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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Sarilumab in Patients with Polymyalgia Rheumatica

    Summary
    EudraCT number
    		 2017-002989-42
    Trial protocol
    		 DK   DE   BE   FR   HU   GB   EE   NL   ES   IT  
    Global end of trial date
    19 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2022
    First version publication date
    02 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15160
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03600818
    WHO universal trial number (UTN)
    		 U1111-1201-0777
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    Final
    Date of interim/final analysis
    07 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of KEVZARA® (sarilumab) in subjects with polymyalgia rheumatica (PMR) as assessed by the proportion of subjects with sustained remission at Week 52 for sarilumab with a 14 weeks corticosteroid (CS) tapering regimen as compared to placebo with a 52 weeks CS tapering regimen.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 All subjects were required to be on greater than or equal to (>=) 7.5 milligrams (mg) of oral CS daily.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 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
    Estonia: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Russian Federation: 4
    Worldwide total number of subjects
    118
    EEA total number of subjects
    58
    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)
    31
    From 65 to 84 years
    85
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 78 active centres (randomised at least 1 subject) in 17 countries. A total of 196 subjects were screened between 09 October 2018 and 19 March 2020, of whom 78 were screen failures. Screen failures were mainly due to not meeting inclusion criteria.

    Pre-assignment
    Screening details
    		 Subjects were randomised to two treatment groups in a 1:1 ratio by interactive response technology. A total of 118 subjects were enrolled and randomised in the study.

    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, Assessor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo+52 Week taper
    Arm description
    		 Subjects received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone or Prednisone matched to placebo tapering oral doses daily for 52 weeks according to the protocol-defined schedule.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to sarilumab, single SC injection q2w for 52 weeks.

    Arm title
    		 Sarilumab 200mg q2w+14 Week Taper
    Arm description
    		 Subjects received sarilumab 200 mg as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sarilumab 200 mg
    Investigational medicinal product code
    SAR153191, REGN88
    Other name
    Kevzara®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sarilumab 200 mg, single SC injection q2w for 52 weeks.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone or Prednisone matched to placebo tapering oral doses daily for 52 weeks according to the protocol-defined schedule.

    Number of subjects in period 1
    		Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Started
    58
    60
    Safety analysis set
    58
    59
    Completed
    36
    42
    Not completed
    22
    18
         Randomised and not treated
    -
    1
         Other-unspecified
    5
    3
         Adverse event
    4
    7
         Lack of efficacy
    9
    4
         Withdrawal by subject
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo+52 Week taper
    Reporting group description
    		 Subjects received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks.

    Reporting group title
    Sarilumab 200mg q2w+14 Week Taper
    Reporting group description
    		 Subjects received sarilumab 200 mg as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52.

    Reporting group values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper Total
    Number of subjects
    		 58 60
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.1 ( 8.5 ) 68.8 ( 7.8 ) -
    Gender categorical
    Units: Subjects
        Male
    		 21 15 36
        Female
    		 37 45 82
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 48 50 98
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 8 9 17

    End points

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    End points reporting groups
    Reporting group title
    Placebo+52 Week taper
    Reporting group description
    		 Subjects received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks.

    Reporting group title
    Sarilumab 200mg q2w+14 Week Taper
    Reporting group description
    		 Subjects received sarilumab 200 mg as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52.

    Primary: Percentage of Subjects Achieving Sustained Remission at Week 52

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    End point title
    		 Percentage of Subjects Achieving Sustained Remission at Week 52
    End point description
    Sustained remission was defined as meeting all of the following parameters: achievement of disease remission (defined as resolution of signs and symptoms of PMR, and normalisation of C-reactive protein [CRP] [less than {<}10 milligrams per litre {mg/L}]) not later than Week 12, absence of disease flare (defined as recurrence of signs and symptoms attributable to active PMR plus an increase in CS dose due to PMR or elevation of erythrocyte sedimentation rate [ESR] attributable to active PMR plus an increase in CS dose due to PMR) from Week 12 through Week 52, sustained reduction of CRP (to <10 mg/L, with absence of successive elevations to >=10 mg/L) from Week 12 through Week 52, and successful adherence to prednisone taper from Week 12 through Week 52. Intent-to-treat (ITT) population that included all subjects who were allocated to a randomised treatment group and were analysed according to treatment group allocated.
    End point type
    Primary
    End point timeframe
    At Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: percentage of subjects
        number (not applicable)
    10.3
    28.3
    Statistical analysis title
    		 Sarilumab versus Placebo
    Comparison groups
    Placebo+52 Week taper v Sarilumab 200mg q2w+14 Week Taper
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0193 [1]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentage
    Point estimate
    18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.15
         upper limit
    		 31.82
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Total Cumulative Corticosteroid Dose

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    End point title
    		 Total Cumulative Corticosteroid Dose
    End point description
    Cumulative dose of CS used for PMR disease was defined as the dose taken up to the end of treatment, including expected prednisone in tapering regimen per protocol, add-on prednisone, CS used in rescue therapy and the use of commercial prednisone (an excess of less than or equal to [<=]100 mg of prednisone during the study treatment period). The total cumulative CS dose was based on the total number of days with complete or partial intake, no imputation was done on missed tablets. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    59
    Units: milligrams
        arithmetic mean (standard deviation)
    2235.8 ( 839.4 )
    1039.5 ( 612.2 )
    Statistical analysis title
    		 Sarilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. If the primary endpoint reaches statistical significance then the secondary endpoint for total cumulative CS dose was tested next.
    Comparison groups
    Placebo+52 Week taper v Sarilumab 200mg q2w+14 Week Taper
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Wilcoxon rank-sum test
    Confidence interval
    Notes
    [2] - Threshold for significance at 0.05 level.

    Secondary: Number of Subjects Who Achieved Disease Remission up to Week 12

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    End point title
    		 Number of Subjects Who Achieved Disease Remission up to Week 12
    End point description
    Disease remission was defined as resolution of signs and symptoms of PMR, and normalisation of CRP (< 10 mg/L). The status of normalisation of CRP (<10 mg/L) was determined based on the last two non-missing post-baseline CRP values measured up to Week 12. If at least one of the value was <10 mg/L, then it was considered as normalisation of CRP. Subjects who took rescue CS due to active PMR prior to Week 12 or who permanently withdrew from the study treatment prior to Week 12 were considered as not achieved disease remission by Week 12. During the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 was permitted if it was successfully treated with a low dose (<=5 mg/day) prednisone add-on taper regimen (completed prior to Week 12) and provided that all other sustained remission parameters were met. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: subjects
    22
    28
    No statistical analyses for this end point

    Secondary: Number of Subjects With Absence of Disease Flare From Week 12 Through Week 52

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    End point title
    		 Number of Subjects With Absence of Disease Flare From Week 12 Through Week 52
    End point description
    Disease flare was defined as either recurrence of signs and symptoms attributable to active PMR plus an increase in CS dose due to PMR, or elevation of ESR attributable to active PMR plus an increase in CS dose due to PMR. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Week 12 Through Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: subjects
    19
    33
    No statistical analyses for this end point

    Secondary: Number of Subjects With Sustained Reduction of CRP From Week 12 Through Week 52

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    End point title
    		 Number of Subjects With Sustained Reduction of CRP From Week 12 Through Week 52
    End point description
    Normalisation (sustained reduction) of CRP was defined as CRP levels <10 mg/L. If there were two or more consecutive visits with CRP >=10 mg/L, then it was categorised as no normalisation of CRP. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Week 12 through Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: subjects
    26
    40
    No statistical analyses for this end point

    Secondary: Number of Subjects With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52

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    End point title
    		 Number of Subjects With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52
    End point description
    Successful adherence to the prednisone taper from Week 12 through Week 52 was defined as subjects who did not take rescue therapy from Week 12 through Week 52 and any excess prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of <=100 mg (or equivalent), such as those employed to manage adverse event (AE) not related to PMR. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Week 12 through Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: subjects
    14
    30
    No statistical analyses for this end point

    Secondary: Time to First Polymyalgia Rheumatica Flare After Clinical Remission up to Week 52

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    End point title
    		 Time to First Polymyalgia Rheumatica Flare After Clinical Remission up to Week 52
    End point description
    Time to first PMR flare was defined as the duration (in days) from randomisation to first PMR flare after clinical remission (defined as resolution of signs and symptoms and normalisation of CRP [<10 mg/L]) and up to 52 weeks. Disease flare was defined as either the recurrence of signs or symptoms attributable to active plus an increase in CS dose due to PMR or elevation of ESR attributable to active PMR plus an increase in CS dose due to PMR. Kaplan-Meier method was used for the analysis. Subjects who never achieved remission were censored at randomisation day; and those who achieved clinical remission and never flared were censored at the end of treatment assessment date up to Week 52. Analysis was performed on ITT population. Here, '99999' is used as a space filler which denotes that at Week 52 the cumulative incidence was less than 50% in the Kaplan-Meier plot. Hence, the upper limit of confidence interval and median value was not reached.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    60
    Units: days
        median (confidence interval 95%)
    99.00 (1.000 to 154.000)
    99999 (93.000 to 99999)
    No statistical analyses for this end point

    Secondary: Composite Glucocorticoid Toxicity Index (C-GTI): Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 52

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    End point title
    		 Composite Glucocorticoid Toxicity Index (C-GTI): Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 52
    End point description
    GTI assessed glucocorticoid (GC) related morbidity and GC-sparing ability of other therapies; composed of 2 components: C-GTI and Specific List. C-GTI contained 9 domains and Specific List contained 23 items (11 domains), used as complementary tool. C-GTI score; sum of 9 domain-specific scores at each visit and Cumulative GTI score; sum of C-GTI scores across each visit. 2 cumulative GTI scores: CWS and AIS at Week 52 are reported in this endpoint. CWS assessed cumulative GC toxicity regardless of whether toxicity had lasting effects or was transient. AIS assessed new therapy effectiveness in decreasing any Baseline GC toxicity over time. Negative scores reflect improvement in CS toxicities from Baseline. CWS, composite score ranged; 0 to 439 and for AIS, composite score ranged; -346 to 439. Both CWS and AIS, minimum score implies least toxicity and maximum score implies most toxicity. ITT. ‘Number of subjects analysed’=subjects evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    57
    60
    Units: units on a scale
    least squares mean (standard error)
        CWS
    57.22 ( 6.678 )
    52.32 ( 6.507 )
        AIS
    2.57 ( 6.275 )
    -4.02 ( 6.115 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious AEs (SAEs) were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalisation, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were the AEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the investigational medicinal product (IMP) to the last dose of the IMP +60 days). Analysis was performed on safety population that included all subjects who had received at least one dose or part of a dose of IMP and were analysed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e. Day 1) up to 60 days after last dose date of study drug (i.e. up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    59
    Units: subjects
        Any TEAE
    49
    56
        TESAE
    12
    8
    No statistical analyses for this end point

    Secondary: Number of Subjects with Potentially Clinically Significant Vital Signs Abnormalities During TEAE Period

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    End point title
    		 Number of Subjects with Potentially Clinically Significant Vital Signs Abnormalities During TEAE Period
    End point description
    Criteria for potentially clinically significant vital sign abnormalities: Systolic Blood Pressure (SBP): <= 95 millimeters of mercury (mmHg) and decrease from baseline (DFB) >= 20 mmHg; >= 160 mmHg and increase from baseline (IFB) >= 20 mmHg. Diastolic blood pressure (DBP): <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg. Heart Rate (HR): <= 50 beats per min (bpm) and DFB >=20 bpm; >=120 bpm and IFB >= 20 bpm. Weight: >=5% DFB; >=5% IFB. TEAE period was defined as the time from the first dose of the IMP to the last dose of the IMP +60 days. Analysis was performed on safety population. Here, 'number of subjects analysed' = subjects evaluable for this endpoint and ‘n’= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    58
    Units: subjects
        SBP <=95 mmHg and DFB >=20 mmHg (n=58,58)
    0
    2
        SBP >=160 mmHg and IFB >=20 mmHg (n=58,58)
    4
    5
        DBP <=45 mmHg and DFB >=10 mmHg (n=58,58)
    1
    0
        DBP >=110 mmHg and IFB >=10 mmHg (n=58,58)
    1
    1
        HR <=50 bpm and DFB >= 20 bpm (n=58,58)
    1
    0
        HR >=120 bpm and IFB >=20 bpm (n=58,58)
    1
    0
        Weight >=5% DFB (n=56,58)
    2
    5
        Weight >=5% IFB (n=56,58)
    9
    12
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities - Hematological Parameter

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities - Hematological Parameter
    End point description
    Criteria for potentially clinically significant laboratory abnormalities included: Hemoglobin (Hb): <= 115 grams per liter (g/L) (Male [M]), <= 95 g/L (Female [F]); >= 185 g/L (M), >= 165 g/L (F); DFB >= 20 g/L . Hematocrit: <= 0.37 volume/volume (v/v) (M); <= 0.32 v/v (F); >= 0.55 v/v (M); >= 0.5 v/v (F). Erythrocytes: >=6 Tera/ liter (L). Platelets: < 100 Giga/L, >= 700 Giga/L. Leukocytes: < 3.0 Giga/L (Non-Black [NB]); < 2.0 Giga/L (Black [B]), >= 16.0 Giga/L. Neutrophils: < 1.5 Giga/L (NB); < 1.0 Giga/L (B). Lymphocytes: > 4.0 Giga/L. Monocytes: > 0.7 Giga/L. Basophils: > 0.1 Giga/L. Eosinophils: > 0.5 Giga/L or > upper limit of normal (ULN) (if ULN >= 0.5 Giga/L). Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    57
    58
    Units: subjects
        Hb: <= 115 g/L (M), <= 95 g/L (F)
    1
    1
        Hb: >=185 g/L(M), >=165 g/L(F)
    0
    1
        Hb: DFB >=20 g/L
    3
    2
        Hematocrit: <= 0.37 v/v(M); <=0.32 v/v(F)
    1
    1
        Hematocrit: >=0.55 v/v(M); >=0.5 v/v(F)
    0
    0
        Erythrocytes: >=6 Tera/L
    0
    0
        Platelets: < 100 Giga/L
    0
    2
        Platelets: >= 700 Giga/L
    0
    0
        Leukocytes:<3.0Giga/L(NB); <2.0Giga/L(B)
    0
    11
        Leukocytes: >= 16.0 Giga/L
    1
    1
        Neutrophils:<1.5Giga/L(NB);<1.0Giga/L(B)
    0
    18
        Lymphocytes: > 4.0 Giga/L
    4
    2
        Monocytes: > 0.7 Giga/L
    12
    8
        Basophils: > 0.1 Giga/L
    16
    13
        Eosinophils:>0.5 Giga/L; >ULN (if ULN>=0.5Giga/L)
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities - Metabolic Parameters
    End point description
    Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 millimoles per liter (mmol/L) and < lower limit of normal (LLN); >=11.1 mmol/L (unfasted [ufas]); >=7 mmol/L (fasted [fas]). HbA1c: >8%. Cholesterol: >=7.74 mmol/L. Triglycerides: >=4.6 mmol/L. C Reactive Protein (CRP): >2 ULN or >10 mg/L (if ULN not provided). Analysis was performed on safety population. Here, 'number of subjects analysed' = subjects evaluable for this endpoint and ‘n’= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    58
    Units: subjects
        Glucose: <=3.9 mmol/L and <LLN (n=56,57)
    1
    2
        Glucose:>=11.1mmol/L(ufas)/>=7mmol/L(fas)(n=56,57)
    14
    5
        HbA1c: >8% (n=58,58)
    4
    2
        Cholesterol: >=7.74 mmol/L (n=58,58)
    4
    8
        Triglycerides: >=4.6 mmol/L (n=58,58)
    1
    3
        CRP: >2 ULN or >10 mg/L (n=58,58)
    37
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities - Renal Function
    End point description
    Criteria for potentially clinically significant abnormalities: Creatinine: >=150 micromol/L (adults); >=30% change from Baseline, >=100% change from Baseline. Creatinine clearance: >=60 to <90 milliliters per minute (mL/min); >=30 to <60 mL/min; >=15 to <30 mL/min; <15 mL/min. Blood urea nitrogen: >=17 mmol/L. Urate: <120 micromol/L; >408 micromol/L. Analysis was performed on safety population. Here, ‘number of subjects analysed’= subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    58
    Units: subjects
        Creatinine: >=150 micromol/L (adults)
    2
    2
        Creatinine: >=30% change from Baseline
    3
    14
        Creatinine: >=100% change from Baseline
    0
    1
        Creatinine clearance: >=60 to <90 mL/min
    30
    29
        Creatinine clearance: >=30 to <60 mL/min
    13
    17
        Creatinine clearance: >=15 to <30 mL/min
    0
    1
        Creatinine clearance: <15 mL/min
    0
    0
        Blood urea nitrogen: >=17 mmol/L
    0
    0
        Urate: <120 micromol/L
    0
    0
        Urate: >408 micromol/L
    16
    16
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Abnormalities - Liver Function
    End point description
    Criteria for potentially clinically significant abnormalities: Albumin: <= 25 g/L. Alanine Aminotransferase (ALT): >3 ULN; >5 ULN; >10 ULN. Aspartate Aminotransferase (AST): >3 ULN; >5 ULN; >10 ULN; >20 ULN. Alkaline Phosphatase: >1.5 ULN. Bilirubin: >1.5 ULN; >2 ULN. ALT and Total Bilirubin: ALT > 3 ULN and Bilirubin > 2 ULN Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    58
    Units: subjects
        Albumin: <= 25 g/L
    0
    0
        ALT: >3 ULN
    2
    0
        ALT: >5 ULN
    1
    0
        ALT: >10 ULN
    0
    0
        AST: >3 ULN
    1
    0
        AST: >5 ULN
    1
    0
        AST: >10 ULN
    1
    0
        AST: >20 ULN
    0
    0
        Alkaline Phosphatase: >1.5 ULN
    1
    0
        Bilirubin: >1.5 ULN
    1
    1
        Bilirubin: >2 ULN
    0
    0
        ALT > 3 ULN and Bilirubin > 2 ULN
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Antidrug Antibodies (ADA) Response

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    End point title
    		 Number of Subjects With Treatment-emergent Antidrug Antibodies (ADA) Response
    End point description
    ADA response categories: 1) Treatment-boosted ADA positive subject: Subject with a positive ADA assay response at Baseline and with at least a 4-fold increase in titer compared to Baseline during TEAE period. 2) Treatment-emergent ADA positive subject: Subject with non-positive assay (meaning negative or missing) response at Baseline but with a positive assay response during the TEAE period (defined as the time from the first dose of the IMP to the last dose of the IMP +60 days). Analysis was performed on ADA population which included subjects who had received at least one dose or part of a dose of IMP and were analysed according to the treatment actually received with at least one post dose evaluable ADA sample.
    End point type
    Secondary
    End point timeframe
    From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60)
    End point values
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    55
    56
    Units: subjects
        Treatment-boosted ADA
    0
    0
        Treatment-emergent ADA
    1
    2
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Serum Trough Concentration (Ctrough) of Sarilumab

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    End point title
    		 Pharmacokinetics (PK): Serum Trough Concentration (Ctrough) of Sarilumab [3]
    End point description
    Ctrough was pre dose concentration of drug. Analysis was performed on PK analysis population: all subjects who had received at least one dose or part of a dose of IMP, were analysed according to the treatment actually received and had at least 1 post-dose non-missing serum sarilumab concentration value. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for placebo arm (Placebo+52 Week Taper) as pre-specified in the protocol.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 0 (Baseline), Week 2, 4, 12, 16, 24, and 52
    Notes
    [3] - 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: Endpoint is reporting data for applicable arm in the study.
    End point values
    		 Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    58
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n=58)
    0.00 ( 0.00 )
        Week 2 (n=56)
    5209.02 ( 4357.37 )
        Week 4 (n=50)
    9259.25 ( 7668.95 )
        Week 12 (n=46)
    17494.20 ( 11146.33 )
        Week 16 (n=42)
    23082.86 ( 15878.92 )
        Week 24 (n=40)
    27289.75 ( 17927.73 )
        Week 52 (n=33)
    27604.95 ( 24880.13 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Serum Drug Concentration of Sarilumab Post-dose at Week 24

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    End point title
    		 Pharmacokinetics: Serum Drug Concentration of Sarilumab Post-dose at Week 24 [4]
    End point description
    Serum concentrations of functional sarilumab were analysed using validated enzyme linked immunosorbent assay. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint. Data for this endpoint was not planned to be collected and analysed for placebo arm (Placebo+52 Week Taper) as pre-specified in the protocol.
    End point type
    Secondary
    End point timeframe
    Post-dose at Week 24
    Notes
    [4] - 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: Endpoint is reporting data for applicable arm in the study.
    End point values
    		 Sarilumab 200mg q2w+14 Week Taper
    Number of subjects analysed
    26
    Units: ng/mL
        arithmetic mean (standard deviation)
    35757.69 ( 15353.96 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose (i.e., Day 1) of IMP to last dose date of IMP + 60 days (i.e., up to Week 60).
    Adverse event reporting additional description
    Reported AEs were TEAEs that developed/worsened in grade or became serious during TEAE period (defined as the time from the first dose of the IMP to the last dose of the SC IMP + 60 days). Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo+52 Week taper
    Reporting group description
    		 Subjects received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks.

    Reporting group title
    Sarilumab 200mg q2w+14 Week Taper
    Reporting group description
    		 Subjects received sarilumab 200 mg as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Subjects received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52.

    Serious adverse events
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 58 (20.69%)
    8 / 59 (13.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine Aminotransferase Increased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erdheim-Chester Disease
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Intramural Haematoma
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant Cell Arteritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Emergency
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic Hypotension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pollakiuria
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia Rheumatica
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Covid-19
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 Pneumonia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Discitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo+52 Week taper Sarilumab 200mg q2w+14 Week Taper
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 58 (72.41%)
    42 / 59 (71.19%)
    Injury, poisoning and procedural complications
    Accidental Overdose
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Fall
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    6 / 58 (10.34%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    Limb Injury
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Skin Laceration
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Vascular disorders
    Hypertension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 58 (3.45%)
    6 / 59 (10.17%)
         occurrences all number
    2
    6
    Nervous system disorders
    Cognitive Disorder
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Headache
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Sciatica
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Blood and lymphatic system disorders
    Increased Tendency To Bruise
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Leukopenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    Neutropenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    0
    9
    General disorders and administration site conditions
    Fatigue
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Injection Site Pruritus
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    7
    Oedema Peripheral
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 59 (5.08%)
         occurrences all number
    5
    3
    Eye disorders
    Dry Eye
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Constipation
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    Diarrhoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    7 / 59 (11.86%)
         occurrences all number
    1
    7
    Gastrooesophageal Reflux Disease
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 59 (6.78%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Rash Pruritic
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Skin Striae
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Depression
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    6 / 58 (10.34%)
    5 / 59 (8.47%)
         occurrences all number
    7
    5
    Insomnia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    9 / 58 (15.52%)
    6 / 59 (10.17%)
         occurrences all number
    9
    6
    Mania
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    9 / 59 (15.25%)
         occurrences all number
    3
    11
    Back Pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    3
    4
    Bursitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    5
    2
    Myalgia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    Osteoarthritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    5 / 58 (8.62%)
    6 / 59 (10.17%)
         occurrences all number
    6
    6
    Pain In Extremity
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Rotator Cuff Syndrome
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    Tendonitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    5
    Infections and infestations
    Cystitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Gastroenteritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Influenza
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Nasopharyngitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 59 (3.39%)
         occurrences all number
    6
    2
    Upper Respiratory Tract Infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    5
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2018
    The following changes were done: i) Exclusion criteria: initial wording was modified with the elimination of, “Based on investigators’ judgment,” and addition of, “Subject who meets any of the following”. ii) Additional wording was added in sections pertaining to ALT discontinuation criteria. iii) Language pertaining to the use of legal representative was modified.
    19 Apr 2021
    The following changes were done: i) Added clinical trial.gov registration number 'NTC03600818'. ii) Changed total expected number of subjects. iii) Changed statistical significance level from 0.01 to 0.05 and updated power. iv) Changed significant level for analysis of primary efficacy endpoint from 0.01 to 0.05. v)Changed total expected number of subjects, Changed significant level for analysis of secondary efficacy endpoints from 0.01 to 0.05 vi) Updated sample size and power calculations. vii) Revised 99% confidence interval (CI) to 95% CI.

    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.
    Protracted recruitment timeline exacerbated by COVID-19 pandemic led to pre-mature termination of study, resulting in a change in the total expected number of subjects and change in the statistical significance level.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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