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    Clinical Trial Results:
    Evaluation of the safety, tolerability, efficacy and immunological responses of the interleukin-2 analogue Aldesleukin (Proleukin®) in the treatment of systemic lupus erythematosus as prototypic autoimmune disease (PRO-IMMUN). A COMBINED PHASE I/IIA, PROSPECTIVE, OPEN-LABEL AND UNCONTROLLED SINGLE-CENTER STUDY TO ANALYSE SAFETY, TOLERABILITY, EFFICACY AND IMMUNOLOGICAL RESPONSES OF LOW-DOSE SUBCUTANEOUS INTERLEUKIN-2 (ALDESLEUKIN, PROLEUKIN®) IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND INCREASED DISEASE ACTIVITY REFRACTORY TO STANDARD THERAPIES.

    Summary
    EudraCT number
    		 2013-001599-40
    Trial protocol
    		 DE  
    Global end of trial date
    19 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions
    Summary report(s)
    		 Final Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    23032013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00004858
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Organisationseinheit für Neue Therapien (Studienabteilung), Charité - Universitätsmedizin Berlin Rheumatologie und klinische Immunologie, CC12, +49 30450 513 061, gerd.burmester@charite.de
    Scientific contact
    Organisationseinheit für Neue Therapien (Studienabteilung), Charité - Universitätsmedizin Berlin Rheumatologie und klinische Immunologie, CC12, +49 30450 513 061, gerd.burmester@charite.de
    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
    26 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of PRO-IMMUN was to evaluate the safety, tolerability and the effects on the Treg population of a cyclic subcutaneous low-dose interleukin-2 regimen using the recombinant human interleukin-2 analogue aldesleukin (Proleukin®) in SLE patients with moderate-to-severe disease activity despite previous treatment with at least two conventional therapies. The primary endpoint was the number of patients who achieved at least a 100% increase (2-fold) in the proportion of CD25hi-expressing cells among circulating CD3+CD4+FoxP3+CD127lo Treg at day 62 (week 9; one day after the 4th treatment cycle) compared to baseline at day 1 (before the 1st treatment cycle). Safety and tolerability were evaluated descriptively by assessment of the incidence, frequency, duration, severity, toxicity grade and the causal relationship to the study medication of any adverse event at every scheduled visit after the screening visit (Visits 2-11) and at every unscheduled visit.
    Protection of trial subjects
    To ensure trial subjects safety study visits took place every 5 to 16 days during the treatment phase (9 weeks) including a detailed physical examination with vital signs (axillary body temperature, pulse rate in resting position, systolic and diastolic blood pressure in resting position), asssesements of disease activity, tolerability, AEs and comprehensive safety laboratory and immunological analyses. Follow-up visits took place 3 weeks (week 12) and 9 weeks (week 18) after last dosing of the IMP. To minimize IMP-associated AEs such as fever, chills, myalgia or arthralgia, patients were recommended to take 500-1000mg of paracetamol prior to s.c. application of the IMP. Diagnostic safety procedures including a 12-lead electrocardiogram, an echocardiography, an abdominal ultrasound and lung function tests were performed during the screening and the follow-up period. At screening and before each of the four treatment cycles the Eastern Cooperative Oncology Group (ECOG) performance status was determined. Patients with an ECOG grade of two or more were not eligible to participate or to continue to participate in this study.
    Background therapy
    		 Corticosteroids at daily doses of ≤ 30mg prednisolone (or equivalent) orally and the following standard-of-care immunosuppressive therapies at stable doses for least 4 weeks prior to the first administration of the IMP (day 1) at the indicated dose ranges: - Azathioprine: 1-2 mg/kg/day orally - Chloroquine or hydroxychloroquine: 200-400 mg/d orally - Mycophenolate mofetil (MMF): 1-3g/d orally - NSAID: oral doses as indicated and allowed Changes in the daily dose of corticosteroids during the study were allowed if considered appropriate by investigator.
    Evidence for comparator
    		 Single-arm study without active comparator
    Actual start date of recruitment
    31 Mar 2014
    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
    Germany: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between March 31, 2014, and May 27, 2016 from the in– and outpatient clinic of the Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie of the Charité – Universitätsmedizin Berlin, Germany

    Pre-assignment
    Screening details
    		 Between March 31, 2014, and May 27, 2016, 13 patients were screened for pre-specified inclusion and exclusion critieria, of whom 10 met the eligibility criteria and were enrolled in the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Low-dose IL-2
    Arm description
    		 The therapeutic regimen consisted of four separate treatment cycles each with daily subcutaneous injections of different doses of aldesleukin for five consecutive days. A consecutive increase of the administered single daily dose of aldesleukin from the previous cycle to the subsequent cycle was scheduled in order to assess the tolerability and the dose-dependency of observed effects. Dose adaptations during the treatment period were applied according to defined dose adaption criteria. Used single doses of aldesleukin: 0.75 million IU, 1.5 million IU and 3.0 million IU per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aldesleukin
    Investigational medicinal product code
    L03A C01
    Other name
    Proleukin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The therapeutic regimen consisted of four treatment cycles each with daily subcutaneous injections of aldesleukin for five consecutive days separated by washout periods of 9 to 16 days in between the cycles. Dose adaptions of the administered daily dose of aldesleukin in the subsequent cycles were conducted according to defined dose adaption criteria. The decision to reduce, maintain or increase the single daily dose in the subsequent treatment cycle was based on clinical, laboratory and immunological findings obtained during the previous cycle. Administered daily dosages per cycle: 1st cycle: 1.5 million IU (7.5 million IU in total) 2nd cycle: 0.75 or 3.0 million IU (3.75 or 15 million IU in total) 3rd cycle: 0.75 or 1.5 million IU (7.5 or 15 million IU in total) 4th cycle: 0.75 or 1.5 million IU (7.5 or 15 million IU in total)

    Number of subjects in period 1
    		Low-dose IL-2
    Started
    10
    Completed
    9
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Mean age (range): 37.7 years (26-54 years) Sex: 1 male, 9 females Mean disease duration (range): 13.3 years (2-35 years) Mean SELENA-SLEDAI score (range): 10 (6-16) Mean daily dose of corticosteroids (range): 9.25 mg/day (5-20 mg/day)

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 10
    Age continuous
    Mean age (range): 37.7 years (26-54 years)
    Units: years
        arithmetic mean (full range (min-max))
    		 37.7 (26 to 54) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 1 1
    Disease duration
    Mean disease duration (range): 13.3 years (2-35 years)
    Units: years
        arithmetic mean (full range (min-max))
    		 13.3 (2 to 35) -
    SELENA-SLEDAI score
    Disease activity measure Mean SELENA-SLEDAI score (range): 10 (6-16)
    Units: points
        arithmetic mean (full range (min-max))
    		 10 (6 to 16) -
    Corticosteroid dose
    Mean daily dose of corticosteroids (range): 9.25 mg/day (5-20 mg/day)
    Units: mg/day
        arithmetic mean (full range (min-max))
    		 9.25 (5 to 20) -

    End points

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    End points reporting groups
    Reporting group title
    Low-dose IL-2
    Reporting group description
    		 The therapeutic regimen consisted of four separate treatment cycles each with daily subcutaneous injections of different doses of aldesleukin for five consecutive days. A consecutive increase of the administered single daily dose of aldesleukin from the previous cycle to the subsequent cycle was scheduled in order to assess the tolerability and the dose-dependency of observed effects. Dose adaptations during the treatment period were applied according to defined dose adaption criteria. Used single doses of aldesleukin: 0.75 million IU, 1.5 million IU and 3.0 million IU per day

    Subject analysis set title
    Analysis population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Definition of analysed population: The primary efficacy endpoint and all secondary endpoints were assessed in all patients who completed at least one treatment cycle (intention-to-treat population excluding screening failures). Last-observation-carried-forward (LOCF) modality was applied for non-completer.

    Primary: Treg response

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    End point title
    		 Treg response
    End point description
    Number of patients who achieved at least a 100% increase from baseline in the proportion of CD25hi-expressing cells among circulating CD3+CD4+FoxP3+CD127lo regulatory T cells at day 62 (after four treatment cycles)
    End point type
    Primary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: number
        100% increase from baseline
    0
    9
    Statistical analysis title
    		 Treg response (continuous variables)
    Statistical analysis description
    Change from baseline in the proportion of CD25hi-expressing cells among circulating CD3+CD4+FOXP3+CD127lo regulatory T cells at day 62
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.002
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    22.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.75
         upper limit
    		 32.53
    Variability estimate
    Standard deviation
    Dispersion value
    11.03
    Notes
    [1] - Two-sided Wilcoxon signed-rank test was used to compare changes in the proportion of CD25hi-expressing cells among circulating CD3+CD4+FOXP3+CD127lo regulatory T cells between baseline and day 62

    Secondary: Clinical response: SELENA-SLEDAI

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    End point title
    		 Clinical response: SELENA-SLEDAI
    End point description
    Absolute change from baseline in SELENA-SLEDAI score at day 62
    End point type
    Secondary
    End point timeframe
    Day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: points
        median (inter-quartile range (Q1-Q3))
    10.0 (7.5 to 12.5)
    5.0 (4.0 to 12.25)
    Statistical analysis title
    		 Clinical response (continuous variables)
    Statistical analysis description
    Absolute change from baseline in SLENA-SLEDAI score at day 62
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.041
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.295
         upper limit
    		 -0.5048
    Variability estimate
    Standard deviation
    Dispersion value
    3.348

    Secondary: Clinical response: PGA

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    End point title
    		 Clinical response: PGA
    End point description
    Absolute change from baseline in PGA score at day 62
    End point type
    Secondary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: points
        median (inter-quartile range (Q1-Q3))
    1.75 (1.5 to 2.125)
    1.25 (0.5 to 2.0)
    Statistical analysis title
    		 Clinical response PGA (continuous variables)
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0039
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9677
         upper limit
    		 -0.3823
    Variability estimate
    Standard deviation
    Dispersion value
    0.4091

    Secondary: Serological response: C3

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    End point title
    		 Serological response: C3
    End point description
    Change from baseline in serum concentrations of the complement factor C3 at day 62
    End point type
    Secondary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    775 (605 to 795)
    805 (737.5 to 832.5)
    Statistical analysis title
    		 Serological response C3 (continuous variables)
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0078
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.17
         upper limit
    		 117.8
    Variability estimate
    Standard deviation
    Dispersion value
    72.45

    Secondary: Serological response: C4

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    End point title
    		 Serological response: C4
    End point description
    Change from baseline in concentration of the complement factor C4 at day 62
    End point type
    Secondary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    95 (75 to 122.5)
    100 (67.5 to 135)
    Statistical analysis title
    		 Serological response C4 (continuous variables)
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1875
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.954
         upper limit
    		 15.95
    Variability estimate
    Standard deviation
    Dispersion value
    12.52

    Secondary: Serological response: anti-dsDNA-Abs

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    End point title
    		 Serological response: anti-dsDNA-Abs
    End point description
    Change from baseline in concentration of anti-dsDNA-antibodies at day 62
    End point type
    Secondary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: U/mL
        median (inter-quartile range (Q1-Q3))
    72.65 (18.13 to 251.7)
    75.75 (18.63 to 255.0)
    Statistical analysis title
    		 Serological response dsDNA (continuous variables)
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5566
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.17
         upper limit
    		 140.7
    Variability estimate
    Standard deviation
    Dispersion value
    136.9

    Secondary: Corticosteroid dose

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    End point title
    		 Corticosteroid dose
    End point description
    Change from baseline in the daily dose of corticosteroids at day 62
    End point type
    Secondary
    End point timeframe
    day 1 to day 62
    End point values
    		 Low-dose IL-2 Analysis population
    Number of subjects analysed
    10
    10
    Units: mg/day
        median (inter-quartile range (Q1-Q3))
    7.5 (5 to 11.25)
    7.5 (5 to 13.75)
    Statistical analysis title
    		 Corticosteroid dose (continuous variables)
    Comparison groups
    Low-dose IL-2 v Analysis population
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.625
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.169
         upper limit
    		 6.669
    Variability estimate
    Standard deviation
    Dispersion value
    6.877

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    31.03.2014-20.10.2016 up to 22 weeks for each participant (including screening and follow-up periods)
    Adverse event reporting additional description
    Safety assessments were performed at every scheduled and unscheduled study visit during the whole study period and included a complete physical examination with vital signs, current history and symptoms, changes in concomitant medications, assessment of adverse events (AE) and safety laboratroy tests.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 Safety and tolerability were evaluated descriptively in patients who received at least one dose of aldesleukin (safety population). Safety assessments were performed at every scheduled and unscheduled study visit during the whole study period and included a complete physical examination of all relevant body systems with vital signs (axillary body temperature, pulse rate in resting position, systolic and diastolic blood pressure in resting position), a complete assessment of current history and symptoms, changes in concomitant medications, assessment of adverse events (AE) and safety laboratory test. Any AE occurring after the screening visit was recorded and assessed according to incidence, frequency, duration, severity, toxicity grade and causal relationship to the study medication.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Peripheral ischemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    7
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    32
    Fever
         subjects affected / exposed
    7 / 10 (70.00%)
         occurrences all number
    15
    Chills
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    6 / 10 (60.00%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2015
    Change of principal investigator and his deputy.

    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.
    - Single-arm study without active comparator - Small number of enrolled subjects (n=10)
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