse RA symptoms. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The Full analysis set (FAS) included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -1.931 ( 0.3460 )
    -2.403 ( 0.3373 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Statistical analysis description
    MMRM = mixed model repeated measures.
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.315 [1]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.472
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.487
         upper limit
    		 1.431
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4569
    Notes
    [1] - Based on MMRM model with the baseline DAS28-CRP score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: Percentage of Participants Achieving American College of Rheumatology (ACR) 20, ACR50 and ACR70 Responses

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    End point title
    		 Percentage of Participants Achieving American College of Rheumatology (ACR) 20, ACR50 and ACR70 Responses
    End point description
    The ACR20, ACR50 or ACR70 was achieved if there was at least a 20%, 50% or 70% improvement from baseline in swollen joint count 66 (SJC66) and tender joint count 68 (TJC68) and 3 or more of the 5 following assessments: participant's assessment of pain, GH, physician’s global assessment of disease activity, participant's assessment of physical function and CRP. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment. Participants with missing ACR assessment at Day 15 were considered as non-responders in the respective analysis.
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: percentage of participants
    number (not applicable)
        ACR20
    63.6
    70.0
        ACR50
    36.4
    70.0
        ACR70
    18.2
    50.0
    Statistical analysis title
    		 Treatment comparison ACR20:AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.807 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.807
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 5.34
    Notes
    [2] - Logistic regression model with the treatment group, country and baseline DAS28-CRP as covariate.
    Statistical analysis title
    		 Treatment comparison ACR70:AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.183
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Treatment comparison ACR50:AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.198
    Method
    		 Fisher exact
    Confidence interval

    Secondary: LS Mean Change From Baseline in SJC66 Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in SJC66 Score at Day 15
    End point description
    A total of 66 joints (33 left, 33 right) were evaluated for swelling. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC66 was calculated as sum of swollen joints with present status on electronic case report form (eCRF). The swollen joint count ranged from 0-66 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -6.24 ( 0.894 )
    -6.66 ( 0.860 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.717 [3]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.98
         upper limit
    		 2.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.136
    Notes
    [3] - The MMRM with the baseline SJC66 score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in TJC68 Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in TJC68 Score at Day 15
    End point description
    A total of 68 joints (34 left, 34 right) were evaluated for tenderness. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC68 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-68 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -9.02 ( 2.463 )
    -7.90 ( 2.362 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.724 [4]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.69
         upper limit
    		 5.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.115
    Notes
    [4] - The MMRM with the baseline TJC68 score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in TJC28 Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in TJC28 Score at Day 15
    End point description
    TJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for tenderness as obtained from the joint count right or left eCRF. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC28 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -6.12 ( 1.251 )
    -6.07 ( 1.208 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.973 [5]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.43
         upper limit
    		 3.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.6
    Notes
    [5] - The MMRM with the baseline TJC28 score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in SJC28 Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in SJC28 Score at Day 15
    End point description
    SJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for swelling as obtained from the joint count right or left eCRF. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC28 was calculated as sum of swollen joints with present status on eCRF. The swollen joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -5.14 ( 0.653 )
    -5.40 ( 0.628 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.757 [6]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 2.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.837
    Notes
    [6] - The MMRM with the baseline SJC28 score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in GH Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in GH Score at Day 15
    End point description
    GH was evaluated as one of the components that comprised the DAS28-score. Participant's GH was measured using PGA of disease activity by means of the visual analogue scale (VAS). The PGA VAS consists of a 100 millimeter (mm) long scale ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -27.7 ( 7.26 )
    -37.4 ( 7.11 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.325 [7]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 30.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.67
    Notes
    [7] - The MMRM with the baseline GH score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in CRP at Day 15

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    End point title
    		 LS Mean Change From Baseline in CRP at Day 15
    End point description
    CRP was evaluated as one of the components that comprised the DAS28-score. The CRP was collected at the local laboratory during screening and central laboratory on Days 1, 8, 15 and 28. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: mg per liter (L)
        least squares mean (standard error)
    -10.830 ( 2.4207 )
    -15.586 ( 2.5245 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.187 [8]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    4.756
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.514
         upper limit
    		 12.025
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4725
    Notes
    [8] - The MMRM with the baseline CRP score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in Participant's Assessment of Pain Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in Participant's Assessment of Pain Score at Day 15
    End point description
    Participant's assessment of pain score was evaluated as one of the components that comprised the ACR. Participant's assessment of pain score was assessed from the amount of pain due to RA on a VAS ranging from 0 (no pain) to 100 (extreme pain). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -27.3 ( 8.17 )
    -43.4 ( 7.71 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.144 [9]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 38.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.49
    Notes
    [9] - The MMRM with the baseline participant's assessment of pain score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in Physician’s Global Assessment of Disease Activity Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in Physician’s Global Assessment of Disease Activity Score at Day 15
    End point description
    Physician's global assessment of disease activity score was evaluated as one of the components that comprised the ACR. The physician's global assessment of disease activity was measured on a VAS ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -37.0 ( 4.38 )
    -40.9 ( 4.30 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.512 [10]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 16
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.73
    Notes
    [10] - The MMRM with the baseline disease activity score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: LS Mean Change From Baseline in Participant's Assessment of Physical Function Score at Day 15

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    End point title
    		 LS Mean Change From Baseline in Participant's Assessment of Physical Function Score at Day 15
    End point description
    Participant's assessment of physical function score was evaluated as one of the components that comprised the ACR. The participant's assessment of physical function across 8 functional areas was measured by health assessment questionnaire. The total score ranging from 0 (no difficulty) to 24 (inability to perform tasks). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment. The FAS included all participants who were randomized and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 AZD9567 Prednisolone
    Number of subjects analysed
    11
    10
    Units: score on a scale
        least squares mean (standard error)
    -0.441 ( 0.1758 )
    -0.571 ( 0.1712 )
    Statistical analysis title
    		 Treatment comparison: AZD9567 Vs prednisolone
    Comparison groups
    AZD9567 v Prednisolone
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.589 [11]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.131
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.631
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2381
    Notes
    [11] - The MMRM with the baseline physical function score as a continuous covariate and country, visit and treatment group as categorical fixed effects, as well as visit interaction with treatment group, using unstructured covariance matrix.

    Secondary: Area Under the Plasma Concentration-Time Curve Until the Last Quantifiable Concentration (AUClast) of AZD9567

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    End point title
    		 Area Under the Plasma Concentration-Time Curve Until the Last Quantifiable Concentration (AUClast) of AZD9567 [12]
    End point description
    The AUClast was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased. The Pharmacokinetic (PK) analysis set included all participants with at least 1 quantifiable AZD9567 concentration with a documented related dosing history.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
    Notes
    [12] - 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: This endpoint was only assessed in participants randomized to AZD9567 reporting group.
    End point values
    		 AZD9567
    Number of subjects analysed
    11
    Units: hour*nanomole per L (h*nmol/L)
        geometric mean (geometric coefficient of variation)
    17800 ( 35.02 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From Time Zero to 6 Hours After Dose (AUC0-6) of AZD9567

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    End point title
    		 Area Under the Concentration-Time Curve From Time Zero to 6 Hours After Dose (AUC0-6) of AZD9567 [13]
    End point description
    The AUC0-6 was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased. The PK analysis set included all participants with at least 1 quantifiable AZD9567 concentration with a documented related dosing history.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
    Notes
    [13] - 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: This endpoint was only assessed in participants randomized to AZD9567 reporting group.
    End point values
    		 AZD9567
    Number of subjects analysed
    11
    Units: h*nmol/L
        geometric mean (geometric coefficient of variation)
    17740 ( 35.34 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of AZD9567

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of AZD9567 [14]
    End point description
    The Cmax of AZD9567 was determined using non-compartmental method. The PK analysis set included all participants with at least 1 quantifiable AZD9567 concentration with a documented related dosing history.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
    Notes
    [14] - 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: This endpoint was only assessed in participants randomized to AZD9567 reporting group.
    End point values
    		 AZD9567
    Number of subjects analysed
    11
    Units: nmol/L
        geometric mean (geometric coefficient of variation)
    4468 ( 26.89 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration (tmax) of AZD9567

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    End point title
    		 Time to Reach Maximum Plasma Concentration (tmax) of AZD9567 [15]
    End point description
    The tmax of AZD9567 was determined using non-compartmental method. The PK analysis set included all participants with at least 1 quantifiable AZD9567 concentration with a documented related dosing history.
    End point type
    Secondary
    End point timeframe
    Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
    Notes
    [15] - 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: This endpoint was only assessed in participants randomized to AZD9567 reporting group.
    End point values
    		 AZD9567
    Number of subjects analysed
    11
    Units: hour
        median (full range (min-max))
    0.67 (0.33 to 1.03)
    No statistical analyses for this end point

    Secondary: Last Plasma Concentration Measured Before the Last Dose (Ctrough) of AZD9567

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    End point title
    		 Last Plasma Concentration Measured Before the Last Dose (Ctrough) of AZD9567 [16]
    End point description
    The Ctrough of AZD9567 was determined using non-compartmental method before the last dose on Day 15. The PK analysis set included all participants with at least 1 quantifiable AZD9567 concentration with a documented related dosing history. 99999 = not calculable due to a zero predose value.
    End point type
    Secondary
    End point timeframe
    Predose on Day 15
    Notes
    [16] - 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: This endpoint was only assessed in participants randomized to AZD9567 reporting group.
    End point values
    		 AZD9567
    Number of subjects analysed
    11
    Units: nmol/L
        geometric mean (geometric coefficient of variation)
    99999 ( 95.67 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study treatment (Day 1) up to 2 weeks after last administration of study treatment, approximately 28 days.
    Adverse event reporting additional description
    The Safety analysis set included all participants who were randomized and received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    AZD9567
    Reporting group description
    		 Participants received AZD9567 40 mg oral suspension and placebo capsules matching with prednisolone, orally once daily, for 2 weeks.

    Reporting group title
    Prednisolone
    Reporting group description
    		 Participants received prednisolone 20 mg oral capsules and placebo oral suspension matching with AZD9567, once daily for 2 weeks.

    Serious adverse events
    		 AZD9567 Prednisolone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Depression suicidal
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 AZD9567 Prednisolone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 11 (90.91%)
    9 / 10 (90.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Thirst
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Mood swings
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Eye pain
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Periorbital swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Oral discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Skin atrophy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Eye infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Oral herpes
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2017
    Modification of AZD9567 dose from 80 to 40 mg.
    19 Mar 2019
    Increase in number of sites from 4-6 to maximum of 10. Addition of erythrocyte sedimentation rate under laboratory (hematology) assessments. Amendment of Appendix D “Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy´s Law” to implement the new reporting process regarding potential Hy's law.

    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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