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    Summary
    EudraCT Number:2018-001339-33
    Sponsor's Protocol Code Number:SCITVITD3
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-06-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001339-33
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, study to determine the added value of vitamin D3 to treatment with subcutaneous immunotherapy in patients with moderate to severe allergic rhinitis/ rhinoconjunctivitis caused by birch pollen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the added value of vitamin D3 to treatment with subcutaneous immunotherapy in patients with birch pollen allergy
    A.3.2Name or abbreviated title of the trial where available
    SCITVITD3
    A.4.1Sponsor's protocol code numberSCITVITD3
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAcademisch medisch centrum Amsterdam
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAcademisch medisch centrum Amsterdam
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademisch medisch centrum Amsterdam
    B.5.2Functional name of contact pointClinical trial Information
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310205666819
    B.5.6E-maill.zuidmeer@amc.uva.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zemplar
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Ltd
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    subcutaneous immunotherapy in allergic rhinitis (AR) patients with allergies to birchpollen
    E.1.1.1Medical condition in easily understood language
    allergic rhinitis patients with allergies to birchpollen
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is the assessment of serological and cellular immunological changes and kinetics thereof induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen in a pre-seasonal short-term course of SCIT.
    To this end, the primary outcome of the study is the IL-10 production by PBMCs in response to allergen-specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo (visit 7).
    E.2.2Secondary objectives of the trial
    Differences in the following parameters will be measured after (5 and) 11 weeks of treatment with SCIT +/- VD3:

    • The IL-10 production by PBMCs in response to allergen-specific or polyclonal stimulation.
    • Cellular composition of PBMC (Th1,2,17,22, Tregs, B cells, and APCs.
    • PBMC proliferatiskinon and cytokine production in response to allergen or polyclonal stimuli.
    • Intracellular cytokines in response to PMA/ionomycin.
    • IgE, IgG and IgG4 responses in serum to birchpollen and Bet v 1.
    • The functional blocking antibody capacity of IgG/IgG4.
    • Titrated SPT with birchpollen extract as a surrogate clinical marker of efficacy.
    • Monitoring of epigenetic changes.
    • Identification of predictive and efficacy-associated biomarkers by transcriptomics on nasal brushing.
    • Clinical efficacy by titrated nasal provocation test, peak nasal inspiratory flow, the combined symptom medication score (CSMS) and an electronic diary (e-diary).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent
    2. Age ≥18 ≤ 65 years
    3. Moderate to severe birch-pollen-induced AR/ARC of at least 2 years according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (Appendix 1, see manual) with or without concomitant mild to moderate persistent asthma
    4. FEV1>70% for patients with a history of asthma, FEV1>70% or PEF>80% for patients without a history of asthma
    5. A positive SPT (mean wheal diameter ≥ 3mm compared to negative control and negative control should be negative) for birch pollen assessed within 1 year before randomization
    6. A positive ImmunoCAP (>0.7 kU/L) for birch pollen
    7. A positive tNPT (for rules when a tNPT is positive see ref 40a)
    E.4Principal exclusion criteria
    1. Clinically relevant co-sensitization (others than hazel, alder and elm) expected during the birch-pollen season.
    2. Chronic asthma with an FEV1<70 % of predicted value.
    3. History of AIT (SCIT or SLIT) with any allergen within the past 5 years
    4. Ongoing AIT (SCIT or SLIT) with any allergen(s) during the study period
    5. Current Treatment with VD3 analogue.
    6. Vaccination within one week before or during the treatment phase.
    7. Immunosuppressive or biological medication (e.g. IL-5, anti-IgE therapy) within the last six months prior to inclusion and up to end of trial (EoT).
    8. Severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs.
    9. Uncontrolled asthma or other active respiratory diseases.
    10. Active malignancies or any malignant disease during the previous 5 years.
    11. Severe uncontrolled diseases that could increase the risk for patients participating in the study, including but not limited to: cardiovascular insufficiency, any severe or unstable lung diseases, endocrine diseases, clinically significant renal or hepatic diseases, or haematological disorders.
    12. Active inflammation or infection of the target organs (nose, eyes or lower airways) at the start of the study.
    13. Moderate to severe nasal obstructive diseases that preclude a TNPT (e.g., septal deviation, nasal polyps) or nasal/sinus surgery in the last 3 months.
    14. Diseases with a contraindication for the use of adrenaline (e.g. hyperthyroidism, glaucoma).
    15. Use of systemic steroids within 4 weeks before start of the study and during the study.
    16. Treatment with systemic and local β-blockers.
    17. Pregnancy, lactation or inadequate contraceptive measures for women of child-bearing age (adequate contraceptive measures will be the use of a contraceptive device or oral contraceptive pill).
    18. Alcohol, drug or medication abuse within the past year.
    19. Any clinically significant abnormal laboratory parameter at screening.
    20. Lack of cooperation or compliance.
    21. Any physical or mental condition that precludes administration of SCIT, compliance or participation in a clinical trial.
    22. Patients who are students or employees of the institution or 1st grade relatives or partners of the investigators
    23. Participation in a clinical trial within 3 months prior to the current trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome of the study is the IL-10 production by PBMCs in response to allergen-specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    5 weeks of treatment
    E.5.2Secondary end point(s)
    • The IL-10 production by PBMCs in response to allergen-specific stimulation after 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
    • The IL-10 production by PBMCs in response to polyclonal stimulation after 5 and 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
    • Determination of the difference between cellular composition of PBMC with respect to Th1, Th2, Th17, Th22, and Treg cells, B cells, and antigen-presenting cells (APC) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
    • Determination of the difference between PBMC proliferation and cytokine production in response to allergen (Bet v 1) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
    • Determination of the difference between PBMC proliferation and cytokine production in response to polyclonal stimuli (αCD3/αCD28) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
    • Determination of the difference between intracellular cytokine measurements in response to PMA/ionomycin induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
    • Determination of the changes in IgE, IgG and IgG4 antibody responses in serum to birch pollen and Bet v 1 induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.
    • Determination of changes in a so-called IgE facilitated allergen-binding assay (FAB) and in a rat basophilic leukemia cell (RBL)-based histamine release test after 5 and 11 weeks of treatment, to monitor the functional blocking antibody capacity of induced IgG/IgG4 antibodies.
    • Evaluation of changes in a titrated skin prick test (SPT) with birch pollen extract after 5 and 11 weeks of treatment, as a surrogate clinical marker of efficacy.
    • Monitoring of epigenetic changes after 5 and 11 weeks of treatment.
    • The identification of predictive and efficacy-associated biomarkers by transcriptomics on nasal brushing taken at after 5 and 11 weeks of treatment.
    • Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, as analysed for the upper airways by titrated nasal provocation test (TNPT), including an objective read-out i.e. peak nasal inspiratory flow (PNIF), after 5 and 11 weeks of treatment.
    • Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, assessed by monitoring symptoms and medication in the birch pollen season with the combined symptom medication score (CSMS) of EAACI and the use of an electronic diary (e-diary). In a subset of patients with allergic asthma, asthma control will be evaluated during birch pollen season.
    E.5.2.1Timepoint(s) of evaluation of this end point
    5 and 11 weeks of treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-05
    P. End of Trial
    P.End of Trial StatusOngoing
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