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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) as a Corticosteroid Sparing Agent in Corticosteroid Dependent Patients with Generalized Myasthenia Gravis

    Summary
    EudraCT number
    		 2013-005099-17
    Trial protocol
    		 LT   EE   HU   CZ   DE   BE  
    Global end of trial date
    14 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2020
    First version publication date
    28 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GTI1306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02473965
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grifols Therapeutics LLC
    Sponsor organisation address
    Research Triangle Park, North Carolina, United States, 27709
    Public contact
    Rhonda Griffin, Grifols Therapeutics LLC, rhonda.griffin@grifols.com
    Scientific contact
    Rhonda Griffin, Grifols Therapetuics LLC, rhonda.griffin@grifols.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
    14 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of intravenous (IV) infusions of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) as compared to placebo in reducing the maintenance dosage of corticosteroids (CS) in CS-dependent subjects with myasthenia gravis (MG) when given as an initial loading dose (2 grams per kilogram [2 g/kg]) followed by 12 maintenance doses (1 g/kg) every 3 weeks through Week 36 by assessing the percent of subjects achieving a 50% or greater reduction in CS dose (prednisone or equivalent) at Week 39 (Visit 14) from Baseline/Week 0 (Visit 1).
    Protection of trial subjects
    Standards for Good Clinical Practice were adhered to for all procedures in this clinical study. The investigators ensured the clinical study was conducted in full conformance with appropriate local laws and regulations and the Declaration of Helsinki.
    Background therapy
    		 Subjects were on systemic CS treatment for at least 3 months and on a stable CS dose of ≥15 milligrams/day (mg/day) and ≤60 mg/day (prednisone equivalent) for the month prior to screening. Subjects on alternate day CS dosing were judged to be on a daily dose equivalent to half their alternate day dose.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2015
    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
    United States: 11
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Poland: 16
    Worldwide total number of subjects
    60
    EEA total number of subjects
    36
    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)
    50
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Sixty subjects with a confirmed diagnosis of generalized MG historically meeting the clinical criteria for MG diagnosis Class II, III, IV or V of the Myasthenia Gravis Foundation of America were randomized. The study was conducted in 8 countries from November 2015 to February 2019.

    Pre-assignment
    Screening details
    		 Subjects had symptoms at screening controlled by CS, had been dependent on systemic CS for at least the preceding 3 months and who had received a stable dose of CS for at least 1 month immediately prior to the screening visit.

    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, Carer, Assessor
    Blinding implementation details
    The investigational product (IP) was prepared by the unblinded site pharmacist or designee, and the infusion solution was visually masked to maintain the blind. The volume of placebo was approximate to that required for the appropriate weight-based dose of IGIV-C in order to maintain blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IGIV-C
    Arm description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IGIV-C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The loading dose of 2 g/kg was divided over 2 days as standard infusion time, and extensions up to 4 days were allowed for tolerability issues or higher weight. The maintenance doses of 1 g/kg were infused in 1 day as standard, and extension was allowed for divided dosage over 2 days for tolerbility issues or higher weight. The limit for IGIV-C infusion was no more than 80 g/day.

    Arm title
    		 Placebo
    Arm description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 0.9% sodium chloride injection, United States Pharmacopeia or equivalent, visually masked and at a volume approximate to that required for the appropriate weight-based dose of IGIV-C to maintain blinding.

    Number of subjects in period 1
    		IGIV-C Placebo
    Started
    30
    30
    Completed
    18
    20
    Not completed
    12
    10
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    2
    3
         Physician decision
    -
    2
         MG worsening
    4
    1
         Adverse event, non-fatal
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IGIV-C
    Reporting group description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Reporting group title
    Placebo
    Reporting group description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Reporting group values
    		 IGIV-C Placebo Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.6 ± 16.99 48.5 ± 14.51 -
    Gender categorical
    Units: Subjects
        Female
    		 16 18 34
        Male
    		 14 12 26
    Race (NIH/OMB)
    Units: Subjects
        White
    		 27 27 54
        Black or African American
    		 0 1 1
        Asian
    		 3 2 5
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 2 2
        Not Hispanic or Latino
    		 30 28 58
    Baseline Daily Prednisone Equivalent Dose Level Stratification Categories
    Units: Subjects
        15 mg to 40 mg/day
    		 29 28 57
        41 to 60 mg/day
    		 1 2 3
    Baseline QMG Total Score
    The Quantitative Myasthenia Gravis (QMG) total score was the sum of the 13 items used to measure spirometry and muscle strength and ranges from 0 to 39 (higher values indicate greater severity of illness). The QMG total scores were used to assess MG worsening.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 12.1 ± 6.98 11.2 ± 6.48 -

    End points

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    End points reporting groups
    Reporting group title
    IGIV-C
    Reporting group description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Reporting group title
    Placebo
    Reporting group description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Primary: Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) from Baseline to Week 39

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    End point title
    		 Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) from Baseline to Week 39
    End point description
    The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group and for the baseline daily prednisone equivalent dose level stratification categories. mITT = modified intent-to-treat.
    End point type
    Primary
    End point timeframe
    Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
    End point values
    		 IGIV-C Placebo
    Number of subjects analysed
    30
    30
    Units: Percentage of subjects
    number (not applicable)
        All mITT subjects
    60.0
    63.3
        15 mg to 40 mg/day (n=29,28)
    58.6
    60.7
        41 mg to 60 mg/day (n=1,2)
    100.0
    100.0
    Statistical analysis title
    		 Unstratified Analysis Using Fisher's Exact Test
    Statistical analysis description
    The Fisher's exact test was used for treatment comparison without adjustment for startified baseline prednisone equivalent dose level due to the small cell size. The odds ratio and confidence intervals are calculated overall (i.e. all mITT subjects).
    Comparison groups
    IGIV-C v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.868
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 2.787

    Secondary: Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) from Baseline to Week 39

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    End point title
    		 Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) from Baseline to Week 39
    End point description
    The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group. Analysis was performed on the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
    End point values
    		 IGIV-C Placebo
    Number of subjects analysed
    30
    30
    Units: Percent change in daily CS dose
        least squares mean (standard error)
    -52.57 ± 8.835
    -54.15 ± 8.835
    Statistical analysis title
    		 IGIV-C versus Placebo
    Statistical analysis description
    Treatment comparison of percent change in daily CS dose from baseline to Week 39. The Analysis of Covariance model included the percent change from baseline in daily CS dose as the dependent variable, treatment as a fixed effect and baseline daily CS dose as covariate.
    Comparison groups
    IGIV-C v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.52
         upper limit
    		 26.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.536

    Secondary: Median Time to First Episode of MG Worsening

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    End point title
    		 Median Time to First Episode of MG Worsening
    End point description
    The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication. Analysis was performed on the mITT population. '99999' indicates that the data is not available.
    End point type
    Secondary
    End point timeframe
    From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14).
    End point values
    		 IGIV-C Placebo
    Number of subjects analysed
    30 [1]
    30 [2]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    99999 (33.10 to 99999)
    99999 (30.10 to 99999)
    Notes
    [1] - The median and 75th percentile were non-estimable as >50% of subjects did not have MG worsening.
    [2] - The median and 75th percentile were non-estimable as >50% of subjects did not have MG worsening.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were collected from Baseline/Week 0 to Week 39 (approximately 9 months).
    Adverse event reporting additional description
    TEAEs are presented for the Safety population which consisted of all randomized subjects who received any amount of study medication. Subjects were classified according to the treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    IGIV-C
    Reporting group description
    		 Investigational Product (IP) Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintencance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Reporting group title
    Placebo
    Reporting group description
    		 IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.

    Serious adverse events
    		 IGIV-C Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    6 / 30 (20.00%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cell carcinoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Myasthenia gravis
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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
    		 IGIV-C Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 30 (70.00%)
    24 / 30 (80.00%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    Red blood cell count decreased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 30 (33.33%)
    3 / 30 (10.00%)
         occurrences all number
    15
    3
    Myasthenia gravis
         subjects affected / exposed
    7 / 30 (23.33%)
    2 / 30 (6.67%)
         occurrences all number
    7
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 30 (16.67%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Rash
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 30 (13.33%)
    6 / 30 (20.00%)
         occurrences all number
    4
    7
    Arthritis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    2
    Myalgia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Back pain
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 30 (16.67%)
         occurrences all number
    0
    6
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 30 (20.00%)
    3 / 30 (10.00%)
         occurrences all number
    7
    3
    Influenza
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
         occurrences all number
    2
    6
    Pneumonia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Viral infection
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Bronchitis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2015
    - The WHO-5 Well-Being Index was added. - Number of study centers was increased. - Inclusion criteria clarifications included: a previous CS taper attempt must have been completed and the CS dose reduction must have been the greatest feasible to attain the lowest feasible CS dose based on observed MG signs and symptoms; intended subjects participating in the study to provide their own informed consent. - Exclusion criteria were modified to extend the timeframe of subjects receiving thymectomies to 6 months. - Clarification was provided that subjects with evidence of malignancy within the past 5 years (non-melanoma skin cancer, carcinoma in situ of cervix was allowed) or thymoma potentially requiring surgical intervention during the course of the study (intent to perform thymectomy) were to be excluded from study participation. - The Independent Safety Review Committee was added. - Clarifications were provided that diphenhydramine, acetaminophen/ibuprofen, and nonsteroidal anti-inflammatory drugs were allowed during the study as pre-medications for study drug infusions. - Concomitant Medications section was changed so that methotrexate at stable dose for 6 months prior to screening was acceptable. - Clarification was provided that each MG assessment should have been performed by the same clinical staff whenever possible. - Addition of waist circumference as a quantitative measure of centripetal obesity, a Cushingoid body habitus (possibly modifiable with CS dose reduction). - The assessment of 7 sentinel Cushingoid features were added at additional times to allow more frequent measures of corticosteroid manifestations and possible impact of CS dose reduction. - Text was added to describe the approach to missing data, for subjects who discontinued the study early due to other reasons, the LOCF method would be used to compute the missing CS dose and drive the primary efficacy endpoint. - Additional hemolysis assessments added for hemolysis surveillance.
    23 Dec 2016
    - Investigator discretion was introduced for final taper step from 5 mg prednisone equivalent daily to 0 mg prednisone equivalent daily as safety measure. - Exclusion criteria were updated to clarify that subjects with any episode of myasthenic crisis or hospitalization for MG exacerbation associated with a previous CS taper attempt and subjects whose only MG treatment was CS alone were not permitted to participate in the study. - Additional safety measures were added for subjects whose CS was tapered to 0 mg prednisone equivalent daily to assure rapid medical evaluation (recommended within 24 hours, allowed up to 48 hours), CS re-initiations and medical intervention. A 4-point QMG increase from Baseline/Week 0 was not required for re-initiating CS. - Clarifications were provided that MG treatment measures for MG crisis or hospitalization for MG exacerbation were always allowed for emergent medical need.

    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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