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    Clinical Trial Results:
    PROOF OF CONCEPT STUDY OF HYQVIA IN PATIENTS WITH IMMUNOGLOBULIN DEFICIENCY AND RECURRENT INFECTIONS WITH CHRONIC FATIGUE SYNDROME

    Summary
    EudraCT number
    		 2016-002370-12
    Trial protocol
    		 DE  
    Global end of trial date
    27 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2022
    First version publication date
    09 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IMI2016-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité Universitätsmedizin Berlin
    Sponsor organisation address
    Augustenburger Platz 1, Berlin, Germany, 13353
    Public contact
    Frau Prof. Dr. Carmen Scheibenbogen, Institut für Medizinische Immunologie, 49 030450524062 , carmen.scheibenbogen@charite.de
    Scientific contact
    PD Dr. med. Patricia Grabowski, Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, patricia.grabowski@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
    19 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to improve chronic fatigue syndrome in patients with chronic immunodeficiency and recurrent infections
    Protection of trial subjects
    Patients are monitored for AE and SAE during IgG infusion as well as the periods between infusions. At home patients are requested to keep a diary where they document all infusions, complaints and problems. Side effects will be documented according to CTC criteria. This clinical study will be conducted in accordance with the principles of Good Clinical Practice (ICH-GCP) and the regulations of the actual Arzneimittelgesetz (AMG) and in accordance with the Declaration of Helsinki version October 1996 (48th General Assembly of the World Medical Association, Somerset West, Republic of South Africa).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    16
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 ME/CFS patients were selected who were diagnosed at the outpatient clinic for immunodeficiencies at the Institute of Medical Immunology at the Charité Universitätsmedizin Berlin (Berlin, Germany) and fulfilled the inclusion criteria. Start of recruitment: 01.09.2016 End of recruitment:

    Pre-assignment
    Screening details
    		 It was planned to include 15 patients in the trial and replace patients receiving less than 3 months of treatment. All 17 patients who were approached agreed to participate in the trial. Assessed for eligibility:17 Allocation: 17

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

    Arms
    Arm title
    		 ME/CFS patients
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    HyQvia
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    0.2-0.8g/kg body weight / month Month 1, day 0: total 0.2 g/kg body weight per month (one infusion). Month 2: total 0.4 g/kg body weight per month (given as one or bi-weekly infusion). Months 3–12: total 0.8 g/kg body weight per month (given as bi-weekly infusion).

    Number of subjects in period 1
    		ME/CFS patients
    Started
    17
    Completed
    12
    Not completed
    5
         Adverse event, non-fatal
    3
         Lack of efficacy
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ME/CFS patients
    Reporting group description
    		 -

    Reporting group values
    		 ME/CFS patients Total
    Number of subjects
    		 17 17
    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)
    		 16 16
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 46 (18 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 8 8
    infection-triggered onset
    Units: Subjects
        received infections
    		 12 12
        no infections
    		 5 5
    age at disease onset
    Units: years
        median (full range (min-max))
    		 36 (15 to 61) -
    Bell’s Functionality Score (Disability Scale Assessment)
    Bell score (max 100 points)
    Units: Bell score
        median (full range (min-max))
    		 30 (20 to 50) -

    End points

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    End points reporting groups
    Reporting group title
    ME/CFS patients
    Reporting group description
    		 -

    Subject analysis set title
    Completers
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    A total of 12 patients received the scheduled 12-months treatment

    Primary: change of the Chalder fatigue scale

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    End point title
    		 change of the Chalder fatigue scale [1]
    End point description
    Univariate comparison of two independent groups was performed using the Mann–Whitney-U test, comparison of two dependent groups was done using the Wilcoxon matched-pairs signed-rank test. A two-tailed p-value of <0.05 was considered statistically significant.
    End point type
    Primary
    End point timeframe
    up to 12 months follow up
    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: This was an investigator-initiated one arm trial
    End point values
    		 Completers
    Number of subjects analysed
    12
    Units: Scale
    median (full range (min-max))
        pre
    27.50 (21.00 to 31.00)
        3 Months
    26.50 (19.00 to 33.00)
        6 months
    22.50 (8.00 to 29.00)
        9 months
    20.50 (14.00 to 28.00)
        12 months
    23.00 (15.00 to 31.00)
    No statistical analyses for this end point

    Primary: change of the SF-36

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    End point title
    		 change of the SF-36 [2]
    End point description
    Univariate comparison of two independent groups was performed using the Mann–Whitney-U test, comparison of two dependent groups was done using the Wilcoxon matched-pairs signed-rank test. A two-tailed p-value of <0.05 was considered statistically significant.
    End point type
    Primary
    End point timeframe
    up to 12 months fallow up
    Notes
    [2] - 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: This was an investigator-initiated one arm trial
    End point values
    		 Completers
    Number of subjects analysed
    12
    Units: Scale
    median (full range (min-max))
        pre
    20.00 (0.00 to 60.00)
        3 months
    30.00 (0.00 to 50.00)
        6 months
    45.00 (10.00 to 65.00)
        9 months
    42.50 (10.00 to 85.00)
        12 months
    42.50 (5.00 to 80.00)
    No statistical analyses for this end point

    Secondary: improvement of the autonomic dysfunction

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    End point title
    		 improvement of the autonomic dysfunction
    End point description
    All patients reported moderate to severe symptoms of autonomic dysfunction assessed by the COMPASS-31 questionnaire. The COMPASS-31 is a questionnaire validated by the Mayo Clinic to assess and quantify symptoms of autonomic dysfunction. 6 categories of organ dysfunction will be assessed with a maximum of 100 being the most severe disturbance.
    End point type
    Secondary
    End point timeframe
    15months
    End point values
    		 Completers
    Number of subjects analysed
    12
    Units: Score
    median (full range (min-max))
        at baseline
    50.9 (12.9 to 73.8)
        6 months
    37.14 (6.99 to 60.06)
        9 months
    36.05 (20.16 to 54.72)
    No statistical analyses for this end point

    Secondary: Functional Assessment

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    End point title
    		 Functional Assessment
    End point description
    One Patient lost the tracker device. All responding patients at month 12 (patients 2, 11, 13 and 16) and also patients 4 and 8 with a response at month 6 and 9 walked more steps during IgG treatment. The number of steps in the five non-responder patients (patients 5, 6, 7, 10, 17) did not increase. There was no seasonal variation in numbers of steps. (See attachment)
    End point type
    Secondary
    End point timeframe
    15 months
    End point values
    		 Completers
    Number of subjects analysed
    6 [3]
    Units: steps per day
    median (full range (min-max))
        pretreatment
    4565 (1062 to 7756)
        at 6 months
    6067 (3017 to 10411)
    Notes
    [3] - Values only from the responders
    No statistical analyses for this end point

    Secondary: Effectiveness to control infections

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    End point title
    		 Effectiveness to control infections
    End point description
    End point type
    Secondary
    End point timeframe
    12 months before treatment and 12 mont during the treatment
    End point values
    		 Completers
    Number of subjects analysed
    11
    Units: Infections
    median (full range (min-max))
        Before
    6 (4 to 12)
        During 12 months
    3.5 (0 to 6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    15 months
    Adverse event reporting additional description
    Patients are monitored for AE and SAE during IgG infusion as well as the periods between infusions. At home patients are requested to keep a diary where they document all infusions, complaints and problems. Side effects will be documented according to CTC criteria. Grade 1 and 2 are non SAEs and Grade 3 are SAE.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    treatment completed
    Reporting group description
    		 -

    Reporting group title
    treatment not completed
    Reporting group description
    		 -

    Serious adverse events
    		 treatment completed treatment not completed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 treatment completed treatment not completed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    5 / 5 (100.00%)
    Injury, poisoning and procedural complications
    injection site reaction
         subjects affected / exposed
    12 / 12 (100.00%)
    5 / 5 (100.00%)
         occurrences all number
    12
    5
    General disorders and administration site conditions
    headache
         subjects affected / exposed
    5 / 12 (41.67%)
    5 / 5 (100.00%)
         occurrences all number
    5
    5
    Blood and lymphatic system disorders
    liver toxicity (ALT/GPT increase)
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 5 (80.00%)
         occurrences all number
    1
    4
    diarrhea
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 5 (40.00%)
         occurrences all number
    2
    2
    Infections and infestations
    flu-like symptoms
         subjects affected / exposed
    12 / 12 (100.00%)
    3 / 5 (60.00%)
         occurrences all number
    12
    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.
    Taken together, our study has several limitations, including a small patient number and a lack of a control arm.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34072494
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