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    Clinical Trial Results:
    A two-year multi-center Phase 3 study to investigate the efficacy and safety of secukinumab in adult patients with active, moderate to severe thyroid eye disease (ORBIT), with a randomized, parallel-group, double-blind, placebo-controlled, 16-week treatment period, and a follow-up/retreatment period

    Summary
    EudraCT number
    		 2020-001611-24
    Trial protocol
    		 DE  
    Global end of trial date
    16 May 2023

    Results information
    Results version number
    		 v1
    This version publication date
    30 May 2024
    First version publication date
    30 May 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CAIN457ADE16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04737330
    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
    16 May 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that secukinumab was superior to placebo with regard to the overall responder rate after 16 weeks of treatment.
    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
    29 Nov 2021
    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
    Germany: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    24
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 5 centers in Germany.

    Pre-assignment
    Screening details
    		 Eligible participants were randomized in a 1:1 ratio to one of the following double-blinded treatment arms: Secukinumab 300 mg (arm 1) and Placebo (arm 2).

    Period 1
    Period 1 title
    Treatment period (Baseline to Week 16)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Secukinumab 300 mg
    Arm description
    		 Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    Other name
    AIN457
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Arm title
    		 Placebo
    Arm description
    		 Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
    Arm type
    		 Placebo

    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 subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Number of subjects in period 1
    		Secukinumab 300 mg Placebo
    Started
    14
    14
    Completed
    12
    12
    Not completed
    2
    2
         Study terminated by sponsor
    1
    2
         Lost to follow-up
    1
    -
    Period 2
    Period 2 title
    Follow-up period (Week 16 to Week 108)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Secukinumab 300 mg
    Arm description
    		 Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Secukinumab
    Investigational medicinal product code
    Other name
    AIN457
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Arm title
    		 Placebo
    Arm description
    		 Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
    Arm type
    		 Placebo

    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 subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Number of subjects in period 2
    		Secukinumab 300 mg Placebo
    Started
    12
    12
    Completed
    8
    9
    Not completed
    4
    3
         Not satisfied
    1
    -
         Study terminated by sponsor
    3
    1
         Therapy national guidelines
    -
    1
         No benefit IMP
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Secukinumab 300 mg
    Reporting group description
    		 Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Reporting group values
    		 Secukinumab 300 mg Placebo Total
    Number of subjects
    		 14 14 28
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 12 12 24
        From 65-84 years
    		 2 2 4
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 53.6 ( 11.85 ) 57.7 ( 10.64 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 9 12 21
        Male
    		 5 2 7
    Smoking History
    Units: Subjects
        Current
    		 3 4 7
        Former
    		 8 6 14
        Never
    		 3 4 7
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 14 14 28

    End points

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    End points reporting groups
    Reporting group title
    Secukinumab 300 mg
    Reporting group description
    		 Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
    Reporting group title
    Secukinumab 300 mg
    Reporting group description
    		 Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

    Primary: Plan A - Proportion of participants achieving overall response

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    End point title
    		 Plan A - Proportion of participants achieving overall response [1]
    End point description
    The proportion of participants achieving overall response was defined as follows: >= 2 points reduction in clinical activity score (CAS) AND >= 2 mm reduction in proptosis from Baseline in the study eye, provided there was no corresponding deterioration in CAS or proptosis (>= 2 point or 2 mm increase, respectively) in the fellow eye after 16 weeks of treatment. Due to premature study discontinuation, purely descriptive analyses were performed for the primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature study discontinuation, purely descriptive analyses were performed for the primary endpoint.
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Yes
    0
    3
        No
    12
    8
        Missing
    2
    3
    No statistical analyses for this end point

    Primary: Plan B - Proportion of participants achieving response in reduction of proptosis

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    End point title
    		 Plan B - Proportion of participants achieving response in reduction of proptosis [2]
    End point description
    The proportion of participants achieving response in reduction of proptosis at Week 16 was defined as follows: reduction of >= 2 mm from Baseline in the study eye without deterioration (>= 2 mm increase) of proptosis in the fellow eye. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the primary endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated)" for the primary endpoint
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Participants
    Notes
    [3] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [4] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan A - Proportion of participants achieving response in reduction of clinical activity score (CAS)

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    End point title
    		 Plan A - Proportion of participants achieving response in reduction of clinical activity score (CAS)
    End point description
    The proportion of participants achieving response in reduction of clinical activity score (CAS) at Week 16 was defined as follows: reduction of >= 2 points from Baseline in the study eye without deterioration (>= 2 points increase) of CAS in the fellow eye. Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Yes
    0
    3
        No
    12
    8
        Missing
    2
    3
    No statistical analyses for this end point

    Secondary: Plan A - Proportion of participants achieving response in reduction of proptosis

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    End point title
    		 Plan A - Proportion of participants achieving response in reduction of proptosis
    End point description
    The proportion of participants achieving response in reduction of proptosis at Week 16 was defined as follows: reduction of >= 2 mm from Baseline in the study eye without deterioration (>= 2 mm increase) of proptosis in the fellow eye. Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Yes
    0
    0
        No
    12
    11
        Missing
    2
    3
    No statistical analyses for this end point

    Secondary: Plan A - Proportion of participants achieving response in diplopia

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    End point title
    		 Plan A - Proportion of participants achieving response in diplopia
    End point description
    The proportion of participants achieving response in diplopia at Week 16 was defined as follows: Baseline diplopia > 0 and a reduction of >= 1 grade with no corresponding deterioration (>= 1 grade worsening) in the fellow eye at Week 16. Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Yes
    1
    1
        No
    11
    11
        Missing
    2
    2
    No statistical analyses for this end point

    Secondary: Plan A - Mean change from Baseline to Week 16 in clinical activity score (CAS) in the study eye

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    End point title
    		 Plan A - Mean change from Baseline to Week 16 in clinical activity score (CAS) in the study eye
    End point description
    Thyroid Eye Disease (TED) activity was assessed using the CAS at the frequency indicated in the study schedule based on the following signs and symptoms in accordance with the European Group on Graves’ Orbitopathy (EUGOGO) guideline: • Symptoms ~ Spontaneous retrobulbar pain ~ Pain on attempted upward or downward gaze • Signs ~ Redness of eyelids ~ Redness of conjunctiva ~ Swelling of caruncle or plica ~ Swelling of eyelids ~ Swelling of conjunctiva (chemosis) For each item present, 1 point is given. The sum of these points is the CAS score, i.e., minimum score of 0 and maximum score of 7. • Inactive TED: CAS < 3. • Active TED: CAS >= 3.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Change from BL at Week 2
    -0.21 ( 0.58 )
    -0.29 ( 0.47 )
        Change from BL at Week 4
    -0.14 ( 1.10 )
    -0.29 ( 0.73 )
        Change from BL at Week 8
    0.00 ( 1.00 )
    -0.21 ( 0.58 )
        Change from BL at Week 12
    -0.67 ( 1.15 )
    -0.57 ( 0.94 )
        Change from BL at Week 16
    0.00 ( 0.95 )
    -0.73 ( 1.10 )
    No statistical analyses for this end point

    Secondary: Plan A - Mean change from Baseline to Week 16 in proptosis in the study eye

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    End point title
    		 Plan A - Mean change from Baseline to Week 16 in proptosis in the study eye
    End point description
    Proptosis measurements were performed at the frequency indicated in the study schedule. The same Hertel instrument, and the same outer intercanthal distance, were to be used for each measurement. Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Change from BL at Week 2
    0.18 ( 0.72 )
    -0.07 ( 0.73 )
        Change from BL at Week 4
    0.18 ( 0.72 )
    0.00 ( 1.18 )
        Change from BL at Week 8
    0.42 ( 1.00 )
    0.43 ( 1.28 )
        Change from BL at Week 12
    0.67 ( 0.98 )
    0.29 ( 1.33 )
        Change from BL at Week 16
    0.83 ( 1.03 )
    0.64 ( 1.03 )
    No statistical analyses for this end point

    Secondary: Plan A - Proportion of participants with improvement in EUGOGO disease severity

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    End point title
    		 Plan A - Proportion of participants with improvement in EUGOGO disease severity
    End point description
    Thyroid Eye Disease (TED) activity was assessed using the CAS at the frequency indicated in the study schedule based on the following signs and symptoms in accordance with the European Group on Graves’ Orbitopathy (EUGOGO) guideline. Improvement in EUGOGO disease severity was categorized: Mild, Moderate to severe and Sight threatening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Baseline|Mild
    0
    0
        Week 2|Mild
    0
    0
        Week 4|Mild
    1
    1
        Week 8|Mild
    0
    1
        Week 12|Mild
    1
    1
        Week 16|Mild
    1
    1
        Baseline|Moderate to severe
    14
    14
        Week 2|Moderate to severe
    14
    14
        Week 4|Moderate to severe
    13
    12
        Week 8|Moderate to severe
    13
    13
        Week 12|Moderate to severe
    11
    13
        Week 16|Moderate to severe
    11
    10
        Baseline|Sight threatening
    0
    0
        Week 2|Sight threatening
    0
    0
        Week 4|Sight threatening
    0
    0
        Week 8|Sight threatening
    0
    0
        Week 12|Sight threatening
    0
    0
        Week 16|Sight threatening
    0
    0
    No statistical analyses for this end point

    Secondary: Plan A - Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 1: Visual functioning) over time

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    End point title
    		 Plan A - Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 1: Visual functioning) over time
    End point description
    The Graves' ophthalmopathy quality of life questionnaire (GO-QOL) contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Baseline
    64.1 ( 23.04 )
    66.6 ( 24.38 )
        Week 2
    62.9 ( 27.71 )
    66.4 ( 20.51 )
        Week 4
    56.7 ( 28.11 )
    66.7 ( 23.82 )
        Week 8
    51.0 ( 27.93 )
    59.1 ( 24.75 )
        Week 12
    54.7 ( 29.45 )
    60.8 ( 28.71 )
        Week 16
    52.1 ( 29.36 )
    61.9 ( 30.42 )
    No statistical analyses for this end point

    Secondary: Plan A - Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 2: Psychosocial functioning) over time

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    End point title
    		 Plan A - Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 2: Psychosocial functioning) over time
    End point description
    The Graves' ophthalmopathy quality of life questionnaire (GO-QOL) contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). Due to premature study discontinuation, purely descriptive analyses were performed for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Baseline
    65.6 ( 22.43 )
    60.3 ( 20.60 )
        Week 2
    68.3 ( 16.16 )
    62.5 ( 29.42 )
        Week 4
    69.2 ( 21.01 )
    56.7 ( 30.37 )
        Week 8
    65.4 ( 20.51 )
    52.2 ( 30.87 )
        Week 12
    63.5 ( 26.09 )
    53.1 ( 34.47 )
        Week 16
    66.2 ( 26.84 )
    56.8 ( 30.55 )
    No statistical analyses for this end point

    Secondary: Plan B - Proportion of participants achieving response in reduction of clinical activity score (CAS)

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    End point title
    		 Plan B - Proportion of participants achieving response in reduction of clinical activity score (CAS)
    End point description
    The proportion of participants achieving response in reduction of CAS at Week 16 was defined as follows: reduction of >= 2 points from Baseline in the study eye without deterioration (>= 2 points increase) of CAS in the fellow eye. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Participants
    Notes
    [5] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [6] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan A - Number of participants with Adverse Events

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    End point title
    		 Plan A - Number of participants with Adverse Events
    End point description
    The distribution of adverse events during Plan A study treatment period was done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs), through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    14
    14
    Units: Participants
        Any adverse event (AE)
    9
    6
        Study treatment related AE
    3
    1
        AE leading to study treatment discontinuation
    0
    0
        Serious adverse event (SAE)
    0
    1
        Study treatment related SAE
    0
    0
        SAE leading to study treatment discontinuation
    0
    0
    No statistical analyses for this end point

    Secondary: Plan B - Proportion of participants achieving response in diplopia

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    End point title
    		 Plan B - Proportion of participants achieving response in diplopia
    End point description
    The proportion of participants achieving response in diplopia at Week 16 was defined as follows: Baseline diplopia > 0 and a reduction of >= 1 grade with no corresponding deterioration (>= 1 grade worsening) in the fellow eye at Week 16. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Participants
    Notes
    [7] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [8] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Proportion of participants achieving overall response

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    End point title
    		 Plan B - Proportion of participants achieving overall response
    End point description
    The proportion of participants achieving overall response was defined as follows: >= 2 points reduction in CAS AND >= 2 mm reduction in proptosis from Baseline in the study eye, provided there was no corresponding deterioration in CAS or proptosis (>= 2 point or 2 mm increase, respectively) in the fellow eye after 16 weeks of treatment. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Participants
    Notes
    [9] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [10] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Mean change from Baseline to Week 16 in clinical activity score (CAS) in the study eye.

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    End point title
    		 Plan B - Mean change from Baseline to Week 16 in clinical activity score (CAS) in the study eye.
    End point description
    Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Participants
    Notes
    [11] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [12] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Mean change from Baseline to Week 16 in proptosis in the study eye.

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    End point title
    		 Plan B - Mean change from Baseline to Week 16 in proptosis in the study eye.
    End point description
    Proptosis is the protrusion of the eyeball. Exophthalmos means the same, and this term is usually used when describing proptosis due to Grave's disease. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Participants
    Notes
    [13] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [14] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Mean change from Baseline to Week 16 in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 1: Visual functioning)

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    End point title
    		 Plan B - Mean change from Baseline to Week 16 in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 1: Visual functioning)
    End point description
    The Graves' ophthalmopathy quality of life questionnaire (GO-QOL) contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Unit on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [15] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [16] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Mean change from Baseline to Week 16 in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 2: Psychosocial functioning)

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    End point title
    		 Plan B - Mean change from Baseline to Week 16 in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score (score 2: Psychosocial functioning)
    End point description
    The Graves' ophthalmopathy quality of life questionnaire (GO-QOL) contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: Unit on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [17] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [18] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Secondary: Plan B - Number of participants with Adverse Events

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    End point title
    		 Plan B - Number of participants with Adverse Events
    End point description
    Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until Week 16
    End point values
    		 Secukinumab 300 mg Placebo
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: Participants
    Notes
    [19] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    [20] - Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are presented for the double-blind treatment period (16 weeks) and for the follow-up/open-label re-treatment period, including AEs in FUP for all patients who received at least one dose of Secukinumab during the entire study up (maximum of 108 weeks).
    Adverse event reporting additional description
    The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Secukinumab 300 mg (Double-blind)
    Reporting group description
    		 Secukinumab 300 mg (Double-blind): Double-blind treatment period (from first dose of study treatment until Week 16)

    Reporting group title
    Any Secukinumab 300 mg (entire study)
    Reporting group description
    		 All events reported from the beginning of the study up until the end of follow-up/open-label retreatment period (from first dose of study treatment up to Week 108)

    Reporting group title
    Placebo (Double-blind)
    Reporting group description
    		 Secukinumab matching placebo (Double-blind): Double-blind treatment period (from first dose of study treatment until Week 16)

    Serious adverse events
    		 Secukinumab 300 mg (Double-blind) Any Secukinumab 300 mg (entire study) Placebo (Double-blind)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Eye disorders
    Endocrine ophthalmopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Graves' disease
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Secukinumab 300 mg (Double-blind) Any Secukinumab 300 mg (entire study) Placebo (Double-blind)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    23 / 26 (88.46%)
    12 / 14 (85.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 26 (11.54%)
    2 / 14 (14.29%)
         occurrences all number
    1
    4
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    2
    4
    1
    Injection site swelling
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Injection site pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Injection site pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    4
    4
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Injection site erythema
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 26 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    2
    4
    0
    Swelling
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Thyroxine free decreased
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Tri-iodothyronine increased
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    5 / 26 (19.23%)
    2 / 14 (14.29%)
         occurrences all number
    9
    20
    7
    Horner's syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    2
    3
    0
    Neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    2
    2
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Conjunctival oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Diplopia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    1
    2
    1
    Swelling of eyelid
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    1
    2
    1
    Pupillary reflex impaired
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Ocular discomfort
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Metamorphopsia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Erythema of eyelid
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Eye swelling
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Eye pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    2
    Visual field defect
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    3
    6
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 26 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Thyroid dermatopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Arthralgia
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 26 (7.69%)
    0 / 14 (0.00%)
         occurrences all number
    2
    4
    0
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0
    COVID-19
         subjects affected / exposed
    4 / 14 (28.57%)
    10 / 26 (38.46%)
    6 / 14 (42.86%)
         occurrences all number
    4
    14
    6
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Borrelia infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 26 (7.69%)
    3 / 14 (21.43%)
         occurrences all number
    0
    2
    3
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
         occurrences all number
    1
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2021
    Amended Protocol Version 01: The main purpose of this amendment is to add additional ophthalmological assessments to the study protocol. Exclusion criterion #13 was specified by the addition of a wash-out period for the prior use of oral corticosteroids. For patients who prematurely discontinue the study or study treatment, the follow-up assessment 12 weeks after last administration of study treatment was amended to an End of Study (EOS) visit which includes safety and efficacy assessments and will be recorded in the eCRF in order to increase data consistency and to comply with current Novartis standards. Furthermore, minor clarifications and corrections of certain aspects and procedures as well as changes to correct formatting errors and administrative inconsistencies were made where applicable. At the time of the amendment, no patients had been screened for inclusion.
    15 Mar 2022
    Amended Protocol Version 02: The main purpose of this amendment is to provide clarification of wording for inclusion criterion 6 and for the requirement of patients to be fasting prior to laboratory assessments. Furthermore, information was added that live vaccinations should not be given until 12 weeks after last study treatment administration to comply with current Novartis standards.

    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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    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
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