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    Clinical Trial Results:
    A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Neutralization of the Interferon Gene Signature and the Clinical Efficacy of IFNα-Kinoid in Adult Subjects with Systemic Lupus Erythematosus

    Summary
    EudraCT number
    2015-001341-86
    Trial protocol
    DE   BE   HR   ES   BG  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Oct 2019
    First version publication date
    31 Oct 2019
    Other versions
    Summary report(s)
    IFN-K-002 CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    IFN-K-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02665364
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Neovacs
    Sponsor organisation address
    3-5 Impasse Reille, Paris, France, 75014
    Public contact
    Valérie Salentey, Neovacs S.A., 33 15310 9300, vsalentey@neovacs.com
    Scientific contact
    Valérie Salentey, Neovacs S.A., 33 15310 9300, vsalentey@neovacs.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    26 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: The primary objective of the main study (at week 36) is to evaluate the neutralization of the IFN gene signature following treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response modified by mandatory CS tapering.
    Protection of trial subjects
    The Phase IIb - IFN-K-002 study was conducted in accordance with the European Union Clinical Trial Directive, and local national laws as applicable, International Conference on Harmonization (ICH) E6 GCP guidelines, and the guidelines of the Declaration of Helsinki, revised form of 64th World Medical Association (WMA) General Assembly, Fortaleza, Brazil , 2013. An independent data safety monitoring board (iDSMB) consisting of experts in the appropriate disciplines, has been set up to oversee the conduct of the study as well as the safety with specific attention on "Lupus flares" and "Infections". Data review meetings held by iDSMB were planned 6 months after randomization of the first subject and then on a 6-monthly basis unless unscheduled meetings are required to adress particular safety concerns.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Sep 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Georgia: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Mexico: 19
    Country: Number of subjects enrolled
    Moldova, Republic of: 20
    Country: Number of subjects enrolled
    Peru: 21
    Country: Number of subjects enrolled
    Philippines: 19
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 3
    Country: Number of subjects enrolled
    Tunisia: 9
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    185
    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)
    185
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 185 subjects positive for IFN gene signature were randomized (1:1) to IFN-K or placebo. One subject was randomized in the IFN-K group and did not receive IFN-K. 184 subjects were treated; 91 subjects received IFN-K; and 93 subjects received Placebo.

    Pre-assignment
    Screening details
    4-week screening period A total of 707 subjects were screened, 185 subjects were randomized.

    Period 1
    Period 1 title
    Main study Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The main study was conducted with a double-blind design (subjects and Investigators were blinded).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Arm title
    IFN-K
    Arm description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    IFN-alpha Kinoid
    Investigational medicinal product code
    IFN-K
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Number of subjects in period 1 [1]
    Placebo IFN-K
    Started
    93
    91
    Completed
    84
    85
    Not completed
    9
    6
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    8
    3
         other
    -
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 185 subjects were randomized. One subject was randomized in IFN-K group and did not receive IFN-K. 184 subjects were treated; 91 subjects received IFN-K and 93 subjects received placebo.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Reporting group title
    IFN-K
    Reporting group description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Reporting group values
    Placebo IFN-K Total
    Number of subjects
    93 91 184
    Age categorical
    The mean (± S.D) age was 39.1 ± 10.7 years
    Units: Subjects
        adultes 18-64 years
    93 91 184
    Gender categorical
    Most subjects 93.5% were female
    Units: Subjects
        Female
    88 84 172
        Male
    5 7 12
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Subject analysis set title
    IFN-K
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Subject analysis sets values
    Placebo IFN-K
    Number of subjects
    93
    91
    Age categorical
    The mean (± S.D) age was 39.1 ± 10.7 years
    Units: Subjects
        adultes 18-64 years
    93
    91
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Most subjects 93.5% were female
    Units: Subjects
        Female
    88
    84
        Male
    5
    7

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at week (W)0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Reporting group title
    IFN-K
    Reporting group description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Subject analysis set title
    IFN-K
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Primary: percent change from baseline in IFN gene signature at W36

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    End point title
    percent change from baseline in IFN gene signature at W36
    End point description
    The biological endpoint aimed at evaluating the neutralization of the IFN gene signature following treatment with IFN-K compared to placebo, as measured by the % change from baseline of the expression of IFN-induced genes.
    End point type
    Primary
    End point timeframe
    Baseline and W36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    87
    Units: percent
        arithmetic mean (standard deviation)
    -0.44 ± 27.34
    -31.04 ± 38.96
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The percent of change from baseline to last available value between W24 and W36 of treatment in the expression of IFN-induced genes was analyzed using an analysis of covariance (ANCOVA) model.
    Comparison groups
    IFN-K v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -30.2802
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.6653
         upper limit
    -19.8951
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.2588

    Primary: BICLA Response with superimposed CS Tapering at Week 36

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    End point title
    BICLA Response with superimposed CS Tapering at Week 36
    End point description
    BICLA responder was defined as a subject who had the following criteria at week 36: - All BILAG A scores at baseline improve to B/C/D and all BILAG B scores improve to C/D at W36, and - No BILAG worsening in other body systems: no new BILAG A or ≥ 2 new BILAG B scores at W36, and - No worsening in SLEDAI-2K total score at W36 compared with baseline, and - No deterioration in Physician Global Assessment (PGA) (< 10% worsening) on Visual Analog Scale (VAS) 100 mm at W36 compared with baseline, and - No addition or increased dose level of anti-malarial drugs or immunosuppressive drugs or CS* between W24 and W36 (*≤5 mg prednisolone or equivalent /day at W24 and no increase until W36).
    End point type
    Primary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    85
    Units: number of patients
    29
    35
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Descriptive statistics for the response to treatment according to BICLA at week 36 were presented by treatment group. The response to treatment according to BICLA was analyzed using a logistic regression with the response rate as dependent variable and treatment as independent variable, while adjusting for the minimization factors used for randomization.
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.34
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.716
         upper limit
    2.657

    Secondary: SRI-4 response at Week 36

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    End point title
    SRI-4 response at Week 36
    End point description
    SLE Responder Index (SRI); SRI-4 responder was defined as a subject who had the following criteria at week 36: - reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and - no new BILAG A at week 36, and - no more than 1 new BILAG B at week 36, and - no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    83
    84
    Units: patient number
    54
    57
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The SRI-4 response was analyzed using a logistic regression using the response rate as dependent variable and treatment as independent variable, while adjusting for the minimization factors used for randomization.
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6243
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.602
         upper limit
    2.329

    Secondary: Composite SRI-4 including CS ≤5mg/day response at Week 36

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    End point title
    Composite SRI-4 including CS ≤5mg/day response at Week 36
    End point description
    SRI-4 plus CS ≤ 5mg/day responder was defined as a participant who had the following criteria at week 36: - reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and - no new BILAG A at week 36, and - no more than 1 new BILAG B at week 36, and - no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline plus corticosteroids (CS) ≤5mg equivalent prednisolone per day at week 36
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    77
    79
    Units: number of patients
    30
    43
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0762
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.938
         upper limit
    3.574

    Secondary: SLEDAI response at Week 36

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    End point title
    SLEDAI response at Week 36
    End point description
    SLE Disease Activity Index (SLEDAI)-2K is an activity index that measures disease activity and records feature of active Lupus as present or not present. There are 24 items in a total of 9 organs/systems; total scores range from 0 (non-active disease) – 105 points. Scores were attributed taking into account disease activity over the previous 10 days. SLEDAI-2K responder was defined as a participant who had reduction of the SLEDAI-2K score of at least 4 points at week 36 compared to baseline.
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    85
    Units: number of patients
    55
    61
    No statistical analyses for this end point

    Secondary: BILAG global score change from baseline at Week 36

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    End point title
    BILAG global score change from baseline at Week 36
    End point description
    British Isles Lupus Assessment Group (BILAG)-2004 index, it categorizes disease activity into 5 different levels from A to E, with Grade A representing very active disease and Grade E indicating no current or previous disease activity. Scoring was based on a total of 101 items, grouped into 9 organ/systems. The BILAG global score change from baseline to Last Available Value (LVA) week 24 and week 36 were presented analyzed.
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    87
    Units: BILAG score
        arithmetic mean (standard deviation)
    -10.76 ± 7.84
    -11.43 ± 8.57
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Baseline to last available value between W24 and W36
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7946
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SELENA-SLEDAI - change from baseline to Week 36

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    End point title
    SELENA-SLEDAI - change from baseline to Week 36
    End point description
    Safety of Estrogens in Systemic Lupus Erythematosus National Assessment (SELENA)-SLEDAI, is a slightly modified version of the SLEDAI. This is a weighted index in which signs and symptoms, laboratory tests, and Physician’s Global Assessment (PGA) for each of nine organ systems are given a weighted score and summed up if present at the time of the visit or in the preceding 10 days. The maximum theoretical score for the SELENA SLEDAI is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    83
    84
    Units: SELENA SLEDAI Score
        arithmetic mean (standard deviation)
    -5.54 ± 4.44
    -5.48 ± 4.30
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9224
    Method
    student - pooled
    Confidence interval

    Secondary: SLICC/ACR-DI change from baseline at Week 36

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    End point title
    SLICC/ACR-DI change from baseline at Week 36
    End point description
    Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus (SLICC/ACR-DI) captures permanent changes which have occurred in patients with SLE, regardless of causality. The questionnaire contains 41 items covering 12 different organ systems.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    83
    82
    Units: SLICC/ACR-DI Score
        arithmetic mean (standard deviation)
    -0.17 ± 0.49
    -0.09 ± 0.59
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    SLICC/ACR-DI was analyzed using Student-pooled
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3258
    Method
    student - pooled
    Confidence interval

    Secondary: CLASI total activity change from baseline at Week 36

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    End point title
    CLASI total activity change from baseline at Week 36
    End point description
    Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was specifically developed to assess the cutaneous manifestations of SLE. It measures both disease activity and permanent damage (e.g. dyspigmentation and scarring) over the entire body surface.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    85
    Units: CLASI Total activity
        arithmetic mean (standard deviation)
    -2.85 ± 3.60
    -3.22 ± 5.94
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6169
    Method
    Student - Satterthwaite
    Confidence interval

    Secondary: LLDAS at Week 36

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    End point title
    LLDAS at Week 36
    End point description
    Lupus low disease activity state (LLDAS) was conceptually defined as ‘a state which, if sustained, is associated with a low likelihood of adverse outcome, considering disease activity and medication safety’. Subsequently defined using consensus methodology, LLDAS is attained if all the following items are met: - SLEDAI-2K ≤4, with no activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal activity - No new features of lupus disease activity compared with the previous assessment - SELENA-SLEDAI physician global assessment (PGA, scale 0–3) ≤1 - Current prednisolone (or equivalent) dose ≤7.5 mg daily - Well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents, excluding investigational drugs
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    85
    Units: patient number
    25
    45
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    IFN-K v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    Pearson's Chi-squared
    Confidence interval

    Secondary: Neutralizing Anti-IFN-alpha antibodies response at W36

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    End point title
    Neutralizing Anti-IFN-alpha antibodies response at W36
    End point description
    Individual serum antibody neutralizing capacity against recombinant IFN-alpha2b was measured by reporter gene assay using Interferon Sensitive Response Element (ISRE) reporter.
    End point type
    Secondary
    End point timeframe
    At week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    0 [1]
    79
    Units: number of patients
    72
    Notes
    [1] - No Neutralizing Anti-IFN-alpha antibodies were performed on placebo subjects
    No statistical analyses for this end point

    Secondary: Composite SRI-4 including CS ≤7,5mg/day response at Week 36

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    End point title
    Composite SRI-4 including CS ≤7,5mg/day response at Week 36
    End point description
    SRI (4) plus CS ≤ 7.5 mg/day responder was defined as a participant who had the following criteria at week 36: - reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and - no new BILAG A at week 36, and - no more than 1 new BILAG B at week 36, and - no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline plus CS ≤7.5mg equivalent prednisolone per day at week 36
    End point type
    Secondary
    End point timeframe
    At Week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    77
    79
    Units: number of patients
    33
    46
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0796
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.932
         upper limit
    3.524

    Other pre-specified: CS mean daily dose at W36

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    End point title
    CS mean daily dose at W36
    End point description
    mean daily dose of corticosteroid (CS) (prednisone equivalent)
    End point type
    Other pre-specified
    End point timeframe
    W36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    84
    85
    Units: mg/day
        arithmetic mean (standard deviation)
    7.06 ± 4.69
    5.42 ± 3.28
    Attachments
    Figure - Corticosteroids-IFN-K-002
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097
    Method
    Student - Satterthwaite
    Confidence interval

    Post-hoc: Composite SRI-4 (CS ≤5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36

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    End point title
    Composite SRI-4 (CS ≤5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36
    End point description
    Subjects who had the following criteria defined as : SRI-4 plus CS ≤5mg/day -excluding IFN-K subjects without positive anti-IFN-alpha neutralizing antibodies
    End point type
    Post-hoc
    End point timeframe
    At week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    77
    72
    Units: number of patients
    30
    40
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    149
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0425
    Method
    Pearson's Chi-squared
    Confidence interval

    Post-hoc: Composite SRI-4 (CS ≤7.5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36

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    End point title
    Composite SRI-4 (CS ≤7.5mg/day) response excluding IFN-K subjects without positive anti-IFNalpha neutralizing antibodies at Week 36
    End point description
    participant who had the following criteria defined as : SRI-4 plus CS ≤7.5mg/day -excluding IFN-K Patients without positive anti-IFN-alpha neutralizing antibodies
    End point type
    Post-hoc
    End point timeframe
    At week 36
    End point values
    Placebo IFN-K
    Number of subjects analysed
    77
    72
    Units: number of patients
    33
    43
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v IFN-K
    Number of subjects included in analysis
    149
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0396
    Method
    Pearson's Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) non serious and serious (SAEs) were collected from the start of study medication to Week 36.
    Adverse event reporting additional description
    Due to IFN-K mechanism of action, i.e. immunization, and the administration route, i.e. intramuscular (IM), some AEs, local and/or systemic AEs, were expected and solicited within 7 days after study Investigational Medicinal Product (IMP) administration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Reporting group title
    IFN-K
    Reporting group description
    Subjects received IFN-K adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 µg at W0, W1, W4 and 1 administration of 120 µg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment.

    Serious adverse events
    Placebo IFN-K
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 93 (12.90%)
    6 / 91 (6.59%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal cancer stage II
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    3 / 93 (3.23%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (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
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         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
    Chest pain
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Kaposi's varicelliform eruption
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo IFN-K
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 93 (79.57%)
    78 / 91 (85.71%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 93 (5.38%)
    0 / 91 (0.00%)
         occurrences all number
    6
    0
    Immune system disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    12 / 93 (12.90%)
    10 / 91 (10.99%)
         occurrences all number
    19
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 93 (2.15%)
    10 / 91 (10.99%)
         occurrences all number
    3
    19
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    0 / 93 (0.00%)
    5 / 91 (5.49%)
         occurrences all number
    0
    8
    Pyrexia
         subjects affected / exposed
    5 / 93 (5.38%)
    2 / 91 (2.20%)
         occurrences all number
    7
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 93 (2.15%)
    7 / 91 (7.69%)
         occurrences all number
    3
    8
    Pain in extremity
         subjects affected / exposed
    1 / 93 (1.08%)
    6 / 91 (6.59%)
         occurrences all number
    1
    6
    Myalgia
         subjects affected / exposed
    7 / 93 (7.53%)
    3 / 91 (3.30%)
         occurrences all number
    7
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 93 (5.38%)
    16 / 91 (17.58%)
         occurrences all number
    6
    17
    Urinary tract infection
         subjects affected / exposed
    9 / 93 (9.68%)
    11 / 91 (12.09%)
         occurrences all number
    10
    11
    Nasopharyngitis
         subjects affected / exposed
    2 / 93 (2.15%)
    7 / 91 (7.69%)
         occurrences all number
    2
    10
    Pharyngitis
         subjects affected / exposed
    3 / 93 (3.23%)
    6 / 91 (6.59%)
         occurrences all number
    4
    7
    Bronchitis
         subjects affected / exposed
    4 / 93 (4.30%)
    5 / 91 (5.49%)
         occurrences all number
    4
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2015
    Amendment #1 (dated 11 August 2015): it amended the protocol Version 2.0 into protocol Version 3.0 as per request of the European Health Authorities. This amendment introduced and update of the promary objective to: - The primary objective of this study is to evaluate the neutralization of the IFN gene signature following treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response criteria.
    08 Dec 2015
    Amendment #2 (dated 08 December 2015), amending the protocol Version 3.0 into protocol Version 4.0, introduced the following modifications: - Addition of the extended follow-up within the IFN-K-002 protocol rather than in a separate protocol: the protocol Version 4.0 therefore integrated an extended follow up period up to a total duration of 5 years (60 months, i.e. 240 weeks) after the last visit of the main study (Visit 12 at week 36). The visit at week 276 (Month 69), i.e. FU10, was then considered as the last planned visit. - complete extended follow-up only for some subjects receiving the active treatment: due to the double-blind study design, all subjects who had completed the main study (up to Visit 12 at week 36) would enter into the extended follow-up period. When the results would be available, only subjects having received IFN-K and having produced anti-IFN-alpha antibodies (neutralizing) would continue the extended follow up. Subjects would remain into the extended follow-up period until they become negative for anti-IFN-alpha neutralizing antibodies or for up to 5 years (60 months, i.e. 240 weeks) after Visit 12, whichever comes first. - frequency of visits during the extended follow-up: subjects would be followed every 6 months, as in the IFN-K-001 study. - regular analyses: for safety purpose, a descriptive analysis would be performed at regular intervals, according to DSUR timelines.
    28 Jan 2016
    Amendment #3 (dated 28 January 2016), amending the protocol Version 4.0 into protocol Version 5.0, introduced the following modifications: - Expansion of geographic areas for the study conduct: worldwide epidemiology studies reported large variations in incidence and prevalence of SLE, reflecting influences of race, ethnicity and socio-economic status; in addition, several studies have demonstrated an overexpression of IFN-alpha inducible genes in SLE subjects and a possible correlation between their expression and the disease activity notably the serological markers. The study being originally planned to be conducted in 3 geographic areas (Europe, Asia-Pacific and Latin-America), the protocol was amended to expand the study to the USA to provide results on an overall population and better cover the specificities of the different ethnicities. - The relationship between the ethnicity and the expression of the IFN gene signature was taken into account in the randomization (minimization factor) and the sample size calculation was revised to ensure statistical power on the primary endpoints.
    11 Apr 2016
    Amendment #4 (dated 11 April 2016), amending the protocol Version 5.0 into protocol Version 6.0, introduced the following modifications: - Complete extended follow-up only for all subjects receiving the active treatment: as requested by Food and Drug Administration (FDA), all subjects having received IFN-K would be followed up for up to 60 months, irrespective of the production of anti-IFN-alpha antibodies at Visit 12 (Week 36) and during the whole extended follow up period. - Modification of inclusion criterion #8: as requested by FDA, the time on treatment and time on stable dose has been increased to 12 weeks prior to study product injection for subjects taking Methotrexate (MTX), Azathioprine (AZA) and Mycophenolate Mofetil (MMF). - Modification of exclusion criterion #11 for US subjects only: as requested by FDA, only subjects with negative screening tests for malignancy according to the American Cancer Society (ACS) guidelines within 12 months before screening Visit could be enrolled; in addition, for subjects with history of treated cancers, only treated basal cell carcinoma was not preventing enrollment. - Modification of an event leading to study product dicontinuation: as requested by FDA, “the occurrence of bronchospasm after administration of study product must be considered as a criterion for study product discontinuation” was revised as “bronchospasm or anaphylactic reaction following the administration of the study product”. - Modification is AE reporting: since not all countries have the same requirements for reporting of fatal, life-threatening events and all other SAEs to Regulatory Health Authorities, the possibility to follow local requirements was added.
    15 May 2017
    Local amendment (amendment #5) for Argentina (dated 15 May 2017), amending the protocol Version 5.0 into protocol Version 6.1: per request of the Argentinian Health Authority, the following modifications have been made: - Modification of exclusion criterion #11 for: “history of malignant cancer, except the following treated cancers: basal cell carcinoma or dermatological squamous cell carcinoma”. - Modification of exclusion criterion #23 for: “cytological abnormalities ≥LSIL (low grade squamous intraepithelial lesions) on a cervical swab at Screening or within 3 months prior to the first planned study product administration”. - Addition of clarification to inclusion criterion #9. - Addition of clarification to exclusion criterion #1.

    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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