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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Efficacy and Safety Study of RV 001, an Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antagonist Antibody (Fully Human), Administered Every 3 Weeks (q3W) by Intravenous (IV) Infusion in Patients Suffering From Active Thyroid Eye Disease (TED)

    Summary
    EudraCT number
    		 2014-000113-31
    Trial protocol
    		 DE   IT   GB   NL  
    Global end of trial date
    22 Feb 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 May 2018
    First version publication date
    10 Mar 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update information to align with CT.gov.

    Trial information

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    Trial identification
    Sponsor protocol code
    TED01RV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01868997
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Horizon Pharma USA, Inc.
    Sponsor organisation address
    150 S. Saunders Road, Lake Forest, Illinois, United States, 60045
    Public contact
    Julie Ball, Horizon Pharma USA, Inc., clinicaltrials@horizonpharma.com
    Scientific contact
    Raymond Douglas, MD, PhD, Cedars-Sinai Medical Center, Raymond.Douglas@cshs.org
    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
    22 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to investigate the efficacy, safety, and tolerability of RV 001 (teprotumumab), a fully human anti-IGF1R antibody, administered q3W for 6 months, in comparison to placebo, in the treatment of participants suffering from active TED.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. The study was conducted in accordance with legal and regulatory requirements including Guidance for Good Clinical Practice (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association 2008). Written informed consent was to be obtained from the subject’s legally acceptable representative and assent by the minor subject, as applicable, before screening or baseline assessments. Instructions were given to the subject's legally acceptable representative in case of emergency or other questions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    87
    EEA total number of subjects
    35
    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)
    74
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 88 [1]
    Number of subjects completed
    		 87

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 randomized, not treated: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 88 subjects were randomized; 1 subject was never dosed and early terminated.
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The pharmacists responsible for preparing the teprotumumab solution or placebo solution for IV use will not be masked. The investigator and all other study site personnel will be masked to the treatment being administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 A placebo infusion (normal saline) was administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions.
    Arm type
    		 Placebo

    Investigational medicinal product name
    sterile normal saline 0.9%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo will be administered q3W by IV infusion over 6 months

    Arm title
    		 Teprotumumab
    Arm description
    		 Teprotumumab administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. All participants started treatment at a dose of 10 mg/kg. At Week 3, the dose was escalated to 20 mg/kg and kept constant for the remainder of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teprotumumab
    Investigational medicinal product code
    RV 001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Teprotumumab will be administered q3W by IV infusion over 6 months

    Number of subjects in period 1
    		Placebo Teprotumumab
    Started
    45
    42
    Completed
    38
    36
    Not completed
    7
    6
         Not specified
    3
    1
         Adverse event
    2
    5
         Lack of efficacy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 A placebo infusion (normal saline) was administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions.

    Reporting group title
    Teprotumumab
    Reporting group description
    		 Teprotumumab administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. All participants started treatment at a dose of 10 mg/kg. At Week 3, the dose was escalated to 20 mg/kg and kept constant for the remainder of the study.

    Reporting group values
    		 Placebo Teprotumumab Total
    Number of subjects
    		 45 42 87
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.1 ± 12.87 51.7 ± 10.78 -
    Gender categorical
    Units: Subjects
        Female
    		 36 28 64
        Male
    		 9 14 23

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 A placebo infusion (normal saline) was administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions.

    Reporting group title
    Teprotumumab
    Reporting group description
    		 Teprotumumab administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. All participants started treatment at a dose of 10 mg/kg. At Week 3, the dose was escalated to 20 mg/kg and kept constant for the remainder of the study.

    Primary: Responder Status at Week 24

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    End point title
    		 Responder Status at Week 24
    End point description
    Number of subjects classified as responders and non-responders at Week 24. Responders were defined as subjects with a reduction in clinical activity score (CAS, see secondary endpoint 'Change From Baseline in CAS' description for details) of ≥ 2 points, and a reduction in proptosis (amount of protrusion of the eye from the orbital rim) of ≥ 2 mm in the study eye, and no deterioration (increase in CAS of ≥ 2 points or increase in proptosis of ≥ 2 mm) in the non-study eye. Subjects who had no assessment at 24 weeks were considered non-responders. Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: subjects
        Responder
    9
    29
        Non-Responder / Missing
    36
    13
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Teprotumumab v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.293
         upper limit
    		 23.825
    Notes
    [1] - Odds ratio, 95% confidence interval, and P-value are obtained from a logistic regression model with treatment and smoking status as covariates.

    Secondary: Overall Average Change From Baseline in Graves' Ophthalmopathy Quality of Life (GO-QOL) Scale - Overall to Week 24 (Mixed-Model Repeated Measures [MMRM])

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    End point title
    		 Overall Average Change From Baseline in Graves' Ophthalmopathy Quality of Life (GO-QOL) Scale - Overall to Week 24 (Mixed-Model Repeated Measures [MMRM])
    End point description
    The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of thyroid eye disorder (TED) by the subjects on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. The transformed overall score is the sum of scores from all 16 questions to a scale of 0 (worst health) to 100 (best health). Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo). A change from baseline of zero was imputed at the first postbaseline visit for subjects with no postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: units on a scale
        least squares mean (standard error)
    6.77 ± 2.251
    17.74 ± 2.423
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Teprotumumab
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    10.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.561
         upper limit
    		 17.375
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.221

    Secondary: Overall Average Change From Baseline in Proptosis of the Study Eye to Week 24 (MMRM)

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    End point title
    		 Overall Average Change From Baseline in Proptosis of the Study Eye to Week 24 (MMRM)
    End point description
    Proptosis is the amount of protrusion of the eye from the orbital rim. Measurements were recorded using the Hertel exophthalmometer. Subjects with a decrease ≥ 2 mm were considered improving, those with an increase or decrease < 2 mm were considered remaining stable, and those with an increase ≥ 2 mm were considered worsening. Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo). A change from baseline of zero was imputed at the first postbaseline visit for subjects with no postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: mm
        least squares mean (standard error)
    -0.15 ± 0.188
    -2.46 ± 0.200
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Teprotumumab
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    -2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.843
         upper limit
    		 -1.772
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.269

    Secondary: Overall Average Change From Baseline in CAS to Week 24 (MMRM)

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    End point title
    		 Overall Average Change From Baseline in CAS to Week 24 (MMRM)
    End point description
    The 7-item European Group on Graves' Ophthalmopathy (EUGOGO) amended CAS was used to evaluate clinical activity. For each of the following items, one point is given: spontaneous orbital pain, gaze evoked orbital pain, eyelid swelling that is considered to be due to active (inflammatory phase) Graves' ophthalmopathy (GO), eyelid erythema, conjunctival redness that is considered to be due to active (inflammatory phase) GO, chemosis, and inflammation of caruncle or plica. The sum of these points is the total score, with 0 indicating no clinical activity and 7 indicating the most severe clinical activity. Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo). A change from baseline of zero was imputed at the first postbaseline visit for subjects with no postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: units on a scale
        least squares mean (standard error)
    -1.85 ± 0.172
    -3.43 ± 0.181
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Teprotumumab
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.073
         upper limit
    		 -1.098
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.245

    Secondary: Overall Average Change From Baseline in GO-QOL Scale - Visual Functioning to Week 24 (MMRM)

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    End point title
    		 Overall Average Change From Baseline in GO-QOL Scale - Visual Functioning to Week 24 (MMRM)
    End point description
    The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of TED by the subjects on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. Transformed Visual Functioning score is the sum of scores from following 8 questions to a scale of 0 (worst health) to 100 (best health): bicycling, driving, moving around the house, walking outdoors, reading, watching television (TV), hobby or pastime, feel hindered. Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo). A change from baseline of zero was imputed at the first postbaseline visit for subjects with no postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: units on a scale
        least squares mean (standard error)
    7.51 ± 2.646
    21.67 ± 2.891
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Teprotumumab
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    14.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.549
         upper limit
    		 21.773
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.827

    Secondary: Overall Average Change From Baseline in GO-QOL Scale - Appearance to Week 24 (MMRM)

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    End point title
    		 Overall Average Change From Baseline in GO-QOL Scale - Appearance to Week 24 (MMRM)
    End point description
    The GO-QOL is a 16-item self-administered questionnaire used to assess the perceived effects of TED by the subjects on their daily physical and psychosocial functioning. Two subscales of the 16-question GO-QOL have been defined: Visual Functioning and Appearance, with 8 questions comprising each subscale. Transformed Appearance score is the sum of scores from the following 8 questions to a scale of 0 (worst health) to 100 (best health): feel appearance has changed, feel being stared at, feel people react unpleasantly, influence on self-confidence, feel socially isolated, influence on making friends, appear less often on photos, try to mask changes in appearance. Intent to Treat Population: all subjects who were randomized to treatment and received at least 1 dose of medication (either teprotumumab or placebo). A change from baseline of zero was imputed at the first postbaseline visit for subjects with no postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Teprotumumab
    Number of subjects analysed
    45
    42
    Units: units on a scale
        least squares mean (standard error)
    6.60 ± 2.656
    12.92 ± 2.836
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Teprotumumab
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.101
    Method
    		 Mixed-Model Repeated Measures
    Parameter type
    		 Difference in Least Squares Mean
    Point estimate
    6.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.255
         upper limit
    		 13.901
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.81

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 72
    Adverse event reporting additional description
    Treatment emergent adverse events (TEAEs) are presented, defined as events with onset at the time of or following the start of treatment with study drug or an event starting before the start of treatment but increasing in severity following the start of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Safety Population: Placebo
    Reporting group description
    		 A placebo infusion (normal saline) was administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. Safety Population: subjects who received at least 1 dose of study treatment, grouped by treatment actually received.

    Reporting group title
    Safety Population: Teprotumumab
    Reporting group description
    		 Teprotumumab administered q3W by IV infusion over a period of 24 weeks for a total of 8 infusions. All participants started treatment at a dose of 10 mg/kg. At Week 3, the dose was escalated to 20 mg/kg and kept constant for the remainder of the study. Safety Population: subjects who received at least 1 dose of study treatment, grouped by treatment actually received.

    Serious adverse events
    		 Safety Population: Placebo Safety Population: Teprotumumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 43 (11.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Hashimoto's encephalopathy
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory bowel disease
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia sepsis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population: Placebo Safety Population: Teprotumumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 44 (47.73%)
    25 / 43 (58.14%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 43 (0.00%)
         occurrences all number
    6
    0
    Dysgeusia
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 43 (6.98%)
         occurrences all number
    2
    4
    Paraesthesia
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Somnolence
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 44 (13.64%)
    3 / 43 (6.98%)
         occurrences all number
    6
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 43 (11.63%)
         occurrences all number
    2
    8
    Nausea
         subjects affected / exposed
    4 / 44 (9.09%)
    8 / 43 (18.60%)
         occurrences all number
    6
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 43 (6.98%)
         occurrences all number
    2
    3
    Dry skin
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Rash
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 43 (6.98%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 44 (4.55%)
    8 / 43 (18.60%)
         occurrences all number
    2
    25
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 43 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 43 (11.63%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2013
    Changed Inclusion Criteria #s 3, 4, and 5
    17 Dec 2013
    Added HgbA1c testing at screening
    25 Apr 2014
    Added text that contraception to continue for 3 months after last dose of study drug
    10 Jun 2014
    Added clarification about definition of women of childbearing potential
    23 Jun 2014
    Added HgbA1c testing at Weeks 24 and 36
    27 Aug 2014
    Added HgbA1c at Weeks 12 and 72 Added language in Section 9.1.1 to allow for dose interruption in subjects who developed hyperglycemia in order to be treated for the adverse event
    28 Sep 2015
    Primary endpoint definition changed and secondary endpoints limited. Changes were made in consultation with key opinion leaders not participating in TED01RV after results from recent and relevant TED clinical trials became available. The goal was to have a more rigorous and clinically meaningful primary outcome measure, and one that would potentially differentiate teprotumumab as a clear improvement over existing therapies.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28467880
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