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    Clinical Trial Results:
    Multicenter, Safety and Efficacy, Open-Label Extension Study Evaluating Teprotumumab (HZN-001) Treatment in Subjects with Thyroid Eye Disease

    Summary
    EudraCT number
    		 2017-002713-58
    Trial protocol
    		 DE   IT  
    Global end of trial date
    17 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2021
    First version publication date
    25 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HZNP-TEP-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03461211
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Horizon Pharma USA, Inc.
    Sponsor organisation address
    1 Horizon Way, Deerfield, IL , United States, 60015
    Public contact
    Senior Medical Director, Horizon Pharma USA, Inc., 001 866-479-6742, clinicaltrials@horizontherapeutics.com
    Scientific contact
    Senior Medical Director, Horizon Pharma USA, Inc., 001 866-479-6742, clinicaltrials@horizontherapeutics.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
    17 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the effect of teprotumumab on the proptosis responder rate (i.e., the percentage of subjects with a ≥ 2 mm reduction from Baseline in the study eye without deterioration [≥ 2 mm increase] of proptosis in the fellow eye) at the EOT Visit.
    Protection of trial subjects
    The Investigators will ensure that this study is conducted in a manner that fully conforms with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” International Conference of Harmonization (ICH) Tripartite Guideline or with local law if it affords greater protection to the subject. It is the responsibility of the Investigator, or a person designated by the Investigator (if acceptable by local regulations), to obtain signed informed consent from each subject prior to participating in this study after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. The Investigator or designee must also explain that the subjects are completely free to refuse to enter the study or to withdraw from it at any time, for any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    51
    EEA total number of subjects
    26
    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)
    43
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were eligible for enrollment in this study (OPTIC-X) if they completed the 24-week double-masked Treatment Period in Study HZNP-TEP-301 (NCT03298867; OPTIC) and were proptosis non-responders or were proptosis responders at Week 24 but met the criteria for re-treatment due to relapse during the Follow-Up Period of HZNP-TEP-301.

    Pre-assignment
    Screening details
    		 The Baseline (Day 1) Visit of this extension study occurred within 14 days after the final visit of Study HZNPTEP-301, which was Week 24 for proptosis non-responders and up to Week 72 for participants who relapsed. The study treatment previously administered in HZNP-TEP-301 (teprotumumab or placebo) remained masked throughout this extension study

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study treatment previously administered in HZNP-TEP-301 (teprotumumab or placebo) remained masked throughout this extension study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Teprotumumab (OPTIC Placebo)
    Arm description
    		 Participants who received placebo in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teprotumumab
    Investigational medicinal product code
    HZN-001
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All study drug dosing was performed at the clinic under the supervision of clinic staff.

    Arm title
    		 Teprotumumab (OPTIC Teprotumumab)
    Arm description
    		 Participants who received teprotumumab in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teprotumumab
    Investigational medicinal product code
    HZN-001
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All study drug dosing was performed at the clinic under the supervision of clinic staff.

    Number of subjects in period 1
    		Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Started
    37
    14
    Proptosis Non- Responders in OPTIC
    36
    5 [1]
    Relapsed During OPTIC Follow-Up Period
    1 [2]
    9 [3]
    Completed
    36
    12
    Not completed
    1
    2
         Adverse event
    1
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone categories are correctly defined.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone categories are correctly defined.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone categories are correctly defined.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Teprotumumab (OPTIC Placebo)
    Reporting group description
    		 Participants who received placebo in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Reporting group title
    Teprotumumab (OPTIC Teprotumumab)
    Reporting group description
    		 Participants who received teprotumumab in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Reporting group values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab) Total
    Number of subjects
    		 37 14 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.5 ± 13.49 56.1 ± 11.52 -
    Gender categorical
    Units: Subjects
        Female
    		 27 11 38
        Male
    		 10 3 13
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 36 14 50
    Race
    Units: Subjects
        Asian
    		 1 2 3
        Black or African American
    		 1 1 2
        White
    		 33 11 44
        Other, Not Specified
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Teprotumumab (OPTIC Placebo)
    Reporting group description
    		 Participants who received placebo in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Reporting group title
    Teprotumumab (OPTIC Teprotumumab)
    Reporting group description
    		 Participants who received teprotumumab in OPTIC received 8 infusions of open-label teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Primary: Percentage of Participants With a ≥ 2 mm Reduction From Baseline in the Study Eye Without Deterioration of Proptosis in the Fellow Eye at Week 24

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    End point title
    		 Percentage of Participants With a ≥ 2 mm Reduction From Baseline in the Study Eye Without Deterioration of Proptosis in the Fellow Eye at Week 24 [1]
    End point description
    Proptosis responders were defined as participants with a ≥ 2 mm reduction from study baseline in proptosis in the study eye, without deterioration (≥ 2 mm increase) of proptosis in the fellow eye at Week 24. Participants missing Week 24 values were considered non-responders, aside from those with missing data related to the COVID-19 pandemic. Intent-to-Treat Population: all participants enrolled in the study. Participants missing Week 24 values were considered non-responders, aside from those with missing data related to the COVID-19 pandemic. One participant in the Teprotumumab (OPTIC Teprotumumab) arm was excluded from all Week 24 summaries due to COVID-19 (visit delayed).
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    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: Descriptive statistics are presented per protocol.
    End point values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Number of subjects analysed
    37
    13
    Units: percentage of participants
        number (not applicable)
    89.2
    53.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a European Group on Graves' Ophthalmopathy (EUGOGO) Amended Clinical Activity Score (CAS) Total Score of 0 or 1 in the Study Eye at Week 24

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    End point title
    		 Percentage of Participants With a European Group on Graves' Ophthalmopathy (EUGOGO) Amended Clinical Activity Score (CAS) Total Score of 0 or 1 in the Study Eye at Week 24
    End point description
    CAS responders were defined as participants with a reduction to a CAS of 0 or 1 (no or minimal inflammatory symptoms) as a categorical response variable at Week 24. The 7-item CAS assigns 1 point for each of the following items present in the study eye: spontaneous orbital pain; gaze evoked orbital pain; eyelid swelling that is considered to be due to active (inflammatory phase) thyroid eye disease/Graves’ ophthalmopathy (TED/GO); eyelid erythema; conjunctival redness that is considered to be due to active (inflammatory phase) TED/GO (ignore “equivocal” redness); chemosis; inflammation of caruncle or plica. The sum of these points is the total score (0 to 7), with higher scores indicating worse symptoms. ITT Population: all participants enrolled in the study. Participants with CAS > 1 at Study Baseline. Per the statistical analysis plan, participants missing Week 24 values were considered non-responders, aside from those with missing data related to the COVID-19 pandemic.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Number of subjects analysed
    32 [2]
    11 [3]
    Units: percentage of participants
        number (not applicable)
    65.6
    36.4
    Notes
    [2] - Participants with CAS > 1 at Study Baseline.
    [3] - Participants with CAS > 1 at Study Baseline.
    No statistical analyses for this end point

    Secondary: Change in Proptosis From Baseline to Week 24

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    End point title
    		 Change in Proptosis From Baseline to Week 24
    End point description
    Mean change from study baseline to Week 24 in proptosis measurement (mm) in the study eye at Week 24. Intent-to-Treat Population: all participants enrolled in the study. Participants with both baseline and Week 24 measurements. One participant in the Teprotumumab (OPTIC Teprotumumab) arm was excluded from all Week 24 summaries due to COVID-19 (visit delayed).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Number of subjects analysed
    36
    11
    Units: mm
        arithmetic mean (standard deviation)
    -3.47 ± 1.732
    -1.77 ± 1.126
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were Diplopia Responders at Week 24

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    End point title
    		 Percentage of Participants Who Were Diplopia Responders at Week 24
    End point description
    Diplopia responders were defined as participants with 1 grade or greater reduction in diplopia score in the study eye without worsening by at least 1 grade in the fellow eye at Week 24. The subjective diplopia score (0=no diplopia; 1=intermittent, i.e. diplopia in primary position of gaze, when tired or when first awakening; 2=inconstant, i.e. diplopia at extremes of gaze; 3=constant, i.e. continuous diplopia in primary or reading position) was recorded for each eye. A participant was considered to have diplopia if a score > 0 is observed in the study eye at study baseline. Intent-to-Treat Population: all participants enrolled in the study. Participants with diplopia at Study Baseline. Per the statistical analysis plan, participants missing Week 24 values were considered non-responders, aside from those with missing data related to the COVID-19 pandemic. One participant in the Teprotumumab (OPTIC Teprotumumab) arm was excluded from all Week 24 summaries due to COVID-19.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Number of subjects analysed
    23
    4
    Units: percentage of participants
        number (not applicable)
    60.9
    75.0
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score

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    End point title
    		 Mean Change From Baseline to Week 24 in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score
    End point description
    The GO-QoL is a 16-item self-administered questionnaire divided into 2 subsets and used to assess the perceived effects of TED by the participants on (i) their daily physical activity as it relates to visual function, and (ii) psychosocial functioning. The sum of the scores from each set of 8 questions was calculated and transformed to a scale from 0 (worst) to 100 (best) – one for visual function (VF), one for appearance (A) and one for the overall combined (VF + A) score. Scores were transformed as follows: Transformed score = [(sum of each score – number of completed items) / (2 * number of completed items)] * 100. The "overall combined (VF + A) score" is also 0 to 100, with higher scores indicating a better outcome. Intent-to-Treat Population: all participants enrolled in the study. Participants with both baseline and Week 24 measurements. One participants in the Teprotumumab (OPTIC Teprotumumab) arm was excluded from the Week 24 summary due to COVID-19 (visit delayed).
    End point type
    Secondary
    End point timeframe
    Study Baseline, Week 24
    End point values
    		 Teprotumumab (OPTIC Placebo) Teprotumumab (OPTIC Teprotumumab)
    Number of subjects analysed
    36
    11
    Units: score on a scale
        arithmetic mean (standard deviation)
    13.39 ± 17.890
    14.73 ± 11.777
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and serious adverse events (AEs): from informed consent through 30 days after study discontinuation. Mean days on study was 332.9 and 218.8 for Placebo (OPTIC Placebo) and Teprotumumab (OPTIC Teprotumumab) arms, respectively.
    Adverse event reporting additional description
    Non-serious AEs: from first dose of study drug through last dose of study drug + 3 weeks (Treatment Period; mean 168.1 and 170.9 days for Placebo and Teprotumumab arms, respectively) or from Week 24 up to Week 48 in the Follow-Up Period (mean 170.1 and 165.0 days for Placebo [OPTIC Placebo] and Teprotumumab [OPTIC Teprotumumab] arms, respectively).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Treatment Period: Teprotumumab (OPTIC Placebo)
    Reporting group description
    		 Participants who received placebo in OPTIC received 8 infusions of teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Reporting group title
    Treatment Period: Teprotumumab (OPTIC Teprotumumab)
    Reporting group description
    		 Participants who received teprotumumab in OPTIC received 8 infusions of teprotumumab every 3 weeks (q3W) for a total of 21 weeks: teprotumumab 10 mg/kg administered on Day 1 and teprotumumab 20 mg/kg administered q3W for the remaining 7 infusions.

    Reporting group title
    Follow-Up Period: No Treatment (OPTIC Placebo)
    Reporting group description
    		 Participants who received placebo in OPTIC and were proptosis non-responders. Participants received 8 infusions of teprotumumab q3W for a total of 21 weeks in OPTIC-X and entered a 24-week Follow-up Period; no trial drug was administered.

    Reporting group title
    Follow-Up Period: No Treatment (OPTIC Teprotumumab)
    Reporting group description
    		 Participants who received teprotumumab in OPTIC and were proptosis non-responders. Participants received 8 infusions of teprotumumab q3W for a total of 21 weeks in OPTIC-X and entered a 24-week Follow-up Period; no trial drug was administered.

    Serious adverse events
    		 Treatment Period: Teprotumumab (OPTIC Placebo) Treatment Period: Teprotumumab (OPTIC Teprotumumab) Follow-Up Period: No Treatment (OPTIC Placebo) Follow-Up Period: No Treatment (OPTIC Teprotumumab)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Period: Teprotumumab (OPTIC Placebo) Treatment Period: Teprotumumab (OPTIC Teprotumumab) Follow-Up Period: No Treatment (OPTIC Placebo) Follow-Up Period: No Treatment (OPTIC Teprotumumab)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 37 (86.49%)
    11 / 14 (78.57%)
    16 / 36 (44.44%)
    2 / 4 (50.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of skin
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Jugular vein distension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thirst
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Erectile dysfunction
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaginal discharge
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nasal discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Paranasal sinus discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Sneezing
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nightmare
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tension
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Post procedural contusion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Procedural headache
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    10
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    2 / 36 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Hypogeusia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyposmia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    White matter lesion
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear and labyrinth disorders
    Autophony
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Deafness Neurosensory
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear discomfort
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Hypoacusis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry eye
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 14 (7.14%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Keratitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lenticular opacities
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ocular discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Punctate keratitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pupillary reflex impaired
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Strabismus
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    2 / 36 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    5 / 37 (13.51%)
    1 / 14 (7.14%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    6
    1
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gingival pain
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gingival recession
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Noninfective gingivitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tongue ulceration
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Diffuse alopecia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Eczema
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Ingrowing nail
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Madarosis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Onychoclasis
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 14 (0.00%)
    4 / 36 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Petechiae
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pruritus generalised
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Rash pruritic
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Polyuria
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Back pain
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 14 (14.29%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Bursitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Exostosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint stiffness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    18 / 37 (48.65%)
    4 / 14 (28.57%)
    3 / 36 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    24
    8
    3
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 14 (7.14%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Sinusitis bacterial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gout
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    1 / 36 (2.78%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Polydipsia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 14 (0.00%)
    0 / 36 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Apr 2018
    • Added inclusion criterion #11 clarifying subjects should not receive treatment for TED between Week 24 of OPTIC and entry into OPTIC-X. • Added language clarifying lack of efficacy/disease progression withdrawal criteria. • Amended and clarified restrictions on previous and planned use of corticosteroids for the treatment of TED and non-TED conditions. • Added restrictions on the use of non-steroid eye drops during the trial. • Added systemic administration of potential ototoxic medications that may be reasonable to avoid, such as aminoglycosides and platinum-based chemotherapy. • Added that medications that may cause muscle spasm/cramps should be avoided during the trial and added donepezil, neostigmine and vincristine to the list of restricted medications. • Defined end of the trial (the last visit date of the last subject in the trial).
    31 Jan 2019
    • Added diplopia responder rate (defined as the percentage of subjects with baseline diplopia >0 in study eye who had a reduction of ≥1 grade with no corresponding deterioration [≥1 grade worsening] in the fellow eye at Week 24) as a secondary endpoint. • Added evaluation of PK parameters of teprotumumab to estimate exposure and understand the PK-PD relationships as an exploratory endpoint. • Changed the number of teprotumumab doses administered from “up to 8 infusions based on Investigator judgment” to “8 infusions.” • Specified the End-of-Treatment Visit as Week 24. • Added 2 additional follow-up contacts (telephone or email) at 6 and 12 months after the last visit to assess any additional TED treatment received since last trial contact. For subjects who were proptosis non-responders after completion of the Treatment Period in OPTIC, the last clinic visit was Month 12, with the follow-up contacts at Month 18 and 24. For subjects who relapsed during the Follow-up Period of OPTIC, the last clinic visit was Week 24, with the follow-up contacts at Month 12 and 18. • Clarified that female subjects of childbearing potential who were sexually active with a non vasectomized male partner must agree to use 2 reliable forms of contraception, one of which was recommended to be hormonal, during the trial and for 180 days after the last dose of trial drug. • Clarified that male subjects who were sexually active with a female partner of childbearing potential must agree to use a barrier contraceptive method from Baseline through 180 days after the last dose of trial drug. • Clarified that CAS criteria for determining relapse refers only to the study eye.
    31 Jan 2019
    (continued) • Amended the CAS relapse criterion to include an increase in CAS of ≥2 points since Week 24 with an absolute CAS ≥4 following the Week 24 Visit of OPTIC. • Specified the minimum duration of trial drug infusions. • Clarified that the weight obtained at Week 12 could be used for the calculation of trial drug dose beginning at Week 12 or Week 15. • Added PK sampling pre- and post-infusion on Day 1, Week 3 and Week 9 of the Treatment Period, with single samples collected at Weeks 1, 4 and 24. • Changed the definition of the end of the trial to date of the last subject contact at Month 24.

    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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