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    Clinical Trial Results:
    A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 2 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects with Active Proliferative Lupus Nephritis

    Summary
    EudraCT number
    		 2015-001442-29
    Trial protocol
    		 BE   HU   DE   ES   GB   FR   IT  
    Global end of trial date
    18 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2021
    First version publication date
    24 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3461C00007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02547922
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca Clinical study Information Center, 1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical study Information Center, 1 8772409479, information.center@astrazeneca.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
    24 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of anifrolumab versus placebo by the relative difference in change from baseline to Week 52 in the 24-hour UPCR in patients with active, proliferative LN.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/ Good Clinical Practice (GCP), applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2015
    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
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Peru: 30
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    145
    EEA total number of subjects
    32
    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)
    143
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects who met all the inclusion and none of the exclusion criteria were randomized at 66 sites in 16 countries. The study was conducted from 30 November 2015 to 18 January 2021.

    Pre-assignment
    Screening details
    		 The screening period was from Day -30 to Day -1. Informed consent form (ICF) was signed prior to screening procedures. All the study assessments were performed as per the schedule of assessment.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 All Anifrolumab
    Arm description
    		 This arm comprises Anifrolumab - Basic Regimen and Anifrolumab - Intensified Regimen. Anifrolumab - Basic Regimen: Subjects were administered with lower dose of Anifrolumab intravenously (IV) every 4 weeks (Q4W) from Week 0 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112. Anifrolumab - Intensified Regimen: Subjects were administered with higher dose of Anifrolumab IV Q4W for first 3 doses followed by lower dose from Week 12 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Anifrolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with lower dose of Anifrolumab every 4 weeks (Q4W) from Week 0 to Week 100 or higher dose of Anifrolumab Q4W for first 3 doses followed by lower dose from Week 12 to Week 100.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were administered with placebo every 4 week from Week 0 to Week 100 in addition to SOC which continued until Week 112.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with placebo intravenously every 4 weeks from Week 0 to Week 100.

    Number of subjects in period 1
    		All Anifrolumab Placebo
    Started
    96
    49
    Completed
    46
    20
    Not completed
    50
    29
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    15
    10
         Physician decision
    3
    2
         PROGRESSIVE DISEASE
    1
    2
         Adverse event, non-fatal
    4
    2
         TECHNICAL PROBLEMS
    1
    -
         Non-responding completer
    12
    9
         Lost to follow-up
    1
    -
         Lack of efficacy
    12
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Anifrolumab
    Reporting group description
    		 This arm comprises Anifrolumab - Basic Regimen and Anifrolumab - Intensified Regimen. Anifrolumab - Basic Regimen: Subjects were administered with lower dose of Anifrolumab intravenously (IV) every 4 weeks (Q4W) from Week 0 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112. Anifrolumab - Intensified Regimen: Subjects were administered with higher dose of Anifrolumab IV Q4W for first 3 doses followed by lower dose from Week 12 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered with placebo every 4 week from Week 0 to Week 100 in addition to SOC which continued until Week 112.

    Reporting group values
    		 All Anifrolumab Placebo Total
    Number of subjects
    		 96 49 145
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 94 49 143
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.1 ( 10.96 ) 34.0 ( 10.18 ) -
    Sex: Female, Male
    Units:
        Female
    		 82 38 120
        Male
    		 14 11 25
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 45 20 65
        Not Hispanic or Latino
    		 51 29 80
        Unknown or Not Reported
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 4 0 4
        Asian
    		 18 10 28
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 6 1 7
        White
    		 42 24 66
        Other
    		 25 14 39

    End points

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    End points reporting groups
    Reporting group title
    All Anifrolumab
    Reporting group description
    		 This arm comprises Anifrolumab - Basic Regimen and Anifrolumab - Intensified Regimen. Anifrolumab - Basic Regimen: Subjects were administered with lower dose of Anifrolumab intravenously (IV) every 4 weeks (Q4W) from Week 0 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112. Anifrolumab - Intensified Regimen: Subjects were administered with higher dose of Anifrolumab IV Q4W for first 3 doses followed by lower dose from Week 12 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered with placebo every 4 week from Week 0 to Week 100 in addition to SOC which continued until Week 112.

    Primary: Relative difference in change from baseline in 24-hour urine protein to creatinine ratio (UPCR)

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    End point title
    		 Relative difference in change from baseline in 24-hour urine protein to creatinine ratio (UPCR)
    End point description
    The efficacy of anifrolumab plus SOC (combination of mycophenolate mofetil and corticosteroids) compared with placebo plus SOC in subjects with active proliferative lupus nephritis (LN) was evaluated. Geometric mean ratio of 24-hour UPCR at week 52 over baseline. Values <1 indicate improvement from baseline.
    End point type
    Primary
    End point timeframe
    From Week 1 (Baseline) up to Week 52
    End point values
    		 All Anifrolumab Placebo
    Number of subjects analysed
    91
    41
    Units: milligram/milligram (mg/mg)
        geometric mean (confidence interval 95%)
    0.305 (0.198 to 0.468)
    0.296 (0.175 to 0.499)
    Statistical analysis title
    		 All Anifrolumab vs Placebo
    Statistical analysis description
    The model includes fixed effects for treatment group, visit, stratification factors, log-transformed 24-hour UPCR at baseline, and treatment-by-visit interaction. All data up to and including the date of discontinuation of study treatment were included in the analysis.
    Comparison groups
    All Anifrolumab v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9052 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.031
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.621
         upper limit
    		 1.713
    Notes
    [1] - The p-values presented are unadjusted and was compared with the respective adjusted significance level (α). If α is not displayed, no formal testing can be performed and the corresponding p-value was nominal.

    Secondary: Proportion of subjects achieving the composite endpoint Complete Renal Response (CRR)

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    End point title
    		 Proportion of subjects achieving the composite endpoint Complete Renal Response (CRR)
    End point description
    CRR was defined as meeting all of the following: -Estimated glomerular filtration rate (eGFR) is ≥60 mL/min/1.73 m^2 or no confirmed decrease of eGFR from baseline of ≥20% -24-hour UPCR ≤ 0.7 mg/mg -No discontinuation of investigational product (IP) or use of restricted medication beyond the protocol allowed threshold before assessment -eGFR was based on Modification of Diet in Renal Disease (MDRD) formula. Subjects treated with restricted medication beyond the protocol allowed threshold, or discontinuing study treatment for other reasons, were regarded as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 All Anifrolumab Placebo
    Number of subjects analysed
    87
    45
    Units: Percentage of subjects
    number (not applicable)
        Responder
    31.0
    31.1
        Non-responder
    69.0
    68.9
    Statistical analysis title
    		 Anifrolumab vs Placebo
    Statistical analysis description
    The responder/non-responder rates (percentages), the difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach.
    Comparison groups
    All Anifrolumab v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9929 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in estimates
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.92
         upper limit
    		 16.76
    Notes
    [2] - At Week 52, the p-values presented are unadjusted and will be compared to the respective adjusted significance level (α). If α is not displayed no formal testing can be performed and the corresponding p-value is nominal.

    Other pre-specified: Number of subjects with adverse events

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    End point title
    		 Number of subjects with adverse events
    End point description
    The AEs (non-serious, serious and adverse event of special interest (AESI)) as variables of safety and tolerability of anifrolimab was assessed. The AESIs are serious infections, including non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, TB (including latent TB), influenza, vasculitis (non-SLE), and MACE (including stroke, acute coronary syndrome, myocardial infarction, or cardiovascular death). Study period: During treatment (DT) and follow-up (FU) data are presented. IMP refers to investigational medicinal product; EAC refers to Event Adjudication Committee; SLE refers to Systemic lupus erythematosus.
    End point type
    Other pre-specified
    End point timeframe
    From screening (Day-30 to -1) period until the follow-up period (Week 112)
    End point values
    		 All Anifrolumab Placebo
    Number of subjects analysed
    96
    49
    Units: Number of subjects
        Subjects with any AE- DT
    90
    44
        Subjects with any acute AE- DT
    26
    14
        Any AE with death outcome- DT
    0
    0
        Any SAE (including events outcome of death)- DT
    19
    8
        Any AE leading to discontinuation of IMP- DT
    11
    5
        Any AE related to IMP- DT
    37
    16
        Any AE of severe intensity- DT
    13
    8
        Any AESI- DT
    24
    8
        Non-opportunistic serious infections- DT
    1
    3
        Opportunistic infections- DT
    1
    1
        Anaphylaxis- DT
    0
    0
        Malignancy- DT
    1
    0
        Herpes zoster- DT
    16
    4
        Tuberculosis/LTB (latent tuberculosis)- DT
    0
    0
        Influenza- DT
    6
    1
        Vasculitis (non-systemic lupus erythematosus)- DT
    0
    0
        Major adverse CV events (CV-EAC)- DT
    0
    1
        Any other significant AE- DT
    0
    0
        Subjects with any AE- FU
    20
    22
        Any AE death outcome- FU
    1
    0
        Any SAE (including events with death outcome)- FU
    3
    3
        Any AE related to IMP- FU
    2
    1
        Any AE of severe intensity- FU
    2
    3
        Any AESI- FU
    2
    2
        Non-opportunistic serious infections- FU
    0
    1
        Opportunistic infections- FU
    0
    0
        Anaphylaxis- FU
    0
    0
        Malignancy- FU
    0
    0
        Herpes zoster- FU
    2
    1
        Tuberculosis/LTB- FU
    0
    0
        Influenza- FU
    0
    0
        Vasculitis (non-SLE)- FU
    0
    0
        Major adverse CV events (CV-EAC)- FU
    0
    0
        Any other significant AE- FU
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Extra-renal flares using Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI 2K) based Flare Assessment Instrument

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    End point title
    		 Extra-renal flares using Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI 2K) based Flare Assessment Instrument
    End point description
    Flare will be defined as any one criterion present in either the Mild/Moderate Flare and/or Severe Flare categories. New or worsened manifestation should only be reported for manifestations of SLE. The SLEDAI-2K score range is 0 to 105 with higher scores representing increased disease activity. Mild/ Moderate flare defined as change in non-renal components of the SLEDAI-2K instrument score of ≥3 but <7 points compared to previous visit. Severe Flare defined as change in non-renal components of the SLEDAI-2K instrument score by ≥7 points compared to previous visit. The flare rate per subject year is defined as the number of subjects with a respective flare divided by the sum of exposure time in days for all subjects in the analysis set multiplied by 365.25.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to week 112
    End point values
    		 All Anifrolumab Placebo
    Number of subjects analysed
    96
    49
    Units: Flare rate per subject year
    number (not applicable)
        Mild/moderate: All flares
    0.017
    0.016
        Mild/moderate: On-treatment
    0.014
    0.010
        Mild/moderate: Off-treatment
    0.003
    0.006
        Severe: All flares
    0.003
    0.006
        Severe: On-treatment
    0.002
    0.004
        Severe: Off-treatment
    0.002
    0.002
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening (Day-30 to -1) period until follow-up (Week 112).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    All Anifrolumab- Treatment Period
    Reporting group description
    		 This arm comprises Anifrolumab - Basic Regimen and Anifrolumab - Intensified Regimen. Anifrolumab - Basic Regimen: Subjects were administered with lower dose of Anifrolumab intravenously (IV) every 4 weeks (Q4W) from Week 0 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112. Anifrolumab - Intensified Regimen: Subjects were administered with higher dose of Anifrolumab IV Q4W for first 3 doses followed by lower dose from Week 12 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112.

    Reporting group title
    All Anifrolumab- Follow up
    Reporting group description
    		 This arm comprises Anifrolumab - Basic Regimen and Anifrolumab - Intensified Regimen. Anifrolumab - Basic Regimen: Subjects were administered with lower dose of Anifrolumab intravenously (IV) every 4 weeks (Q4W) from Week 0 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112. Anifrolumab - Intensified Regimen: Subjects were administered with higher dose of Anifrolumab IV Q4W for first 3 doses followed by lower dose from Week 12 to Week 100, in addition to pre-specified standard of care (SOC) which continued until Week 112.

    Reporting group title
    Placebo- Treatment period
    Reporting group description
    		 Subjects were administered with placebo every 4 week from Week 0 to Week 100 in addition to SOC which continued until Week 112.

    Reporting group title
    Placebo- Follow up
    Reporting group description
    		 Subjects were administered with placebo every 4 week from Week 0 to Week 100 in addition to SOC which continued until Week 112.

    Serious adverse events
    		 All Anifrolumab- Treatment Period All Anifrolumab- Follow up Placebo- Treatment period Placebo- Follow up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 96 (19.79%)
    3 / 96 (3.13%)
    8 / 49 (16.33%)
    3 / 49 (6.12%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Lupus endocarditis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 96 (1.04%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 96 (1.04%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Lupus nephritis
         subjects affected / exposed
    2 / 96 (2.08%)
    1 / 96 (1.04%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess bacterial
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster pneumonia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis disseminated
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa bacterial
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Anifrolumab- Treatment Period All Anifrolumab- Follow up Placebo- Treatment period Placebo- Follow up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 96 (72.92%)
    0 / 96 (0.00%)
    33 / 49 (67.35%)
    0 / 49 (0.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 96 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 96 (0.00%)
    10 / 49 (20.41%)
    0 / 49 (0.00%)
         occurrences all number
    8
    0
    11
    0
    Nausea
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 96 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    2
    0
    Dyspepsia
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Vomiting
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Abdominal pain
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    10
    0
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 96 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    16 / 96 (16.67%)
    0 / 96 (0.00%)
    5 / 49 (10.20%)
    0 / 49 (0.00%)
         occurrences all number
    19
    0
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    15 / 96 (15.63%)
    0 / 96 (0.00%)
    9 / 49 (18.37%)
    0 / 49 (0.00%)
         occurrences all number
    22
    0
    16
    0
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 96 (15.63%)
    0 / 96 (0.00%)
    8 / 49 (16.33%)
    0 / 49 (0.00%)
         occurrences all number
    26
    0
    10
    0
    Bronchitis
         subjects affected / exposed
    11 / 96 (11.46%)
    0 / 96 (0.00%)
    6 / 49 (12.24%)
    0 / 49 (0.00%)
         occurrences all number
    11
    0
    6
    0
    Herpes zoster
         subjects affected / exposed
    10 / 96 (10.42%)
    0 / 96 (0.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
         occurrences all number
    10
    0
    4
    0
    Pharyngitis
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 96 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    10
    0
    2
    0
    Oral herpes
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 96 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    7
    0
    6
    0
    Herpes simplex
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 96 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    2
    0
    Influenza
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 96 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2016
    Minimum dose of MMF updated from ≤ 1.5 g/day to ≤ 1.0 g/day; Inclusion criteria: numbers 4(b), 7, and 9 to 14 were updated; Exclusion criteria: numbers 2, 6, 13(b), 14(g), 15, 17, 19, 26, 27, 32, and 36(b) were updated; Restricted medication list updated: danazol, dapsone, sulfasalazine, and prednisolone removed; cholestyramine added; Clarification that the methylprednisolone pulse can be administered on 2 consecutive days but that the cumulative dose must not exceed 500 mg and that oral corticosteroids (OCS) burst and taper means one burst and taper of corticosteroids between Week 8 and Week 40 for increased extrarenal SLE disease activity or for non-SLE activity is allowed from randomization to Week 40; Section 3.3.3.1 was updated to provide clarity to the Investigators whether reaching the target MMF dose of 2 gm/day was mandatory or just recommended. Texts were added to clarify that the requirements for MMF dose escalation have to be met only once; Text in Section 6.5.1 has been reworded to amend the definition of “serious non-opportunistic” infection; Safety data have been updated in Section 1.3 based on the new Investigator’s Brochure (version 9.0, dated 18 November 2015)
    03 Sep 2016
    Update of study design with addition of second-year extension period: • Patients who met the renal portion of the PRR definition were eligible to receive blinded IP between Week 52 and Week 100; • Eligible patients continued in the same randomized treatment group from Year 1; • Ineligible patients did not receive IP at Week 52 and completed the follow-up visits; • Clarification of standard of care treatments added.; • Clarification of efficacy and safety assessment time points added; • Clarification of time points for sampling schedule added; • Additional exploratory endpoints and objectives added; • Statistical analyses updated to include second-year extension period. Database was soft-locked and primary analysis performed when all patients completed Week 52 or discontinued the study prior to Week 52. Investigators and patients who continue in the second-year extension will remain blinded; AstraZeneca and AstraZeneca’s delegates will be unblinded at primary analysis.
    13 Dec 2017
    The renal function and proteinuria components of renal response criteria were modified by changing 24-hour UPCR and eGFR cut-off values; CRR cut-off values for UPCR and eGFR were changed; CRR at Week 52 was made a secondary endpoint; Changes to statistical analysis: • Text added describing strong control of the familywise error rate will be performed for the primary and secondary endpoints for the pooled anifrolumab group compared with placebo as well as the respective tests for the individual anifrolumab regimens; • Considerations described for the testing strategy to account for multiplicity considerations; • The sample size will provide approximately 86% power with a 2-sided alpha of 0.049; • Relevant sections of the CSP were updated to be consistent with the SAP; Possibility of conducting an interim analysis was added; Exclusion criterion no. 14 was modified: changed to > 2.5 × ULN for AST and ALT; Clarification on a number of study procedures 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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