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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group, phase III multicenter study of intravenous secukinumab to compare efficacy at 16 weeks with placebo and to assess safety and tolerability up to 52 weeks in subjects with active Ankylosing Spondylitis or nonradiographic axial SpondyloArthritis

    Summary
    EudraCT number
    		 2019-001177-90
    Trial protocol
    		 BE   GR   SE   CZ   BG   IT  
    Global end of trial date
    20 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Dec 2023
    First version publication date
    10 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457P12301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04156620
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    20 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo in subjects with active axSpA (AS and nr-axSpA) based on the proportion of subjects achieving an ASAS40 response.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2019
    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
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Bulgaria: 24
    Country: Number of subjects enrolled
    Colombia: 28
    Country: Number of subjects enrolled
    Czechia: 76
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Guatemala: 18
    Country: Number of subjects enrolled
    India: 31
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Malaysia: 22
    Country: Number of subjects enrolled
    Philippines: 14
    Country: Number of subjects enrolled
    Poland: 76
    Country: Number of subjects enrolled
    Russian Federation: 86
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    526
    EEA total number of subjects
    192
    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)
    510
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 769 participants were screened for the study and 527 participants were randomized However, one patient was mis-randomized and never received any study drug and is therefore not included in the table below.

    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, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AIN457 6 mg/kg - 3 mg/kg i.v.
    Arm description
    		 Participants received AIN457 (secukinumab) 6 mg/kg i.v. at baseline, followed by AIN457 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52)
    Arm type
    		 Experimental

    Investigational medicinal product name
    secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg at Week 4 up to Week 52

    Investigational medicinal product name
    secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/kg loading dose at baseline

    Arm title
    		 Placebo - AIN457 3 mg/kg i.v.
    Arm description
    		 Participants received i.v. placebo at baseline visit, Weeks 4, 8, and 12, followed by AIN457 (secukinumab) 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)
    Arm type
    		 placebo, experimental

    Investigational medicinal product name
    secukinumab
    Investigational medicinal product code
    AIN457
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg at Week 16 up to Week 52

    Investigational medicinal product name
    placebo matching secukinumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0 mg/kg every 4 weeks for 16 weeks

    Number of subjects in period 1
    		AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Started
    264
    262
    Completed Period 1
    255
    253
    Started Period 2
    255
    251
    Completed Period 2
    233
    235
    Completed
    227
    233
    Not completed
    37
    29
         Adverse event - TP 1
    5
    2
         Adverse event - TP 2
    5
    6
         Pregnancy - TP 2
    1
    1
         Death - TP 2
    1
    -
         Physician decision - TP 2
    4
    2
         Lost to follow-up TP 1
    1
    1
         New therapy for study indication - TP 2
    1
    -
         Subject decision - TP 1
    3
    5
         Subject decision - TP 2
    11
    9
         Progressive disease - TP 1
    -
    1
         Lost to follow-up - TP 2
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AIN457 6 mg/kg - 3 mg/kg i.v.
    Reporting group description
    		 Participants received AIN457 (secukinumab) 6 mg/kg i.v. at baseline, followed by AIN457 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52)

    Reporting group title
    Placebo - AIN457 3 mg/kg i.v.
    Reporting group description
    		 Participants received i.v. placebo at baseline visit, Weeks 4, 8, and 12, followed by AIN457 (secukinumab) 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)

    Reporting group values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v. Total
    Number of subjects
    		 264 262 526
    Age Categorical
    Units: participants
        < 65 years
    		 253 257 510
        65 - 75 years
    		 8 4 12
        >= 75 years
    		 3 1 4
    Sex: Female, Male
    Units: participants
        Female
    		 99 84 183
        Male
    		 165 178 343
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 180 179 359
        Black or African American
    		 7 6 13
        Asian
    		 59 47 106
        American Indian or Alaska Native
    		 17 25 42
        Multiple
    		 1 5 6
    Disease condition
    Units: Subjects
        Ankylosing spondylitis
    		 208 205 413
        Non-radiographic axial spondylarthritis
    		 56 57 113
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 77.61 ± 18.006 78.08 ± 18.444 -

    End points

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    End points reporting groups
    Reporting group title
    AIN457 6 mg/kg - 3 mg/kg i.v.
    Reporting group description
    		 Participants received AIN457 (secukinumab) 6 mg/kg i.v. at baseline, followed by AIN457 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52)

    Reporting group title
    Placebo - AIN457 3 mg/kg i.v.
    Reporting group description
    		 Participants received i.v. placebo at baseline visit, Weeks 4, 8, and 12, followed by AIN457 (secukinumab) 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)

    Primary: Percentage of participants who achieved an ASAS40 (Assessment of SpondyloArthritis International Society criteria)

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    End point title
    		 Percentage of participants who achieved an ASAS40 (Assessment of SpondyloArthritis International Society criteria)
    End point description
    ASAS40 is ≥ 40% and an absolute improvement from baseline of ≥20 units (range 0–100) in ≥ 3 of the following 4 domains: back pain [10 cm visual analogue scale (VAS)], patient global assessment of disease activity (10 cm VAS), physical function (BASFI; range 0–100) and inflammation (mean score of items 5 and 6 of the BASDAI; both 10 cm VAS) without any worsening in the remaining domain. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    40.85 (34.94 to 46.76)
    22.94 (17.86 to 28.02)
    Statistical analysis title
    		 ASAS40
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    17.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.12
         upper limit
    		 25.71

    Secondary: Percentage of participants who achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) major improvement

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    End point title
    		 Percentage of participants who achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) major improvement
    End point description
    ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient’s global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: < 1.3 between inactive disease and moderate disease activity; < 2.1 between moderate disease activity and high disease activity; and > 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for “minimal clinically important improvement” and a change of ≥ 2.0 units for “major improvement" .
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    27.99 (22.86 to 33.12)
    7.54 (4.44 to 10.64)
    Statistical analysis title
    		 ASDAS CRP major improvement
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    20.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.45
         upper limit
    		 26.44

    Secondary: The change from baseline in total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

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    End point title
    		 The change from baseline in total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
    End point description
    BASDAI consists of a 0 through 10 scale (0 indicating no problem and 10 indicating the worst problem, captured as a continuous VAS), which was used to answer six questions pertaining to the five major symptoms of AS: fatigue, spinal pain, peripheral joint pain / swelling,, areas of localized tenderness (enthesitis, or inflammation of tendons and ligaments), morning stiffness duration, morning stiffness severity. To give each symptom equal weight, the mean of the two scores relating to morning stiffness is taken into account (questions 5 and 6). The resulting 0 to 10 score is added to the scores for questions 1 through 4. The resulting 0 to 50 score is divided by 5 to give a final 0 10 BASDAI score.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    253
    247
    Units: scores on a scale
        least squares mean (standard error)
    -2.70 ± 0.144
    -1.69 ± 0.144
    Statistical analysis title
    		 BASDAI
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean change
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.38
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.189

    Secondary: Percentage of participants who achieved an ASAS 5/6 (Assessment of SpondyloArthritis International Society criteria)

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    End point title
    		 Percentage of participants who achieved an ASAS 5/6 (Assessment of SpondyloArthritis International Society criteria)
    End point description
    The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    43.92 (37.94 to 49.90)
    21.77 (16.77 to 26.77)
    Statistical analysis title
    		 ASAS 5/6
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    22.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.36
         upper limit
    		 29.95

    Secondary: The change from baseline in total Bath Ankylosing Spondylitis Functional Index (BASFI)

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    End point title
    		 The change from baseline in total Bath Ankylosing Spondylitis Functional Index (BASFI)
    End point description
    The BASFI is a set of 10 questions designed to determine the degree of functional limitation in subjects with AS. The questions were chosen on the basis of predominant input from subjects with AS. The first eight questions consider activities related to functional anatomy. The final two questions assess the subjects’ ability to cope with everyday life. A 0-10 scale (captured as a continuous VAS) is used to answer the questions. The BASFI score is the mean of the ten scales – a value between 0 and 10.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    253
    247
    Units: scores on a scale
        least squares mean (standard error)
    -2.33 ± 0.147
    -1.39 ± 0.148
    Statistical analysis title
    		 BASFI
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean change
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 -0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.194

    Secondary: The change from baseline in Short Form-36 Physical Component summary (SF-36 PCS)

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    End point title
    		 The change from baseline in Short Form-36 Physical Component summary (SF-36 PCS)
    End point description
    The Short Form-36 Physical Component Summary (SF-36 PCS) is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales (domains) that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The eight domains are based on a scale from 0-100 while PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    254
    247
    Units: scores on a scale
        least squares mean (standard error)
    7.70 ± 0.473
    4.69 ± 0.473
    Statistical analysis title
    		 SF-36 PCS
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean change
    Point estimate
    3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 4.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.615

    Secondary: The change from baseline in Ankylosing Spondylitis Quality of Life (ASQol)

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    End point title
    		 The change from baseline in Ankylosing Spondylitis Quality of Life (ASQol)
    End point description
    The ASQoL is a self-administered questionnaire designed to assess health-related quality of life in adult subjects with AS. The ASQoL contains 18 items with a dichotomous yes/no response option. A single point is assigned for each “yes” response and no points for each “no” response, resulting in overall scores that range from 0 (least severity) to 18 (highest severity). As such, lower scores indicate better quality of life. Items include an assessment of mobility/energy, self care and mood/emotion. The recall period is “at the moment”.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    254
    247
    Units: scores on a scale
        least squares mean (standard error)
    -4.65 ± 0.291
    -2.88 ± 0.290
    Statistical analysis title
    		 ASQol
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean change
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.51
         upper limit
    		 -1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.373

    Secondary: The change from baseline in High sensitivity C-Reactive Protein (hsCRP)

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    End point title
    		 The change from baseline in High sensitivity C-Reactive Protein (hsCRP)
    End point description
    This assessment (laboratory assessment) was performed in order to identify the presence of inflammation, to determine its severity and to monitor the response to treatment. Exponentially transformed LSM, the geometric mean ration of post-baseline/baseline. A value <1 indicates a reduced CRP
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    246
    248
    Units: mg/L
        least squares mean (standard error)
    0.39 ± 1.063
    0.89 ± 1.062
    Statistical analysis title
    		 hsCRP
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    494
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Relative LS mean change
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.51

    Secondary: Percentage of participants who achieved an ASAS20 (Assessment of SpondyloArthritis International Society criteria)

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    End point title
    		 Percentage of participants who achieved an ASAS20 (Assessment of SpondyloArthritis International Society criteria)
    End point description
    The ASAS Response Criteria (ASAS20) is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    63.94 (58.19 to 69.70)
    40.53 (34.62 to 46.44)
    Statistical analysis title
    		 ASAS20
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    23.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.61
         upper limit
    		 31.66

    Secondary: The percentage of participants achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease.

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    End point title
    		 The percentage of participants achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease.
    End point description
    ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient’s global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: < 1.3 between inactive disease and moderate disease activity; < 2.1 between moderate disease activity and high disease activity; and > 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for “minimal clinically important improvement” and a change of ≥ 2.0 units for “major improvement”
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    15.66 (11.53 to 19.78)
    3.08 (1.00 to 5.15)
    Statistical analysis title
    		 ASDAS CRP inactive disease
    Statistical analysis description
    Week 16
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    12.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.96
         upper limit
    		 17.19

    Secondary: Percentage of participants who achieved ASAS20 (Assessment of SpondyloArthritis International Society criteria) partial remission.

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    End point title
    		 Percentage of participants who achieved ASAS20 (Assessment of SpondyloArthritis International Society criteria) partial remission.
    End point description
    ASAS partial remission criteria are defined as a value not above 2 units in each of the four main ASAS domains on a scale of 0-10. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    264
    262
    Units: percentage of participants
        number (confidence interval 95%)
    14.76 (10.49 to 19.03)
    4.20 (1.77 to 6.63)
    Statistical analysis title
    		 ASAS20 partial remission
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Marginal difference
    Point estimate
    10.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.64
         upper limit
    		 15.47

    Secondary: Change from baseline in Pittsburgh Sleep Quality Index (PSQI)

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    End point title
    		 Change from baseline in Pittsburgh Sleep Quality Index (PSQI)
    End point description
    The PSQI is a self-report questionnaire that assesses sleep quality over a 1-month time interval. Consisting of 19 items, the PSQI measures several different aspects of sleep, offering seven component scores and one composite score. The component scores consist of subjective sleep quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, habitual sleep efficiency (i.e., the percentage of time in bed that one is asleep), sleep disturbances, use of sleeping medication, and daytime dysfunction. Each item is weighted on a 0–3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denoted a healthier sleep quality.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 AIN457 6 mg/kg - 3 mg/kg i.v. Placebo - AIN457 3 mg/kg i.v.
    Number of subjects analysed
    249
    246
    Units: scores on a scale
        least squares mean (standard error)
    -2.42 ± 0.222
    -1.76 ± 0.221
    Statistical analysis title
    		 PSQI
    Comparison groups
    AIN457 6 mg/kg - 3 mg/kg i.v. v Placebo - AIN457 3 mg/kg i.v.
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0234
    Method
    		 Regression, Logistic
    Parameter type
    		 LS mean change
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.292

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported for a maximum of 478 days for participants on AIN457 (including placebo switchers) and 182 days for participants on placebo which includes the 84 days in safety follow up.
    Adverse event reporting additional description
    Any subjects randomized to Placebo were counted under 'Placebo' before being switched to AIN457 and under 'Any AIN457' after being switched to AIN457. The 6 mg/kg loading dose followed by the 3 mg/kg maintenance dose is the regimen which was specified in the protocol and SAP and approved by the FDA for this trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Any AIN457
    Reporting group description
    		 Any AIN457

    Serious adverse events
    		 Placebo Any AIN457
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 261 (1.15%)
    32 / 517 (6.19%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seminoma
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 517 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression suicidal
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 517 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 517 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Choroiditis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 517 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 517 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 517 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 517 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 517 (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: 2%
    Non-serious adverse events
    		 Placebo Any AIN457
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 261 (13.41%)
    172 / 517 (33.27%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 261 (3.45%)
    17 / 517 (3.29%)
         occurrences all number
    10
    27
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 261 (0.77%)
    12 / 517 (2.32%)
         occurrences all number
    2
    12
    Diarrhoea
         subjects affected / exposed
    5 / 261 (1.92%)
    18 / 517 (3.48%)
         occurrences all number
    5
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 261 (0.38%)
    20 / 517 (3.87%)
         occurrences all number
    1
    32
    Infections and infestations
    COVID-19
         subjects affected / exposed
    10 / 261 (3.83%)
    65 / 517 (12.57%)
         occurrences all number
    10
    71
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 261 (2.30%)
    22 / 517 (4.26%)
         occurrences all number
    6
    23
    Urinary tract infection
         subjects affected / exposed
    1 / 261 (0.38%)
    11 / 517 (2.13%)
         occurrences all number
    1
    11
    Rhinitis
         subjects affected / exposed
    2 / 261 (0.77%)
    11 / 517 (2.13%)
         occurrences all number
    2
    12
    Nasopharyngitis
         subjects affected / exposed
    7 / 261 (2.68%)
    32 / 517 (6.19%)
         occurrences all number
    7
    32
    Pharyngitis
         subjects affected / exposed
    1 / 261 (0.38%)
    13 / 517 (2.51%)
         occurrences all number
    1
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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