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    Summary
    EudraCT Number:2015-003202-16
    Sponsor's Protocol Code Number:PB/0046
    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:2015-08-31
    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 number2015-003202-16
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled study to compare the safety and immune effects of multiple doses of vitamin D3 in patients with allergic rhinitis/rhino-conjunctivitis caused by birch pollen and healthy control subjects.
    Een gerandomiseerde, dubbel blind, placebo gecontrolleerde studie voor het onderzoeken van de veiligheid en immuuneffecten van meerdere vitamine D3 dosissen in patiënten met allergische rhinitis/rhino-conjuctivitis veroorzaakt door berkenpollen en gezonde controle proefpersonen.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DBPC-Dose-finding-trial of Vitamin D3 for SCIT in birch pollen allergic patients
    A.3.2Name or abbreviated title of the trial where available
    DBPC-Dose-finding-trial of Vitamin D3 for SCIT in birch pollen allergic patients
    A.4.1Sponsor's protocol code numberPB/0046
    A.5.4Other Identifiers
    Name:BM4SITNumber:Protocol ID
    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 SponsorAcademic Medical Centre
    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 supportAMC
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Centre
    B.5.2Functional name of contact pointAMC
    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
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 rhinits (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 to evaluate whether 2.5 µg VD3 analogue (Zemplar® – Abbvie) in multiple subcutaneously administered doses induces a more favourable (read: anti-inflammatory) systemic immune modulation both in general parameters and allergen-specific responses in birch pollen allergic subjects more resembling the response observed in gender, age and study site matched healthy control subjects. To this end, the primary outcome of the study is the observed IL-10 production as marker of the induction of a more anti-inflammatory systemic immune response, at start, at 4 weeks of treatment and follow-up, comparing birch pollen allergic subjects and healthy controls in a placebo-controlled design. The target is a statistically significant increase in IL-10 production upon polyclonal and/or allergen specific stimulation in allergic subjects, more resembling the response expected to be seen in healthy controls.
    E.2.2Secondary objectives of the trial
    1) The reactivity, cellular composition and detailed characterization of antigen-presenting cell (APC) and T cells in the PBMC, using proliferation, detailed cell surface marker expression, and cytokine production (beyond IL-10) in response to polyclonal and allergen-specific stimulation.
    2) To evaluate the safety and tolerability, both systemically and locally, of the VD3 analogue Zemplar® administered by the subcutaneous route during each treatment visit and at the follow up visit compared to placebo. To evaluate blood safety biochemistry/haematology parameters, urinalysis, vital signs and ECG, lung function before and after treatment with 2,5 μg VD3 analogue (Zemplar®) in multiple subcutaneously administered doses compared to placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria for study subjects:
    1. Signed informed consent
    2. Age ≥18 ≤ 60 years
    3. Allergic rhinitis/rhino-conjunctivitis related to birch pollen with or without concomitant mild to moderate persistent asthma based on relative symptoms and allergy tests.
    4. 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 OR a positive serum specific anti-birch IgE-test (>0.7 U/ml)

    In order to be eligible to participate in this study as a gender, age and location matched healthy control, a subject must meet all of the following criteria:
    1. Signed informed consent
    2. Age, gender and location matched to a study subject. An age matched control is defined as the age of the study subject ± 5 years.
    3. No history of respiratory allergies and no nasal symptoms at screening.
    4. A negative SPT (a positive outcome is defined as a mean wheal diameter ≥ 3mm compared to negative control and negative control should be negative) assessed within 1 year before randomization OR a negative serum specific IgE test for aeroallergens.
    E.4Principal exclusion criteria
    1. A history of allergen-specific immunotherapy (SCIT or SLIT) with any allergen(s) within the 5 years before inclusion/screening visit
    2. Treatment with parenteral Vitamin D3 analogue in the year before inclusion
    3. Significant, ongoing nasal symptoms caused by other allergens at study onset
    4. A history of Hypercalcemia, Hypophosphatemia or vitamin D toxicity
    5. Any vaccination within one week before randomization
    6. Treatment with experimental products within the last 3 months or during the study
    or biologicals (including anti-IgE or TNF- α treatment) within the last 6 months or during the study
    7. Severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs
    8. Uncontrolled asthma or other active respiratory diseases
    9. Malignancies or any malignant disease during the previous 5 years
    10. Severe uncontrolled diseases that could increase the risk for subjects 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 hematological disorders
    11. Active inflammation or infection of the target organs (nose, eyes or lower airways) at the start of the study
    12. Use of preparations containing calcium or magnesium such as thiazide, diuretics, antacides.
    13. Use of systemic steroids within 4 weeks before screening and during the study
    14. Daily use of ketoconazole cream or immunosuppressive creams at planned injection site less than 7 days before or during the study
    15. Pregnancy, lactation or inadequate contraceptive measures for women of child-bearing age (adequate contraceptive measures will be the use of a contraceptive device or –pill)
    16. Any clinically significant abnormal laboratory parameter at screening
    17. Any physical or mental condition that precludes compliance or participation in a clinical trial
    18. Subjects who are employees or students of the institution or 1st grade relatives or partners of the investigators
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome of the study is the observed Il-10 production in response to polyclonal and allergen-specific stimulation after 4 weeks of treatment with VD3 analogue Zemplar® compared to placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The immune effects will be measured at 4 weeks of treatment and 4 weeks after the treatment period. A baseline measurement will be done tight before the first injection with VD3 or placebo.
    E.5.2Secondary end point(s)
    • Comparison of ΔIL-10 between allergic subjects and healthy controls
    • Cellular composition of PBMC with respect to Th1, Th2, Th17, Th22, and Treg cells, B cells, and antigen-presenting cells (APC)
    • PBMC proliferation and cytokine production in response to allergen (Bet v 1)
    • PBMC proliferation and cytokine production in response to polyclonal stimuli (αCD3/αCD28)
    • Intracellular cytokine measurements in response to PMA/ionomycin
    • Blood safety biochemistry/haematology parameters, urinalysis, vital signs and ECG, lung function will be determined at baseline and at the follow up visit.
    • Safety and tolerability (local and systemic reactions / [serious] adverse events) of the VD3 analogue Zemplar® administered via the subcutaneous route will be evaluated at each treatment visit and the follow up visit.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety measurements and vital signs will be done at each visit. ECG and lungfunction will be done at the randomisation visit and at the follow up visit. urinalysis will be done at screening and follow up.
    30 minutes after each injection the injection location will be checked.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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 trial4
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 48
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 48
    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 Decision2015-08-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-20
    P. End of Trial
    P.End of Trial StatusOngoing
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