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    Clinical Trial Results:
    Study of efficacy of low-dose recombinant human interleukin-2 in immunological changes associated with depression (IL2REG)

    Summary
    EudraCT number
    		 2019-001696-36
    Trial protocol
    		 IT  
    Global end of trial date
    06 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2024
    First version publication date
    29 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IL2REG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ospedale San Raffaele
    Sponsor organisation address
    60 Olgettina, Milano, Italy, 20132
    Public contact
    Psichaitria e Psicobiologia Clinica, Francesco Benedetti, hsrsanraffaele@hsr.postecert.it
    Scientific contact
    Psichaitria e Psicobiologia Clinica, Francesco Benedetti, hsrsanraffaele@hsr.postecert.it
    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 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    prove the improvement of T regulatory cells response following add-on treatment with IL-2 (Aldesleukin) in patients affected by mood disorder win an ongoing depressive episode
    Protection of trial subjects
    The persons responsible for the quality control of clinical studies will take all necessary precautions to ensure the confidentiality of information relating to the investigational medicinal products, the study, the study participants and in particular the identity of the participants and the results obtained. These persons, as well as the investigators themselves, are bound by professional secrecy (in accordance with the conditions set out in Articles 623 and 622 of the Italian Penal Code (R.D. 19 ottobre 1930, n. 1398)). During and after the clinical study, all data collected about the study participants and sent to the sponsor by the investigators (or any other specialised collaborators) will be anonymised. Under no circumstances will the names and addresses of the subjects be shown. The sponsor will ensure that each subject has agreed in writing for any personal information about him or her which is strictly necessary for the quality control of the study to be accessed
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2019
    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
    Italy: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    32
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruitment has taken place from November 2019 to April 2023. The first patient was recruited on January 2020

    Pre-assignment
    Screening details
    		 Inclusion criteria: age 18-65 years, a depressive episode according to DSM-V criteria in the course of bipolar or major depressive disorder, a score at the MADRS> 17, and be already on an anti-depressant and/or mood stabilizer. 108 patients have been screened, 66 refused, 6 didn't met inclusion criteria

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Treatments was manufactured according to a list provided by an independent person and assigning a treatment arm to each treatment number. • randomization lists were kept strictly confidential until the time of un-blinding, and were not accessible by anyone involved in the study; • the treatment was administered by a physician who did not participate in any other phase of the study preventing the identification of treatment by patients, investigators and study personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IL-2
    Arm description
    		 Subjects treated with aldesleukin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    1±10% MIU/day in a volume of 0,07 ml for subcutaneous injection

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Water per injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    0.07 ml of sterile water for injection was subcutaneously injected

    Number of subjects in period 1
    		IL-2 Placebo
    Started
    24
    12
    induction phase
    24
    12
    maintenance phase
    18
    11
    Completed
    18
    10
    Not completed
    6
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    -
         covid lockwdown
    -
    2
         Lost to follow-up
    2
    -
         covid lockdown
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IL-2
    Reporting group description
    		 Subjects treated with aldesleukin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 IL-2 Placebo Total
    Number of subjects
    		 24 12 36
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Baseline age of all subjects divided per arm
    Units: years
        arithmetic mean (standard deviation)
    		 52.12 ( 10.46 ) 48.23 ( 15.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 8 22
        Male
    		 10 4 14
    MADRS
    depression severity as measured by the Montgomery–Åsberg Depression Rating Scale
    Units: points
        arithmetic mean (standard deviation)
    		 32.87 ( 7.52 ) 31.61 ( 7.47 ) -
    Subject analysis sets

    Subject analysis set title
    BD-IL2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in regulatory t cells in patients with bipolar disorder treated with IL2

    Subject analysis set title
    MDD-IL2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in T regulatory cells in patients with Major depression treated with IL-2

    Subject analysis set title
    BD-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Bipolar depressed patients treated with Placebo

    Subject analysis set title
    MDD-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in regulatory t cells in patients with Major depression treated with placebo

    Subject analysis sets values
    		 BD-IL2 MDD-IL2 BD-Placebo MDD-Placebo
    Number of subjects
    12
    12
    6
    6
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Baseline age of all subjects divided per arm
    Units: years
        arithmetic mean (standard deviation)
    53.09 ( 5.48 )
    16.17 ( 18.82 )
    50.00 ( 13.91 )
    46.17 ( 13.78 )
    Gender categorical
    Units: Subjects
        Female
    6
    6
    3
    3
        Male
    6
    6
    3
    3
    MADRS
    depression severity as measured by the Montgomery–Åsberg Depression Rating Scale
    Units: points
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    IL-2
    Reporting group description
    		 Subjects treated with aldesleukin

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    BD-IL2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in regulatory t cells in patients with bipolar disorder treated with IL2

    Subject analysis set title
    MDD-IL2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in T regulatory cells in patients with Major depression treated with IL-2

    Subject analysis set title
    BD-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Bipolar depressed patients treated with Placebo

    Subject analysis set title
    MDD-Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Changes in regulatory t cells in patients with Major depression treated with placebo

    Primary: Change in T regulatory cells

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    End point title
    		 Change in T regulatory cells
    End point description
    change in T regulatory cells after the induction period. delta score Day 0-Day5
    End point type
    Primary
    End point timeframe
    baseline-day5
    End point values
    		 IL-2 Placebo BD-IL2 MDD-IL2 BD-Placebo MDD-Placebo
    Number of subjects analysed
    24
    12
    12
    12
    6
    6
    Units: frequences
        arithmetic mean (standard deviation)
    1.20 ( 2.36 )
    0.22 ( 1.24 )
    1.82 ( 2.38 )
    0.65 ( 2.30 )
    0.06 ( 1.10 )
    0.40 ( 1.48 )
    Statistical analysis title
    		 primary endpoint
    Comparison groups
    IL-2 v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 LR chi-square type I test
    Parameter type
    		 Likelihood ratio
    Point estimate
    4.603
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.602
         upper limit
    		 4.604
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.2
    Notes
    [1] - Homogeneity of slopes analysis within the generalized linear model, likelihood ratio method to estimate significance, per protocol sample (28 completers) Confidence limits not available (only available for Wald estimates within the GLZM)
    [2] - Confidence limits not available for LR chi square type I testing (only available for Wald estimates within the GLZM), relevant fields have been completed with dummy numbers just to allow to go on in saving the page

    Secondary: Effect of treatment on depressive symptoms

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    End point title
    		 Effect of treatment on depressive symptoms
    End point description
    Changes in depressive symptoms at the end of the study
    End point type
    Secondary
    End point timeframe
    Baseline-end of follow-up
    End point values
    		 IL-2 Placebo BD-IL2 MDD-IL2 BD-Placebo MDD-Placebo
    Number of subjects analysed
    24
    12
    12
    12
    6
    6
    Units: points
        arithmetic mean (standard deviation)
    22.83 ( 11.63 )
    18.75 ( 11.22 )
    21.36 ( 10.57 )
    24.07 ( 12.76 )
    21.00 ( 12.57 )
    15.60 ( 9.39 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall trial
    Adverse event reporting additional description
    NA
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    patients treated with IL2
    Reporting group description
    		 All subjects treated with IL-2

    Serious adverse events
    		 patients treated with IL2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 patients treated with IL2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 24 (12.50%)
    General disorders and administration site conditions
    allergic reaction
    Additional description: 2 mild allergic reaction which resolved spontaneously 1 mild allergic reaction which resolved with antihistamine treatment
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3

    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.
    The trial started at the beginning of 2020 in coincidence with the covid-19 pandemia. Lock-downs have affected the compliance of the patients to come to the hospital for treatment administration and controls

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38367846
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