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    Clinical Trial Results:
    Molecular and Cellular Mechanism in the course of Immunotherapy with a Phleum pratense oral lyophilisate

    Summary
    EudraCT number
    		 2012-005092-14
    Trial protocol
    		 ES  
    Global end of trial date
    26 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2017
    First version publication date
    13 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GT-24
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01854736
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK-Abelló S.A.
    Sponsor organisation address
    Miguel Fleta, 19, Madrid, Spain,
    Public contact
    Pilar Rico Nieto, ALK-Abelló S.A., 34 913276100, pilar.rico@alk.net
    Scientific contact
    Santiago Martín , ALK-Abelló S.A., 34 913276100, santiago.martin@alk.net
    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
    04 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify changes in immunological markers measured in grass allergic subjects during treatment with Grazax.
    Protection of trial subjects
    First Treatment Dose Subjects stayed at the clinic for 20-30 minutes after the first dosing (visit 2 and visit 8), according to SmPC, in order to enable subject and physician to discuss any side effects and possible actions. Subjects without significant reactions left the clinic 20-30 minutes after the first dose of IMP has been given. Subject were instructed when leaving the clinic to contact immediately if the reaction reoccurs or a new reaction of similar severity appears. In the case of a medical emergency, the subject were instructed to dial the local emergency telephone number. If an investigator determines that a subject cannot leave the clinic but needs further medical observation or attention not otherwise available at the clinical trials site, the subject were to be transferred to the appropriate facility including an emergency room.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jun 2013
    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
    Spain: 47
    Worldwide total number of subjects
    47
    EEA total number of subjects
    47
    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)
    47
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment start period was from Jun2013 until Feb2014.

    Pre-assignment
    Screening details
    		 Adult subjects suffering from rhinoconjunctivitis with/without asthma due to sensitization to grass pollen.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Treatment
    Arm description
    		 Phleum pratense grass pollen allergen extract Grazax®
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRAZAX
    Investigational medicinal product code
    68398
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    75000 SQ-T The daily dose of trial medication is one tablet, which should preferably be taken in the morning. The tablet is placed under the tongue and swallowing should be avoided for one minute. Eating and drinking is not allowed within five minutes after trial medication intake

    Arm title
    		 Placebo
    Arm description
    		 Placebo Treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    Placebo has not specific dose The daily dose of trial medication is one tablet, which should preferably be taken in the morning. The tablet is placed under the tongue and swallowing should be avoided for one minute. Eating and drinking is not allowed within five minutes after trial medication intake

    Number of subjects in period 1
    		Active Treatment Placebo
    Started
    23
    24
    Completed
    14
    17
    Not completed
    9
    7
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    1
    -
         Pregnancy
    1
    2
         Lost to follow-up
    4
    4
         Protocol deviation
    2
    -

    Baseline characteristics

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

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 47 47
    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)
    		 47 47
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.3 ( 9.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 22 22
        Male
    		 25 25
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) is all randomised subjects in accordance with the ICH intent-to-treat principle.

    Subject analysis set title
    Completed subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set is all completed subjects in the FAS with no major protocol violations. The PP Analysis Set will be the population for efficacy analyses.

    Subject analysis set title
    Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set comprises all randomised subjects and is identical to the FAS.

    Subject analysis sets values
    		 FAS Completed subjects Safety Analysis set
    Number of subjects
    47
    31
    47
    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)
    47
    31
    47
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.3 ( 9.97 )
    35.6 ( 9.44 )
    34.3 ( 9.97 )
    Gender categorical
    Units: Subjects
        Female
    22
    17
    22
        Male
    25
    14
    25

    End points

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    End points reporting groups
    Reporting group title
    Active Treatment
    Reporting group description
    		 Phleum pratense grass pollen allergen extract Grazax®

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo Treatment

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) is all randomised subjects in accordance with the ICH intent-to-treat principle.

    Subject analysis set title
    Completed subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis set is all completed subjects in the FAS with no major protocol violations. The PP Analysis Set will be the population for efficacy analyses.

    Subject analysis set title
    Safety Analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set comprises all randomised subjects and is identical to the FAS.

    Primary: Ratios to baseline of specific IgE to Phl p 1 + Phl p 5

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    End point title
    		 Ratios to baseline of specific IgE to Phl p 1 + Phl p 5
    End point description
    Serum specific IgE to Phl p 1 and Phl p 5 are calculated by summing the values of IgE to Phl p 1 and Phl p 5. Ratios are calculated dividing the values at each visit by the values at Visit 2
    End point type
    Primary
    End point timeframe
    Along the treatment period, from baseline to end of treatment: Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7 and Visit 8
    End point values
    		 Active Treatment Placebo
    Number of subjects analysed
    14
    17
    Units: Ratio
        arithmetic mean (standard error)
    3.211 ( 0.444 )
    1.207 ( 0.403 )
    Statistical analysis title
    		 Analysis of IgE during the trial
    Comparison groups
    Active Treatment v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Mean difference
    Point estimate
    -2.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.231
         upper limit
    		 -0.778
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6
    Notes
    [1] - ANOVA for repeated measures with visits as withing factor and treatment (active or placebo) as between factor

    Secondary: Global evaluation of rhinoconjunctivitis

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    End point title
    		 Global evaluation of rhinoconjunctivitis
    End point description
    Efficacy assessments included a subjective evaluation of rhinoconjunctivitis in a VAS and physician and patient-rated clinical global improvement for the peer protocol population. The VAS was done in visit 1 (only applicable if the visit is performed within the GPS 2013), visit 5, and visit 7. The physician and patient-rated clinical global improvement was performed in visit 5 and 7
    End point type
    Secondary
    End point timeframe
    Visit 1, Visit 5 and visit 7, after peak of grass pollen season.
    End point values
    		 FAS
    Number of subjects analysed
    30
    Units: Subjects
    30
    Attachments
    		 Untitled (Filename: Efficacy analyses.docx)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent signature to end visit
    Adverse event reporting additional description
    From the first trial related activity after the subject signed the informed consent until the follow-up telephone contact.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    		 Subjects receiving GRAZAX

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo

    Serious adverse events
    		 Active treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Biochemical pregnancy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Umbilical hernia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 23 (82.61%)
    19 / 24 (79.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
    5 / 24 (20.83%)
         occurrences all number
    5
    8
    General disorders and administration site conditions
    Sensation of foreign body
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 24 (4.17%)
         occurrences all number
    5
    1
    Chest discomfort
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Food Allergy
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 24 (4.17%)
         occurrences all number
    5
    1
    Oral allergy syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    7 / 23 (30.43%)
    7 / 24 (29.17%)
         occurrences all number
    9
    9
    Gastrointestinal disorders
    Oral pruritus
         subjects affected / exposed
    11 / 23 (47.83%)
    1 / 24 (4.17%)
         occurrences all number
    22
    1
    Oedema mouth
         subjects affected / exposed
    7 / 23 (30.43%)
    1 / 24 (4.17%)
         occurrences all number
    11
    1
    Tongue pruritus
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 24 (0.00%)
         occurrences all number
    6
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 24 (4.17%)
         occurrences all number
    2
    6
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    11 / 23 (47.83%)
    0 / 24 (0.00%)
         occurrences all number
    17
    0
    Cough
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 24 (20.83%)
         occurrences all number
    2
    5
    Asthma
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 24 (12.50%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 23 (34.78%)
    8 / 24 (33.33%)
         occurrences all number
    10
    18
    Influenza
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 24 (8.33%)
         occurrences all number
    7
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Tonsillitis
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2013
    This amendment is prepared in order to add a new site to clinical trial and update the information regarding in vitro evaluations to be performed
    01 Oct 2013
    This amendment is prepared in order to change one of the inclusion criteria (I4), documented positive specific IgE to Phl p 5, for documented positive specific IgE to Phleum pratense.
    03 Feb 2015
    This amendment is prepared in order to Reduce the follow-up period in the protocol. It is considered that the information obtained from the 5-year trial and from the present two-year trial covers the aims of the trial without having subjects exposed to an additional experimental year. The 5-year trial has shown that the instauration of the key immunological modifications are established during the second year of treatment. Add 20 ml of blood to the sample extraction at visits 7 and 8. The additional sample will be used to purify and freeze peripheral blood mononuclear cells (PBMC) in order to isolate in the future the specific lymphocytic populations responsible for individual B and T regulatory responses, which are at present difficult. This may lead to identify the underlying mechanisms behind the long-term tolerance induction.

    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.
    None reported
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    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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