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    Clinical Trial Results:
    A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety of Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Achieving Renal Response in Subjects with Active Lupus Nephritis

    Summary
    EudraCT number
    		 2016-004045-81
    Trial protocol
    		 BG   ES   NL   PL   HR  
    Global end of trial date
    10 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2021
    First version publication date
    12 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AUR-VCS-2016-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03021499
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aurinia Pharmaceuticals Inc.
    Sponsor organisation address
    1203-4464 Markham St, Victoria, Canada,
    Public contact
    Clinical Trials Information, Aurinia Pharmaceuticals Inc., 1 (250) 744-2487, clinicaltrials@auriniapharma.com
    Scientific contact
    Clinical Trials Information, Aurinia Pharmaceuticals Inc., 1 (250) 744-2487, clinicaltrials@auriniapharma.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
    10 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of Orelvo (voclosporin) compared with placebo in achieving renal response after 52 weeks of therapy in subjects with active lupus nephritis (LN)
    Protection of trial subjects
    A Data and Safety Monitoring Board (DSMB) was constituted to monitor the safety of study participants and to evaluate the safety and efficacy of voclosporin in the treatment of active LN. The DSMB comprised three members, including a nephrologist and a rheumatologist, who were independent of Aurinia and recognized for their clinical expertise in LN. Safety criteria included AEs, serious adverse events (SAEs) and abnormal clinical laboratory tests. Efficacy was evaluated using the primary endpoint of renal response and other relevant markers of disease activity as recommended by the committee. Blinded and partially unblinded (where appropriate) individual subject data were reviewed on an ongoing basis for safety and efficacy, and final results were reviewed for safety and efficacy findings. The DSMB also evaluated protocol adherence and subject withdrawal. Based on the observed benefits or adverse effects, the DSMB made recommendations to Aurinia concerning continuation, termination, or modifications of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2017
    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
    Japan: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Malaysia: 12
    Country: Number of subjects enrolled
    Philippines: 23
    Country: Number of subjects enrolled
    Thailand: 22
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Vietnam: 15
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Belarus: 14
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Colombia: 21
    Country: Number of subjects enrolled
    Dominican Republic: 13
    Country: Number of subjects enrolled
    Guatemala: 13
    Country: Number of subjects enrolled
    Mexico: 18
    Country: Number of subjects enrolled
    Peru: 19
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    357
    EEA total number of subjects
    12
    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)
    355
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening will include provision of informed consent, physical examination including weight and height, medical history (including SLE and LN history), vital signs measurements, 12-lead ECG, and review of prior and concomitant medications and entry criteria.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Voclosporin
    Arm description
    		 Voclosporin 23.7 mg BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voclosporin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Voclosporin was orally administered at a dose of 23.7 mg BID given as three 7.9 mg softgel capsules per dose for 52 weeks

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo softgel capsules
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo softgel capsules were orally administered at a dose of 3 capsules BID for 52 weeks

    Number of subjects in period 1
    		Voclosporin Placebo
    Started
    179
    178
    Completed
    163
    147
    Not completed
    16
    31
         Adverse event, serious fatal
    1
    5
         Physician decision
    2
    3
         Lack of Efficacy
    -
    1
         Prohibited medication required
    1
    -
         Protocol Non-compliance
    1
    1
         Consent withdrawn by subject
    7
    14
         Adverse event, non-fatal
    1
    -
         Subject withdrew prior to first dose
    1
    -
         Lost to follow-up
    1
    3
         Unblinding of Study Treatment
    -
    1
         Pregnancy
    1
    -
         Subject Decided to Stop Medication
    -
    2
         Subject Moved to a new Country
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Voclosporin
    Reporting group description
    		 Voclosporin 23.7 mg BID

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo softgel capsules

    Reporting group values
    		 Voclosporin Placebo Total
    Number of subjects
    		 179 178 357
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 179 176 355
        From 65-84 years
    		 0 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.8 ± 10.93 33.6 ± 11.00 -
    Gender categorical
    Units: Subjects
        Female
    		 161 152 313
        Male
    		 18 26 44
    Race
    Units: Subjects
        White
    		 68 61 129
        Black or African American
    		 21 13 34
        American Indian or Alaska Native
    		 0 4 4
        Asian
    		 53 56 109
        Multiple Race
    		 0 1 1
        Other
    		 37 43 80
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 57 59 116
        Not Hispanic or Latino
    		 122 118 240
        Unknown
    		 0 1 1
    Years since diagnosis of systemic lupus erythematosus
    Number of years since diagnosis of systemic lupus erythematosus
    Units: years
        arithmetic mean (standard deviation)
    		 6.6 ± 6.41 6.9 ± 6.07 -
    Years since diagnosis of lupus nephritis
    Number of years since diagnosis of lupus nephritis
    Units: years
        arithmetic mean (standard deviation)
    		 4.6 ± 5.07 4.7 ± 4.89 -
    Years since first significant proteinuria
    Number of years since first significant proteinuria
    Units: years
        arithmetic mean (standard deviation)
    		 4.8 ± 5.2 4.6 ± 4.51 -
    Baseline Urine Protein Creatinine Ratio
    Baseline Urine Protein Creatinine Ratio (Average of pre-randomization values)
    Units: mg/mg
        arithmetic mean (standard deviation)
    		 4.14 ± 2.711 3.87 ± 2.363 -
    Baseline estimated glomerular filtration rate
    Baseline estimated glomerular filtration rate CKD Epi formula (lowest pre-randomization value)
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    		 92.1 ± 30.60 90.4 ± 28.97 -

    End points

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    End points reporting groups
    Reporting group title
    Voclosporin
    Reporting group description
    		 Voclosporin 23.7 mg BID

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo softgel capsules

    Primary: Number of Participants with Adjudicated Renal Response at Week 52

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    End point title
    		 Number of Participants with Adjudicated Renal Response at Week 52
    End point description
    The primary efficacy endpoint was the number of subjects showing renal response at Week 52. Renal response was adjudicated based on blinded data by an independent Clinical Endpoints Committee based on meeting the following criteria: - UPCR of ≤0.5 mg/mg, and - eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, and - Received no rescue medication for LN and - Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52, prior to assessment Note: To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR <60 mL/min/1.73 m2 AND confirmed >20% drop from BL) and have an associated treatment-related or disease-related AE that impacted eGFR Withdrawals prior to Week 52 with insufficient Week 52 data to determine response were defined non responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for respon
    End point type
    Primary
    End point timeframe
    52 Weeks
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
    73
    40
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The primary endpoint was the proportion of subjects showing renal response at Week 52 as adjudicated by the Clinical Endpoints Committee.
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.64
         upper limit
    		 4.27

    Secondary: Number of Participants with Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or less

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    End point title
    		 Number of Participants with Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or less
    End point description
    End point type
    Secondary
    End point timeframe
    52 Weeks
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: participants
    116
    78
    No statistical analyses for this end point

    Secondary: Number of Participants with Renal Response at Week 24

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    End point title
    		 Number of Participants with Renal Response at Week 24
    End point description
    Number of subjects showing renal response at Week 24. Renal response was adjudicated based on blinded data by an Independent Clinical Endpoints Committee based on: - UPCR of ≤0.5 mg/mg, and - eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, and - Received no rescue medication for LN, and did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 16 through 24, just prior to the renal response assessment. Note: To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR <60 mL/min/1.73 m2 AND confirmed >20% drop from BL) & have an associated treatment-related or disease-related AE that impacted eGFR. Subjects who withdrew prior to the Week 24 assessment and provided insufficient Week 24 data to determine response were defined as non-responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
    58
    35
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Voclosporin
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Cox
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.34
         upper limit
    		 3.72

    Secondary: Number of Participants with Partial Renal Response at Weeks 24 & 52

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    End point title
    		 Number of Participants with Partial Renal Response at Weeks 24 & 52
    End point description
    Number of subjects with partial Renal Response (defined as a 50% reduction in UPCR from baseline) at week 24 and at week 52. Baseline UPCR is the average of 2 pre-randomisation values.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
        Partial Response at Week 24
    126
    89
        Partial Response at Week 52
    125
    92
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 3.79
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 3.51

    Secondary: Number of Participants achieving, and remaining in, renal response (Urine Protein Creatinine ratio ≤0.5 mg/mg)

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    End point title
    		 Number of Participants achieving, and remaining in, renal response (Urine Protein Creatinine ratio ≤0.5 mg/mg)
    End point description
    Duration in days until second occurrence of UPCR >0.5 mg/mg in subjects who achieve a reduction in UPCR to below 0.5 mg/mg
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
        Subjects Achieving UPCR ≤0.5 mg/mg
    116
    78
        Subjects with Second Occurrence of UPCR >0.5 mg/mg
    53
    37
        Subjects without Second Occurrence UPCR >0.5 mg/mg
    63
    41
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.646
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.25

    Secondary: Number of Participants achieving 50% reduction in Urine Protein Creatinine Ratio

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    End point title
    		 Number of Participants achieving 50% reduction in Urine Protein Creatinine Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
        Participants with 50% UPCR Reduction
    173
    135
        Participants without 50% UPCR Reduction
    6
    43
    No statistical analyses for this end point

    Secondary: Time to 50% Reduction in Urine Protein Creatinine Ratio (Number of Days)

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    End point title
    		 Time to 50% Reduction in Urine Protein Creatinine Ratio (Number of Days)
    End point description
    Time in days to reduction in Urine Protein Creatinine ratio to decrease by 50% compared to baseline. Baseline is the average of two pre-randomisation values.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: days
        median (confidence interval 95%)
    29 (29 to 32)
    63 (57 to 87)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Time taken to reach 50% reduction in urine protein creatinine ratio
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.62
         upper limit
    		 2.6

    Secondary: Change From Baseline in estimated Glomerular Filtration Rate

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    End point title
    		 Change From Baseline in estimated Glomerular Filtration Rate
    End point description
    Change from baseline by visit in estimated Glomerular Filtration rate (eGFR). eGFR is corrected to a maximum value of 90 ml/min/1.73 m2
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 and 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: mL/min/1.73m2
    arithmetic mean (standard deviation)
        Baseline
    78.3 ± 15.83
    77.4 ± 16.98
        Week 2 Change from Baseline
    -1.5 ± 9.44
    3.3 ± 10.12
        Week 4 Change from Baseline
    -0.4 ± 10.39
    3.2 ± 9.86
        Week 8 Change from Baseline
    -0.9 ± 13.1
    3.8 ± 11.27
        Week 12 Change from Baseline
    -0.3 ± 11.74
    3.3 ± 12.85
        Week 16 Change from Baseline
    -0.1 ± 12.27
    2.8 ± 13.25
        Week 20 Change from Baseline
    -0.7 ± 12.09
    3.2 ± 13.04
        Week 24 Change from Baseline
    -0.3 ± 13.8
    2.8 ± 13.84
        Week 30 Change from Baseline
    -0.8 ± 14.2
    1.8 ± 14.4
        Week 36 Change from Baseline
    -1.9 ± 14.89
    1.5 ± 14.84
        Week 42 Change from Baseline
    -2.8 ± 16.7
    1.5 ± 15.53
        Week 48 Change from Baseline
    -3.6 ± 17.2
    1.1 ± 15.71
        Week 52 Change from Baseline
    -1.5 ± 16.16
    1.5 ± 15
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 2
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 -1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 4
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 8
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 -1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 12
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 16
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 20
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.121
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.41
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 30
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.42
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 36
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.102
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.43
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 42
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.44
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 48
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 -1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.45
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    Change from Baseline in Corrected eGFR (mL/min/1.73m2) at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46

    Secondary: Change in Baseline in Urinary Protein Creatinine Ratio

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    End point title
    		 Change in Baseline in Urinary Protein Creatinine Ratio
    End point description
    Change from baseline by visit in Urine Protein Creatinine ratio. Baseline is the average of two pre-randomisation values.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 and 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: mg/mg
    arithmetic mean (standard deviation)
        Baseline
    4.14 ± 2.711
    3.87 ± 2.363
        Week 2 Change from Baseline
    -1.46 ± 1.991
    -0.7 ± 2.312
        Week 4 Change from Baseline
    -1.98 ± 2.29
    -1.07 ± 2.155
        Week 8 Change from Baseline
    -2.23 ± 2.213
    -1.43 ± 2.448
        Week 12 Change from Baseline
    -2.56 ± 2.293
    -1.48 ± 2.688
        Week 16 Change from Baseline
    -2.75 ± 2.462
    -1.58 ± 2.81
        Week 20 Change from Baseline
    -2.74 ± 2.968
    -1.54 ± 2.82
        Week 24 Change from Baseline
    -2.74 ± 2.567
    -1.59 ± 2.899
        Week 30 Change from Baseline
    -2.66 ± 3.336
    -1.7 ± 3.112
        Week 36 Change from Baseline
    -2.74 ± 2.871
    -1.63 ± 3.188
        Week 42 Change from Baseline
    -2.91 ± 2.522
    -1.78 ± 3.39
        Week 48 Change from Baseline
    -2.71 ± 2.807
    -1.8 ± 3.004
        Week 52 Change from Baseline
    -2.65 ± 2.872
    -1.88 ± 3.05
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 2
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 4
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.13
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.187
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 8
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.181
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 12
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 -0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.196
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 16
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 -0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.214
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 20
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.63
         upper limit
    		 -0.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.241
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.59
         upper limit
    		 -0.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.222
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 30
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 -0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.284
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 36
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 -0.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.264
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 42
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 -0.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.256
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 48
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.56
         upper limit
    		 -0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.256
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    Change from Baseline in UPCR (mg/mg) at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.52
         upper limit
    		 -0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27

    Secondary: Number of Participants with Renal Response with Low Dose Steroids

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    End point title
    		 Number of Participants with Renal Response with Low Dose Steroids
    End point description
    Programmed Renal Response while on low dose steroids (<2.5 mg/day) for the preceding 8 weeks at weeks 24 and 52
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Participants
        Renal Response at Week 24
    32
    16
        Renal Response at Week 52
    64
    36
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Renal Response at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 4.71
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Renal Response at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.48
         upper limit
    		 4

    Secondary: Change from Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI)

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    End point title
    		 Change from Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI)
    End point description
    SELENA-SLEDAI were analyzed using a mixed effect model repeated measures (MMRM) analysis with treatment arm, visit, treatment by visit interaction, biopsy class, MMF use at baseline, region, and baseline UPCR included as covariates in the model. Results are expressed as differences between treatment arms along with the associated 95% CI. The least squares means (LS means) and their corresponding 95% confidence intervals of the change from baseline values are also presented for each visit and for the overall change.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Scores on a Scale
    least squares mean (confidence interval 95%)
        Week 24 Change from Baseline
    -4.5 (-5.4 to -3.7)
    -4.1 (-5.0 to -3.2)
        Week 52 Change from Baseline
    -6 (-6.7 to -5.2)
    -5.5 (-6.3 to -4.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change from Baseline at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.373
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 0.6
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change from Baseline at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.277
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.4

    Secondary: Change from Baseline in Patient Report Outcomes

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    End point title
    		 Change from Baseline in Patient Report Outcomes
    End point description
    Health-related quality of life (HRQoL) information was collected using the Short Form Health Survey (SF-36) HRQoL assessment and the LupusPRO (v1.7) assessment. - SF-36 is a 36-item patient-reported questionnaire of patient health - LupusPro assessment is a patient-reported questionnaire regarding the effect of lupus or its treatment on the patient’s health, quality of life, and the medical care received related to lupus.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 52
    End point values
    		 Voclosporin Placebo
    Number of subjects analysed
    179
    178
    Units: Scores on a scale
    least squares mean (confidence interval 95%)
        SF-36 Change from Baseline at Week 24
    6.64 (4.34 to 8.93)
    7.11 (4.80 to 9.42)
        SF-36 Change from Baseline at Week 52
    10.44 (8.04 to 12.83)
    10.81 (8.37 to 13.25)
        LupusPRO HRQOL Change from Baseline at Week 24
    7.76 (5.40 to 10.13)
    6.06 (3.68 to 8.45)
        LupusPRO HRQOL Change from Baseline at Week 52
    9.24 (6.78 to 11.70)
    9.84 (7.33 to 12.35)
        LupusPRO non-HRQOL Change from Baseline at Week 24
    1.06 (-1.32 to 3.44)
    2.94 (0.54 to 5.35)
        LupusPRO non-HRQOL Change from Baseline at Week 52
    4.08 (1.60 to 6.56)
    3.74 (1.22 to 6.26)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    SF-36 Change from Baseline Week 24
    Comparison groups
    Placebo v Voclosporin
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.733
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.21
         upper limit
    		 2.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.389
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    SF-36 Change from Baseline at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.801
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.29
         upper limit
    		 2.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.481
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    LupusPRO HRQOL Change from Baseline at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.239
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 4.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.442
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    LupusPRO HRQOL Change from Baseline at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.695
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.62
         upper limit
    		 2.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.535
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    LupusPRO non-HRQOL Change from Baseline at Week 24
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.72
         upper limit
    		 0.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.439
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    LupusPRO non-HRQOL Change from Baseline at Week 52
    Comparison groups
    Voclosporin v Placebo
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.826
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.826
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.67
         upper limit
    		 3.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.531

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs occurring after first dose and up to 30 days post-last dose of voclosporin/placebo
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Voclosporin
    Reporting group description
    		 Voclosporin 23.7 mg BID

    Reporting group title
    Placebo Oral Capsule
    Reporting group description
    		 Matching placebo

    Serious adverse events
    		 Voclosporin Placebo Oral Capsule
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 178 (20.79%)
    38 / 178 (21.35%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         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
    Pleural effusion
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus pleurisy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         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
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus encephalitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropsychiatric lupus
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 178 (2.25%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    1 / 178 (0.56%)
    4 / 178 (2.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    3 / 178 (1.69%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         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
    7 / 178 (3.93%)
    8 / 178 (4.49%)
         occurrences causally related to treatment / all
    1 / 8
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastroenteritis
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         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 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 178 (0.56%)
         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
    		 Voclosporin Placebo Oral Capsule
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    161 / 178 (90.45%)
    156 / 178 (87.64%)
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    43 / 178 (24.16%)
    15 / 178 (8.43%)
         occurrences all number
    61
    19
    Vascular disorders
    Hypertension
         subjects affected / exposed
    35 / 178 (19.66%)
    14 / 178 (7.87%)
         occurrences all number
    38
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 178 (16.29%)
    11 / 178 (6.18%)
         occurrences all number
    34
    16
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    11 / 178 (6.18%)
    11 / 178 (6.18%)
         occurrences all number
    11
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 178 (10.11%)
    10 / 178 (5.62%)
         occurrences all number
    19
    11
    Leukopenia
         subjects affected / exposed
    7 / 178 (3.93%)
    10 / 178 (5.62%)
         occurrences all number
    8
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    34 / 178 (19.10%)
    21 / 178 (11.80%)
         occurrences all number
    43
    23
    Abdominal pain upper
         subjects affected / exposed
    13 / 178 (7.30%)
    1 / 178 (0.56%)
         occurrences all number
    13
    2
    Abdominal pain
         subjects affected / exposed
    10 / 178 (5.62%)
    2 / 178 (1.12%)
         occurrences all number
    11
    3
    Nausea
         subjects affected / exposed
    10 / 178 (5.62%)
    17 / 178 (9.55%)
         occurrences all number
    10
    18
    Dyspepsia
         subjects affected / exposed
    10 / 178 (5.62%)
    3 / 178 (1.69%)
         occurrences all number
    10
    3
    Vomiting
         subjects affected / exposed
    5 / 178 (2.81%)
    12 / 178 (6.74%)
         occurrences all number
    6
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 178 (7.30%)
    3 / 178 (1.69%)
         occurrences all number
    13
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 178 (5.62%)
    5 / 178 (2.81%)
         occurrences all number
    10
    5
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    11 / 178 (6.18%)
    5 / 178 (2.81%)
         occurrences all number
    14
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 178 (4.49%)
    17 / 178 (9.55%)
         occurrences all number
    9
    20
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 178 (17.42%)
    26 / 178 (14.61%)
         occurrences all number
    44
    33
    Viral upper respiratory tract infection
         subjects affected / exposed
    20 / 178 (11.24%)
    18 / 178 (10.11%)
         occurrences all number
    24
    20
    Urinary tract infection
         subjects affected / exposed
    17 / 178 (9.55%)
    13 / 178 (7.30%)
         occurrences all number
    25
    14
    Herpes zoster
         subjects affected / exposed
    13 / 178 (7.30%)
    9 / 178 (5.06%)
         occurrences all number
    13
    9
    Influenza
         subjects affected / exposed
    12 / 178 (6.74%)
    10 / 178 (5.62%)
         occurrences all number
    15
    12
    Gastroenteritis
         subjects affected / exposed
    7 / 178 (3.93%)
    10 / 178 (5.62%)
         occurrences all number
    8
    10
    Pharyngitis
         subjects affected / exposed
    3 / 178 (1.69%)
    9 / 178 (5.06%)
         occurrences all number
    3
    11
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 178 (1.69%)
    9 / 178 (5.06%)
         occurrences all number
    3
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2017
    1. Time point for primary efficacy endpoint changed from Week 24 to Week 52 2. Change in the primary and secondary efficacy endpoints for renal response 3. Addition of secondary efficacy endpoint for decrease in eGFR 4. Change in the time window of the biopsy used for screening and to include Class V lupus nephritis 5. Change in handling increases in blood pressure or hypertension and pulse 6. Change in stratification of randomization 7. Addition of the evaluation of biomarkers 8. Clarification of regarding definition of treatment emergent adverse events 9. Editorial changes for clarification made throughout

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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