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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy, Active-Comparator, Multicenter Study to Evaluate the Efficacy and Safety of Rituximab Versus MMF in Patients With Pemphigus Vulgaris

    Summary
    EudraCT number
    2014-000382-41
    Trial protocol
    DE   ES   IT   FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA29330
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02383589
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    28 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy of rituximab compared with Mycophenolate Mofetil (MMF) in achieving sustained complete remission, evaluated by the Pemphigus Disease Area Index (PDAI), and assessed at Week 52 in subjects with moderate-to-severely active PV; to evaluate the safety of rituximab compared with MMF with a focus on adverse events and safety laboratory values.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    Subjects received 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) before entering the trial.
    Evidence for comparator
    MMF is considered standard of care treatment for pemphigus vulgaris according to published expert treatment guidelines
    Actual start date of recruitment
    26 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    135
    EEA total number of subjects
    41
    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)
    117
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    In this international study, 135 subjects were enrolled at 49 academic centers throughout North America, Europe, the Middle East, and South America.

    Pre-assignment
    Screening details
    Subjects must have had a confirmed diagnosis of PV within the previous 24 months (by skin or mucosal biopsy and immunohistochemistry) and evidence of moderate-to-severely active disease at screening.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rituximab (RTX)
    Arm description
    Subjects received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Subjects also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    RTX (1000 mg) was administered by intravenous (IV) infusion on Day 1 and Day 15, with repeat RTX administration on Day 168 and Day 182, provided that specific safety criteria had been met.

    Investigational medicinal product name
    MMF-matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MMF-matching placebo was administered PO twice daily (Q12H).

    Arm title
    Mycophenolate Mofetil (MMF)
    Arm description
    Subjects received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Subjects also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.
    Arm type
    Active comparator

    Investigational medicinal product name
    RTX-matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    RTX-matching placebo was administered by IV infusion on Day 1 and Day 15, with repeat RTX administration on Day 168 and Day 182, provided that specific safety criteria had been met.

    Investigational medicinal product name
    Mycophenolate mofetil
    Investigational medicinal product code
    Other name
    Cellcept
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MMF (500 mg) was administered per os (PO) twice daily (every 12 hours [Q12H]), starting with a total dose of 1 g/day on Day 1, and increased to 2g/day in divided doses by Week 2

    Number of subjects in period 1
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Started
    67
    68
    Completed
    66
    58
    Not completed
    1
    10
         Non-compliance with study drug
    -
    1
         Consent withdrawn by subject
    -
    5
         Adverse Event
    1
    3
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab (RTX)
    Reporting group description
    Subjects received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Subjects also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52

    Reporting group title
    Mycophenolate Mofetil (MMF)
    Reporting group description
    Subjects received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Subjects also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.

    Reporting group values
    Rituximab (RTX) Mycophenolate Mofetil (MMF) Total
    Number of subjects
    67 68 135
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    54 63 117
        From 65-84 years
    13 5 18
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    50.66 ± 12.98 46.34 ± 13.08 -
    Sex: Female, Male
    Units: Subjects
        Male
    32 30 62
        Female
    35 38 73
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    13 21 34
        Not Hispanic or Latino
    45 41 86
        Not Stated
    9 6 15
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    3 1 4
        Black or African American
    1 2 3
        White
    49 51 100
        Unknown
    14 13 27

    End points

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    End points reporting groups
    Reporting group title
    Rituximab (RTX)
    Reporting group description
    Subjects received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Subjects also received MMF matching placebo orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52

    Reporting group title
    Mycophenolate Mofetil (MMF)
    Reporting group description
    Subjects received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Subjects also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.

    Subject analysis set title
    Intent-to-Treat (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomized subjects who received any part of an infusion of study drug or oral administration of study drug were included in the intent-to-treat (ITT) population. Sensitivity analyses of the efficacy outcomes were performed using the ITT population. Subjects who prematurely withdrew from the study for any reason and for whom an assessment was not performed for whatever reason were still included in the ITT analysis.

    Subject analysis set title
    Modified ITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population included all subjects who were randomized and received any part of an infusion of study drug or oral administration of study drug. Subjects who received the incorrect therapy from that assigned were summarized according to the therapy actually received. This population was used for the analyses of safety outcomes.

    Primary: Percentage of Subjects (Excluding Telemedicine [TM] Subjects) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score

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    End point title
    Percentage of Subjects (Excluding Telemedicine [TM] Subjects) Who Achieved Sustained Complete Remission, Evaluated by the Pemphigus Disease Area Index (PDAI) Activity Score
    End point description
    The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes.
    End point type
    Primary
    End point timeframe
    From Baseline up to 52 Weeks (up to clinical cut-off date (CCOD) of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62 [1]
    63 [2]
    Units: Percentage
    number (not applicable)
        Week 52
    40.3
    9.5
    Notes
    [1] - Only subjects for whom data were collected are included in the analysis.
    [2] - Only subjects for whom data were collected are included in the analysis.
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in proportion
    Point estimate
    30.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.7
         upper limit
    45.15
    Notes
    [3] - The analysis was stratified by the stratification factors applied at randomization.

    Secondary: Cumulative Oral Corticosteroid Dose

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    End point title
    Cumulative Oral Corticosteroid Dose
    End point description
    The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62 [4]
    63 [5]
    Units: milligram (mg)
        median (inter-quartile range (Q1-Q3))
    2775.00 (2146.88 to 3610.00)
    4005.00 (2662.50 to 5815.00)
    Notes
    [4] - Only subjects for whom data were collected are included in the analysis.
    [5] - Only subjects for whom data were collected are included in the analysis.
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Total Number of Protocol Defined Disease Flares

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    End point title
    Total Number of Protocol Defined Disease Flares
    End point description
    Disease flare is defined as appearance of three or more new lesions a month that do not heal spontaneously within 1 week, or by the extension of established lesions, in a subject who has achieved disease control. The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62 [6]
    63 [7]
    Units: Number
        Number of subjects with at least one flare
    5
    26
        Number of flares
    6
    44
    Notes
    [6] - Only subjects for whom data were collected are included in the analysis.
    [7] - Only subjects for whom data were collected are included in the analysis.
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Negative Binominal Regression
    Parameter type
    Adjusted Rate Ratio
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.29
    Notes
    [8] - The model was adjusted for the following covariates in addition to log (each subject’s duration in study) as an offset: treatment, region, duration of illness, baseline PDAI activity score, and baseline prednisone dose.

    Secondary: Time to Initial Sustained Complete Remission

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    End point title
    Time to Initial Sustained Complete Remission
    End point description
    The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes. Only subjects for whom data were collected are included in the analysis. The end point couldnot be analyzed due to the limited number of events. The median is not estimable due to limited number of events. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62
    63
    Units: Weeks
        median (confidence interval 95%)
    9999 (32.1 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    4.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.97
         upper limit
    11.81
    Notes
    [9] - P-value is from a stratified log-rank test used to test the time to first disease flare between the RTX and MMF treatment arms over the 52-week treatment period, adjusting for the stratification factors applied at randomization

    Secondary: Time to Protocol-Defined Disease Flare

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    End point title
    Time to Protocol-Defined Disease Flare
    End point description
    Disease flare is defined as the appearance of three or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a subject who has achieved disease control. The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes. The median is not estimable due to limited number of events. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62 [10]
    63 [11]
    Units: Weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (36.9 to 9999)
    Notes
    [10] - Only subjects for whom data were collected are included in the analysis.
    [11] - Only subjects for whom data were collected are included in the analysis.
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.39
    Notes
    [12] - P-value is from a stratified log-rank test used to test the time to first disease flare between the RTX and MMF treatment arms over the 52-week treatment period, adjusting for the stratification factors applied at randomization

    Secondary: Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score

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    End point title
    Change in Health-Related Quality of Life (HRQoL), as Measured by the Dermatology Life Quality Index (DLQI) Score
    End point description
    The modified intent-to-treat (mITT) population included subjects in the ITT population, excluding the 10 telemedicine (TM) subjects. This population was used in the analyses of efficacy outcomes. Only subjects for whom data were collected are included in the analysis. The measure type represents Estimated Mean estimated from adjusted MMRM.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    62 [13]
    63 [14]
    Units: Number
    arithmetic mean (standard error)
        Baseline
    10.14 ± 7.89
    11.09 ± 8.52
        Week 52
    -8.874 ± 0.532
    -6.002 ± 0.662
    Notes
    [13] - The number of subjects analyzed is 57 at Baseline and 45 at Week 52
    [14] - The number of subjects analyzed is 58 at Baseline and 27 at Week 52
    Statistical analysis title
    Superiority
    Comparison groups
    Rituximab (RTX) v Mycophenolate Mofetil (MMF)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [15]
    Method
    Mixed Model Repeated Measures
    Parameter type
    Difference in Estimated Means
    Point estimate
    -2.872
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.577
         upper limit
    -1.167
    Notes
    [15] - P-value is from Mixed Model Repeated Measures (MMRM) with unstructured covariance matrix, adjusting for treatment, region, duration of illness, baseline DLQI score, visit, and an interaction terms for visit × baseline DLQI score and visit × treatment

    Secondary: Percentage of Subjects With Adverse Events (AE), Serious Adverse Events (SAE), and Corticosteroid-Related Adverse Events

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    End point title
    Percentage of Subjects With Adverse Events (AE), Serious Adverse Events (SAE), and Corticosteroid-Related Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a participant to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. A serious adverse event is an adverse event that results in death or is life-threatening or requires/prolongs hospitalization or results in persistent/significant disability/incapacity or congenital abnormality/birth defect. Adverse events of Grade 3 of higher are severe and life-threatening adverse events CS-related adverse events - causality as determined by the investigator.
    End point type
    Secondary
    End point timeframe
    Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    67
    68
    Units: Percentage
    number (not applicable)
        Subjects with AE
    85.1
    88.2
        Subjects with SAE
    22.4
    14.7
        Subjects with Corticosteroid (CS) -Related AE
    34.3
    38.2
        Subjects with CS-Related AE of Grade 3 or higher
    1.5
    7.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anti-Drug Antibodies (ADA)

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    End point title
    Percentage of Subjects With Anti-Drug Antibodies (ADA) [16]
    End point description
    Subjects with treatment-induced and treatment-enhanced anti-drug antibodies. The clinical relevance of anti-rituximab antibody formation in RITUXAN treated pemphigus vulgaris (PV) subjects is unclear. The safety population (all subjects who were randomized and received any part of an infusion of study drug), only subjects for whom data were collected are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to 52 Weeks (up to CCOD of 28 November 2018)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Rituximab (RTX)
    Number of subjects analysed
    63 [17]
    Units: Percentage
        number (not applicable)
    31.7
    Notes
    [17] - Only subjects for whom data were collected are included in the analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN)

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    End point title
    Percentage of Subjects with Immunoglobulin (Ig) Levels Below Lower Limit of Normal (LLN)
    End point description
    In the RITUXAN arm, low IgG levels were commonly observed and low IgM levels were very commonly observed; however, there was no evidence of an increased risk of serious infections after the development of low IgG or IgM. The safety population included all subjects who were randomized and received any part of an infusion of study drug or oral administration of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 16, 24, 40 and 52; (end of treatment: up to Week 52) (up to CCOD of 28 November 2018)
    End point values
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Number of subjects analysed
    67
    68
    Units: Percentage
    number (not applicable)
        Baseline (IgA)
    0
    0
        Week 16 (IgA)
    0
    1.8
        Week 24 (IgA)
    1.7
    2.2
        Week 40 (IgA)
    0
    2.7
        Week 52 (IgA)
    0
    3.6
        Baseline (IgG)
    6.1
    6.0
        Week 16 (IgG)
    9.8
    1.8
        Week 24 (IgG)
    3.4
    2.2
        Week 40 (IgG)
    3.5
    0
        Week 52 (IgG)
    4.3
    0
        Baseline (IgM)
    7.6
    11.9
        Week 16 (IgM)
    24.6
    23.2
        Week 24 (IgM)
    27.1
    28.3
        Week 40 (IgM)
    29.8
    24.3
        Week 52 (IgM)
    29.8
    28.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to Week 52 (up to CCOD of 28 November 2018)
    Adverse event reporting additional description
    The safety population included all subjects who were randomized and received any part of an infusion of study drug or oral administration of study drug. Subjects who received the incorrect therapy from that assigned were summarized according to the therapy actually received. This population was used for the analyses of safety outcomes.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Rituximab (RTX)
    Reporting group description
    Participants received rituximab by IV infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met. Participants also received MMF matching placebo orally Q12H from Day 1 to Week 52.

    Reporting group title
    Mycophenolate Mofetil (MMF)
    Reporting group description
    Participants received Mycophenolate Mofetil (MMF) orally twice daily (every 12 hours, Q12H) from Day 1 to Week 52. Participants also received rituximab matching placebo by intravenous (IV) infusion on Days 1 and 15 with repeat administration on Days 168 and 182 provided specific safety criteria had been met.

    Serious adverse events
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 67 (22.39%)
    10 / 68 (14.71%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    3 / 67 (4.48%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SMALL CELL LUNG CANCER
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 67 (1.49%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    PARAESTHESIA
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INCARCERATED UMBILICAL HERNIA
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    URINARY RETENTION
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BURSITIS INFECTIVE
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rituximab (RTX) Mycophenolate Mofetil (MMF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 67 (62.69%)
    41 / 68 (60.29%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    12 / 67 (17.91%)
    5 / 68 (7.35%)
         occurrences all number
    19
    6
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    6 / 67 (8.96%)
    2 / 68 (2.94%)
         occurrences all number
    6
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    4 / 67 (5.97%)
    3 / 68 (4.41%)
         occurrences all number
    4
    3
    Blood and lymphatic system disorders
    LYMPHOPENIA
         subjects affected / exposed
    8 / 67 (11.94%)
    1 / 68 (1.47%)
         occurrences all number
    14
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    4 / 67 (5.97%)
    2 / 68 (2.94%)
         occurrences all number
    4
    2
    HEADACHE
         subjects affected / exposed
    10 / 67 (14.93%)
    6 / 68 (8.82%)
         occurrences all number
    17
    7
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    4 / 67 (5.97%)
    4 / 68 (5.88%)
         occurrences all number
    5
    4
    FATIGUE
         subjects affected / exposed
    5 / 67 (7.46%)
    3 / 68 (4.41%)
         occurrences all number
    8
    3
    OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 67 (2.99%)
    6 / 68 (8.82%)
         occurrences all number
    2
    8
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    1 / 67 (1.49%)
    6 / 68 (8.82%)
         occurrences all number
    1
    6
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    3 / 67 (4.48%)
    10 / 68 (14.71%)
         occurrences all number
    5
    11
    NAUSEA
         subjects affected / exposed
    2 / 67 (2.99%)
    4 / 68 (5.88%)
         occurrences all number
    4
    4
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    2 / 67 (2.99%)
    5 / 68 (7.35%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    6 / 67 (8.96%)
    2 / 68 (2.94%)
         occurrences all number
    6
    2
    BACK PAIN
         subjects affected / exposed
    6 / 67 (8.96%)
    1 / 68 (1.47%)
         occurrences all number
    6
    1
    Metabolism and nutrition disorders
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    5 / 67 (7.46%)
    0 / 68 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 67 (8.96%)
    8 / 68 (11.76%)
         occurrences all number
    8
    12
    ORAL CANDIDIASIS
         subjects affected / exposed
    6 / 67 (8.96%)
    6 / 68 (8.82%)
         occurrences all number
    8
    6
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 67 (8.96%)
    5 / 68 (7.35%)
         occurrences all number
    9
    6
    URINARY TRACT INFECTION
         subjects affected / exposed
    5 / 67 (7.46%)
    2 / 68 (2.94%)
         occurrences all number
    6
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2014
    (1) It was clarified that certain additional safety criteria must have been met in order to resume either rituximab/placebo or MMF/placebo after treatment interruption, and to receive repeat rituximab/placebo infusions on Day 168 and Day 182. (2) The option to administer rituximab/placebo study drug at a faster infusion rate at Day 168 and Day 182 was removed. (3) Progression of PV, worsening, disease flare, or treatment failure was not to be recorded as an AE or SAE, and was to be captured as efficacy assessment data only. (4) The following sections were added: a section on dosage modification and treatment interruption, a section on the efficacy and safety of MMF in PV, and a section on side effects known to be associated with MMF. (5) Additional criteria for study treatment discontinuation were added, including severe allergic or anaphylactic study treatment-related reaction, NCI CTCAE Grade 4 (life-threatening) event during or within 24 hours of an infusion, and pure red cell aplasia. (6) Text was added to clarify the management of specific AEs, particularly infections and IRRs: - Infections: repeat infusions of rituximab (or matching placebo) were only to be considered after any infection had fully resolved. Additionally, it was clarified that infections should be treated according to the local standard of care instead of symptomatically; - IRRs: it was clarified that subjects who experienced a Grade 4 (life-threatening) event during an infusion were to have their infusion stopped, and that additional infusions should not be given. (7) It was clarified that prolonged peripheral blood B cell depletion was an expected outcome of rituximab treatment and was not to be considered a toxicity. (8) Instructions regarding the initial dose of prednisone or equivalent in the range of 1.0 to 1.5 mg/kg/day was updated to 60 to 120 mg/day from 80 to 120 mg/day.
    06 Jul 2015
    (1) The PDAI in Appendix 4 was replaced with a corrected version. In the previous version of the protocol (Version 2), the PDAI was reproduced with permission from Clinics of Dermatology (2012); however, in 2015, it was discovered that Clinics of Dermatology had published an erroneous version of the PDAI that omitted the column to evaluate the number of lesions if </=3 for disease activity. The erroneous version of the PDAI was replaced with the validated version, and the protocol was updated to reflect the correct information, including instructions on the scoring method. (2) During an iDMC organizational meeting on 7 Feb 2015, the iDMC advised the Sponsor to consider that clinical definitions of treatment failure may not be the same as the statistical definition of treatment failure (i.e., non-responder). Relevant section of the protocol was therefore amended, per the iDMC recommendation, to align the clinical definitions of treatment failure with “non-responder” classification for the primary analysis. To achieve this, one definition was amended and two definitions were deleted to avoid treatment bias and premature rescue. (3) The non-responder rule was updated to clarify the scenarios in which subjects will be imputed as non-responders. The previous wording referred to the non-responder categorization being applied at the time of withdrawal or treatment failure. This wording was potentially misleading given that the primary endpoint required a 16-week consecutive duration at any time during the 52-week treatment period. Therefore, additional wording was added for clarification purposes and did not deviate from the original intent.
    15 Jan 2016
    (1) A typographical error stating that urine and serum pregnancy tests were being performed at the sensitivity of 50 mIU/mL was corrected, as pregnancy tests were being performed at the recommended sensitivity of 25 mIU/mL. (2) It was clarified that female subjects who were not postmenopausal must have had two negative pregnancy test results prior to starting study treatment, with a specific time interval between the two pregnancy tests. The timing for the serum pregnancy test during the screening period was changed to clarify that the screening pregnancy test must have been performed 8 to 10 days before the baseline/Day 1 urine pregnancy test (i.e., between Day -8 and Day -10) instead of at Day -1 to Day -28. (3) Contraception requirements were updated to include male patients who had undergone a vasectomy and female partners of male subjects who received MMF. (4) Wording was included that male subjects should advise their female partners to use a highly effective method of contraception during the study and for 12 months after stopping treatment. (5) Footnote “o” in the schedule of assessments was changed to address a typographical error. In the previous version of the protocol (Version 3), the footnote specified that certain blood chemistry values were to be collected at Weeks 1, 15, 24, and 26; however, Week 15 was incorrect, and the timing was changed to Weeks 1, 2, 24, and 26.
    15 Jan 2016
    (6) It was clarified that, before Week 12, patients who experienced treatment failure required an early withdrawal visit and were to be followed in the SFU period to receive standard-of-care treatment. (7) The inclusion criterion regarding first confirmed diagnosis of PV within the previous 24 months based on histological features of acantholysis via skin or mucosal biopsy was revised to include additional acceptable confirmatory tests for PV diagnosis besides tissue-bound IgG antibodies by direct immunofluorescence on the surface of affected epithelium. The diagnosis of PV was based on histological features of acantholysis via skin or mucosal biopsy and one of the following: tissue-bound IgG antibodies by direct immunofluorescence on the surface of affected epithelium or serological detection of serum Dsg3 autoantibodies against epithelial cell surface either by indirect immunofluorescence microscopy or by enzyme-linked immunosorbent assay. (8) It was clarified that the iDMC would review the safety data of TM subjects.
    19 Dec 2017
    The protocol was amended to address FDA’s recommendation that data obtained from TM subjects was considered to be exploratory in nature and therefore the primary analysis for establishing efficacy was to be based on the ITT population for subjects who were not recruited via TM. The following changes were made to the protocol to address this recommendation, as follows: (1) An additional minimum of 8 non-TM subjects was to be recruited into this study to maintain sufficient statistical power for the primary analysis, thereby increasing the overall enrollment from approximately 124 to approximately 132 subjects with PV. (2) The Statistical Considerations section was updated, stipulating that all efficacy outcomes would be analyzed using the mITT population and excluding subjects who were enrolled via TM. (3) he primary efficacy outcome measure was revised to reflect the exclusion of TM subjects. (4) A new primary analysis population was added, the mITT population, which included subjects in the ITT population, excluding the 10 subjects enrolled via TM. This population was to be used in the analyses of efficacy outcomes. (5) The analysis population to be used for the secondary efficacy endpoints was changed to the mITT population. (6) Exploratory analyses were updated to include a statement on descriptive statistics for evaluation of the 10 subjects recruited via TM. (7) In addition, the following change has been made: An exploratory objective and exploratory outcome measure to evaluate the proportion of subjects experiencing treatment failure in each treatment arm were added.

    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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