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    Clinical Trial Results:
    Explorative Untersuchung zum Einfluss der Vitamin D-vermitteltenr Modulation der initialen subkutanen Gräserpollen-spezifischen Immuntherapie bei Allergikern mit Gräserpollen-induzierter Rhinokonjunktivitis mit/ohne allergischem Asthma

    Summary
    EudraCT number
    		 2010-021775-80
    Trial protocol
    		 DE  
    Global end of trial date
    13 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2021
    First version publication date
    16 Sep 2021
    Other versions
    Summary report(s)
    		 Final_report_ProGIT_2010-021775-80

    Trial information

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    Trial identification
    Sponsor protocol code
    ProGIT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01466465
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Margitta Worm, Charité - Universitätsmedizin Berlin Dpt. of Dermatology Division of Allergy and Immunology, margitta.worm@charite.de
    Scientific contact
    Margitta Worm, Charité - Universitätsmedizin Berlin Dpt. of Dermatology Division of Allergy and Immunology, margitta.worm@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
    12 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to determine whether concomitant vitamin D supplementation promotes that the allergen specific immunotherapy-induced action onset regarding the intracutaneous test reaction to 500 SBU grass pollen.
    Protection of trial subjects
    All clinical tests (blood draw, skin prick test, intracutaneous test, conjunctival provocation tests) and therapeutic interventions (immunotherapy injection) were performed according to defined SOPs and clinical standards. An patient insurance in accordance with the Medicines Act, Section 40, Paragraph 3) was provided for the probands for travel to the study center and for potential therapeutic side effects. As no specific e.g. painful procedures were performed, no specific procedures were required.
    Background therapy
    		 All participants were grass pollen-allergic and all patients were treated with a regular grass pollen-specific immunotherapy according to the manufacturer's instructions.
    Evidence for comparator
    		 Vitamin D receptors control the IgE class switch in B lymphocytes. Activated immune cells can synthesize the active metabolite of vitamin D, calcitriol, from its precursor. In mice, adjacent vitamin D to specific immunotherapy enhance the immunoregulation and beneficial impact on experimental murine allergic airway inflammation. Also in human, vitamin D supplementation can target immune cells, including B lymphocytes. In summary, supplementation of vitamin D to otherwise deficient individuals should enhance the immunomodulatory effect of specific immunotherapy.
    Actual start date of recruitment
    18 Oct 2011
    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: 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)
    36
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment via the in-house outpatients clinics of grass pollen-allergic individuals with hay fever +/- allergic asthma, who planned a specific immunotherapy

    Pre-assignment
    Screening details
    		 Grass pollen allergy No sun/UV-exposure planned during the treatment period (November-April) No contraindication against immunotherapy (e.g. uncontroled asthma, planned pregnancy)

    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, Monitor, Data analyst, Assessor
    Blinding implementation details
    The participants were randomly assigned to the vitamin D or placebo group by the Charité pharmacology Dept. The cholecalciferol or placebo control drug (neutral oil, Migliol® carrier substance of Vigantol®) was packaged identically to maintain the double-blind character. The safety laboratory (serum 25OHD, calci-um, phosphate) were checked by unblinded study personel to exclude a bias by the blinded physician who were in direct contact within direct contact with the study participants

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vitamin D
    Arm description
    		 active drug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vigantol Öl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    vitamin D (5,333 I.U./day) was orally applied by 8 drops daily (2013/2014 10 drops due to a new packaging device and drop size). It was applied daily between visit 1 and 10 in 3 consecutive treatment years (total 3x 4.5 months).

    Arm title
    		 Placebo
    Arm description
    		 Migliol® (neutral carrier oil)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Migliol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    The comparator was orally applied by 8 drops daily (2013/2014 10 drops due to a new packaging device and drop size). It was applied daily between visit 1 and 10 in 3 consecutive treatment years (total 3x 4.5 months).

    Number of subjects in period 1
    		Vitamin D Placebo
    Started
    18
    18
    Completed
    12
    11
    Not completed
    6
    7
         Consent withdrawn by subject
    2
    4
         Adverse event, non-fatal
    1
    -
         Pregnancy
    1
    -
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 36 36
    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)
    		 36 36
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 32.5 ( 1.8 ) -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 14 14
        Male
    		 22 22
    25OHD
    mean 25-hydroxyvitamin D
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 41.1 ( 1.9 ) -
    Grass-Ig
    determines the concentration of grass pollen-specific IgE in the serum
    Units: kUA/L
        arithmetic mean (standard deviation)
    		 30.8 ( 11.1 ) -
    Subject analysis sets

    Subject analysis set title
    Vitamin D Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all data

    Subject analysis set title
    Placebo group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All data

    Subject analysis sets values
    		 Vitamin D Group Placebo group
    Number of subjects
    18
    18
    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)
    18
    18
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    33 ( 1.7 )
    32 ( 1.8 )
    Gender categorical
    Gender
    Units: Subjects
        Female
    8
    6
        Male
    10
    12
    25OHD
    mean 25-hydroxyvitamin D
    Units: nmol/L
        arithmetic mean (standard deviation)
    40.4 ( 2.9 )
    41.7 ( 2.6 )
    Grass-Ig
    determines the concentration of grass pollen-specific IgE in the serum
    Units: kUA/L
        arithmetic mean (standard deviation)
    27.4 ( 14.5 )
    127.6 ( 42.6 )

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 active drug

    Reporting group title
    Placebo
    Reporting group description
    		 Migliol® (neutral carrier oil)

    Subject analysis set title
    Vitamin D Group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all data

    Subject analysis set title
    Placebo group
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All data

    Primary: Intracutaneous 500 SBU

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    End point title
    		 Intracutaneous 500 SBU
    End point description
    Wheal sizes of the intracutaneous test with 500 SBU grass pollen were compared between the verum and placebo group at V11, V2-11 and V3-11. Analysis of the ITT population shows a weak, but significant reduction of the wheal diameter of the highest allergen-dose (500 SBU) after 1 and 3 treatment years, but not after 2 years or follow up. However, the reduction was independent of vitamin D or placebo intake (p=0.5-0.3). This results from the high variability and thus limited group size. At the end of the study, a trend towards a reduced wheal diameter in the vitamin D group was observed when compared to the placebo group (p=0.085).
    End point type
    Primary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: mm
    median (inter-quartile range (Q1-Q3))
        ICT500
    17 (12 to 19)
    18 (17 to 20)
    Attachments
    		 ICT500
    Statistical analysis title
    		 T-Test
    Statistical analysis description
    Student's T-Test
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [1] - T-Test

    Secondary: Area under the curve of the intracutaneous test

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    End point title
    		 Area under the curve of the intracutaneous test
    End point description
    The area under the curve (AUC) of the titrated intracutaneous test after the 1st, 2nd and 3rd treatment year. The AUC in this setting is mostly dependent on the wheal diameters of the highest pollen concentrations, which were underlying a significant variation. However, overall the AUC of the grass pollen-intracutaneous reaction is significantly reduced compared to baseline after first year (p=0.003) or third year (p=0.0001), but not to follow-up (p=0.5, not shown), the latter most likely due to a small group size or test allergen-batch variation (left). These data support that higher allergen concentrations are required for mediating a positive test result, as expected. Here, the comparison of the groups show comparable data between vitamin D and placebo at all time points (right).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: AUC
    number (not applicable)
        AUC-ICT
    7208
    7664
    Attachments
    		 AUC-ICT
    Statistical analysis title
    		 AUC-ICT
    Statistical analysis description
    comparison of the area under the curve of both groups
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Area under the curve - conjuncitval provocation test

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    End point title
    		 Area under the curve - conjuncitval provocation test
    End point description
    The overall AUC of the grass-pollen-specific conjunctival provocation test is increased follow-ing immunotherapy, by trend already after the first treatment year failing statistical significance, and more pronounced after all three treatment years (p=0.0010, after FU p=0.0008, not shown). This effect is expected and reflecting higher allergen concentration thresholds to elicit an allergic reaction. However, intergroup differences were not detectable between the vitamin D or placebo subgroup until FU (0.040, higher in the placebo group).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: AUC
        number (not applicable)
    110000
    310000
    Attachments
    		 AUC-CPT
    Statistical analysis title
    		 AUC-CPT
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Retrospectiv symptom score (RSS)

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    End point title
    		 Retrospectiv symptom score (RSS)
    End point description
    The retrospective symptom score (RSS) significantly improved in the ITT (after 1-3 treatment years p<0.0001) and also both treatment groups (PP) by immunotherapy ranging from p=0.0001-0.0039 (data not shown). Finally, at the follow-up visit both study groups were com-parable. Regarding the increased scores at year 2 and 3, a higher pollen count compared to year 1 must be considered (2012=45 particles per m3 (ppm), 2013=110 ppm, 2014=236 ppm).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: points
    number (not applicable)
        RSS
    12
    10
    Attachments
    		 RSS
    Statistical analysis title
    		 RSS-stats
    Statistical analysis description
    comparison between both study groups
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Seasonal global symptoms (SGS)

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    End point title
    		 Seasonal global symptoms (SGS)
    End point description
    General symptom score of the grass pollen season before treatment (2011) to the treat-ment after (2012, 2013 and follow-up 2014). The data show that immunotherapy reduces the symptoms regarding eyes, nose and the lung, which is significant after 3 treatment (Fig.SGS left). This data is strong, as the maximum and overall pollen counts were in-creasing (by coincidence, 2012=45, 2013=110, 2014=236). However, subgroup analysis re-veal no significant difference between the vitamin D and placebo group (Fig.SGS, right).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: points
    number (not applicable)
        SGS
    2
    2
    Attachments
    		 SGS
    Statistical analysis title
    		 SGS-stats
    Statistical analysis description
    comparison between both study groups
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Skin prick test (SPT)

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    End point title
    		 Skin prick test (SPT)
    End point description
    The data show that a limited but highly significant reduction of the grass pollen-specific skin prick test reaction by specific immunotherapy in % of control (histamine) but also absolute values (mm of the wheal, data not shown). However, comparison between both groups did not identify specific inter-group differences.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: wheal/histamin in %
    number (not applicable)
        SPT
    188
    150
    Attachments
    		 SPT
    Statistical analysis title
    		 SPT-stats
    Statistical analysis description
    compare both groups
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Symptom-Medication-Score (SMS)

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    End point title
    		 Symptom-Medication-Score (SMS)
    End point description
    Symptom-medication-score (SMS) during grass pollen season 2012, 2013 and 2014. For the pollen season 2012 the data shows a pollen-associated increase of the combined symptom-medication-score (SMS) as self-documented from the participants during summer. The data show comparable data between both groups (blue=vitamin D, red dotted=placebo group, both n= 14 returned data sets).
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: points
    number (not applicable)
        SMS
    3.3
    4.1
    Attachments
    		 SMS-year1
    Statistical analysis title
    		 SMS-stats
    Statistical analysis description
    comparing both groups
    Comparison groups
    Placebo group v Vitamin D Group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Grass-Ig

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    End point title
    		 Grass-Ig
    End point description
    Grass-pollen specific Ig-induction. Before SIT, the data show comparable specific IgE serum concentrations between the groups. Specific IgG4 was low/below the detection thresh-old in all participants. As expected, SIT strongly induces specific IgE, but interestingly in the vitamin D group this process is almost abolished. In summary, analysis of the grass pollen-specific IgE serum concentrations are statistically significant between both groups (p=0.031).
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    		 Vitamin D Group Placebo group
    Number of subjects analysed
    18
    18
    Units: LU/ml
        Grass-Ig
    27
    128
    Statistical analysis title
    		 Grass-Ig
    Statistical analysis description
    to compare vitamin D and placebo group
    Comparison groups
    Vitamin D Group v Placebo group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - to compare vitamin D and placebo group

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    all participants
    Reporting group description
    		 77 adverse events occurred in overall 31 different of 36 randomized participants. Most of these were associated to the flu-season during winter (upper respiratory tract infections, headaches), immunotherapy updosing (local skin reactions). All of the AE’s recovered during the study period. 1 SAE occurred independent of the treatment.

    Serious adverse events
    		 all participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 36 (2.78%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Immune system disorders
    Reactive Arthritis
    Additional description: In a treatment-free interval (during the first grass-pollen season), a sexually transmitted uro-genital infection with Ureaplasma induced a reactive arthritis required treatment with methotrexate (banned drug, study exclusion)
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 all participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 36 (100.00%)
    Nervous system disorders
    Nervous system AEs
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    9
    Eye disorders
    Ophthalmic AEs
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Gastrointestinal disorders
    Gastrointestinal AEs
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Respiratory AEs
         subjects affected / exposed
    18 / 36 (50.00%)
         occurrences all number
    31
    Skin and subcutaneous tissue disorders
    Skin disorders
         subjects affected / exposed
    12 / 36 (33.33%)
         occurrences all number
    17
    Renal and urinary disorders
    Urogenital AEs
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorder
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2011
    issue that Vigantol was off-market in 2010-Summer 2011
    14 Apr 2012
    introduction of a questionaire to assess the symptom-medication-score during pollen season
    11 Jul 2012
    prolongation for 2 more study years

    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.
    High drop rate over 3 years (vitD n=18->12, plc n=18->11) due to the extension from originally planned 1 year to a 3 year trial. Most of the drop out probands were reporting changes in the occupation or left Berlin, so they could not further attend.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32750735
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