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    Clinical Trial Results:
    A Phase I-IIa trial on low-dose IL-2 (Aldesleukin) treatment for immunological dysregulation in common variable immunodeficiency (CVID)

    Summary
    EudraCT number
    		 2015-003369-27
    Trial protocol
    		 DE  
    Global end of trial date
    05 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2020
    First version publication date
    04 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REGAIN
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00010424
    Sponsors
    Sponsor organisation name
    Medical Center - University of Freiburg
    Sponsor organisation address
    Breisacher Str. 153, Freiburg, Germany, 79110
    Public contact
    Dr. rer. nat. Annette Uhlmann , Clinical Trials Unit, Medical Center - University of Freiburg, +49 761 270 77771, annette.uhlmann@uniklinik-freiburg.de
    Scientific contact
    Prof. Dr. med. Klaus Warnatz, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, +49 761 270 77640, klaus.warnatz@uniklinik-freiburg.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
    06 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety (esp. with respect to autoimmunity) of different doses of low-dose s.c. Aldesleukin treatment in in common variable immunodeficiency (CVID) patients with autoimmune enteropathy (AIE)
    Protection of trial subjects
    Risk-based monitoring done according to ICH-GCP E6 and standard operating procedures (SOP) to verify that patients’ rights and wellbeing are protected.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    2
    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)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 2
    Number of subjects completed
    		 2

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single arm trial, no blinding possible

    Arms
    Arm title
    		 Aldesleukin
    Arm description
    		 Patients with autoimmune enteropathy occurring in the context of common variable immunodeficiency were treated with a cyclic, subcutaneous application of IL-2 (Aldesleukin) at different dose levels (0.5-2.0 MIO IE/day) during a period of 4 - 6 months. Each patient started with an induction cycle (1 MIO IE Aldesleukin/day on five consecutive days followed by nine days without treatment). The following maintenance cycles had a duration of three days followed by 11 days without treatment. IL-2 dosage was adjusted according to adverse events, frequency of Treg cells and clinical efficacy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aldesleukin
    Investigational medicinal product code
    Other name
    Interleukin-2, IL-2, Proleukin
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Different dose levels (0.5-2.0 MIO IE/day) during a period of 4 - 6 months. Each patient started with an induction cycle (1 MIO IE Aldesleukin/day on five consecutive days followed by nine days without treatment). The following maintenance cycles had a duration of three days followed by 11 days without treatment. IL-2 dosage was adjusted according to adverse events, frequency of Treg cells and clinical efficacy. Treatment duration was intended to be six months /per patient.

    Number of subjects in period 1
    		Aldesleukin
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 2 2
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 2 2
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 47 (36 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Aldesleukin
    Reporting group description
    		 Patients with autoimmune enteropathy occurring in the context of common variable immunodeficiency were treated with a cyclic, subcutaneous application of IL-2 (Aldesleukin) at different dose levels (0.5-2.0 MIO IE/day) during a period of 4 - 6 months. Each patient started with an induction cycle (1 MIO IE Aldesleukin/day on five consecutive days followed by nine days without treatment). The following maintenance cycles had a duration of three days followed by 11 days without treatment. IL-2 dosage was adjusted according to adverse events, frequency of Treg cells and clinical efficacy.

    Primary: Safety (combined primary endpoint)

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    End point title
    		 Safety (combined primary endpoint) [1]
    End point description
    Safety (combined primary endpoint): - Any adverse event with CTCAE grade ≥ 3 if not defined otherwise below (except injection site reaction grade 3) - Increasing lymphocytic infiltration or villous atrophy on histopathological analysis/ gastroduodenoscopy - Flare of pre-existing, previously silent, immune dysregulatory disorder (e.g. lymphocytic lung infiltration) requiring immunosuppressive treatment with > 20mg prednisolone equivalent - Percentage of Foxp3+CD127lo Treg among CD3+CD4+ T cells > 50% - Severe impairment of heart, liver or kidney function (CTCAE grade ≥ 3) - Cytopenia: - leukocyte count: < 2.000/ µl or - neutropenia < 1000/ µl or - platelets: < 50.000/ µl or - haemoglobin <8g/dl - Development of autoantibodies (ANA, RF) during the treatment phase
    End point type
    Primary
    End point timeframe
    during the trial
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only two participants were included in trial. Descriptive statistics were used to evaluate the results of the study.
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: Number of adverse events
    0
    No statistical analyses for this end point

    Secondary: IBDQ score

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    End point title
    		 IBDQ score
    End point description
    Increase of IBDQ score by at least 16 points compared to baseline according to the different dose levels.
    End point type
    Secondary
    End point timeframe
    during the trial
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: Number of patients
    2
    No statistical analyses for this end point

    Secondary: Stool frequency

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    End point title
    		 Stool frequency
    End point description
    Reduction of daily stool frequency by 3 stools compared to baseline according to the different dose levels
    End point type
    Secondary
    End point timeframe
    during the trial
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: Number of patients
    1
    No statistical analyses for this end point

    Secondary: Weight gain

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    End point title
    		 Weight gain
    End point description
    Weight gain of ≥ 2kg at EOT visit compared to baseline in each patient.
    End point type
    Secondary
    End point timeframe
    end of trial
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: Number of patients
    1
    No statistical analyses for this end point

    Secondary: Norovirus infection

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    End point title
    		 Norovirus infection
    End point description
    Clearance of (chronic) norovirus infection during treatment was analysed at 2, 4 and 6 months after initiation of treatment in each norovirus-positive patient at baseline. Patient 001 was negative for norovirus infection and therefore not included in this analysis (reporting group). Patient 002 was a norovirus carrier at baseline level and at all control measurements throughout the treatment.
    End point type
    Secondary
    End point timeframe
    2, 4 and 6 months after initiation of treatment
    End point values
    		 Aldesleukin
    Number of subjects analysed
    1
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Resolution of lymphocytic infiltration and villous atrophy

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    End point title
    		 Resolution of lymphocytic infiltration and villous atrophy
    End point description
    Resolution of lymphocytic infiltration and villous atrophy in gastroduodenoscopy + histopathology will be analyzed in each patient at follow-up compared to baseline.
    End point type
    Secondary
    End point timeframe
    after the low-dose IL-2 treatment
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: Number of patients
    0
    No statistical analyses for this end point

    Secondary: Expansion of Tregs

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    End point title
    		 Expansion of Tregs
    End point description
    End point type
    Secondary
    End point timeframe
    % of Tregs measured before each cycle and on day 4 of every cycle and on day 6 of the induction cycle(s).
    End point values
    		 Aldesleukin
    Number of subjects analysed
    2
    Units: % of CD25hi Treg
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the treatment and follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Investigations
    Eosinophil count increased
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    3
    Lymphopenia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    3
    Injection site induration
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Rash papular
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Despite intensive efforts no further eligible patients could be recruited
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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