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    Summary
    EudraCT Number:2016-004827-22
    Sponsor's Protocol Code Number:BM41-VD3
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-05-01
    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 number2016-004827-22
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, double-dummy study to determine the safety/tolerability of a simultaneous subcutaneous treatment of BM41 and vitamin D 3 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
    Study to determine the safety/tolerability of the simultaneous treatment of BM41-vaccine and vitamin D 3 in patients with birch pollen allergy.
    A.3.2Name or abbreviated title of the trial where available
    BM41ViD
    A.4.1Sponsor's protocol code numberBM41-VD3
    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 Center
    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 Center
    B.5.2Functional name of contact pointLaurian Jongejan
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.4CountryNetherlands
    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 No
    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.3.1Product nameBM41 160µg/ml
    D.3.4Pharmaceutical form Suspension 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) Yes
    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.IMP: 2
    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 placeboSuspension for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    D.8 Placebo: 2
    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
    moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen (with or without concomitant mild to moderate persistent asthma)
    E.1.1.1Medical condition in easily understood language
    moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen (with or without mild to moderate persistent asthma)
    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 demonstrate safety/tolerability of subcutaneous treatment with BM41 alone, VD3 alone and a simultaneous subcutaneous treatment with BM41 and VD3 in comparison to placebo in patients with moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen in a pre-seasonal short-term course of SCIT.
    E.2.2Secondary objectives of the trial
    The secondary objectives include demonstration of clinical efficacy of SCIT with BM41, with BM41+VD3, and with VD3, all three compared to placebo. Efficacy will be analysed for the upper airways by TNPT and PNIF. Moreover, the clinical efficacy of SCIT with BM41, with BM41+VD3, and with VD3, is evaluated on birch seasonal allergic symptoms and medication use, by control of rhinitis symptoms, Health-Related Quality of Life and “well-days/severe days”, compared to placebo.
    The assessment of serological and cellular immunological changes induced by SCIT with BM41, BM41+VD3, and VD3, compared to placebo, the onset of clinical and immunological changes induced by SCIT with BM41 compared to BM41+VD3, the indentification of predictive and efficacy-associated biomarkers by transcriptomics on nasal brushing, the assessment of the hypoallergenicity of BM41 and possible de-novo sensitization to BM41 by tSPT. In a subset of patients, asthma control will be evaluated during birch pollen season.
    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) 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 TNPT for birch pollen at screening (Lebel score ≥6)
    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 endpoint is the number of treatment-related systemic reactions (classified in accordance with the WAO-grading system) in the BM41/VD3 treatment group compared to BM41/Placebo2, VD3/Placebo1 and Placebo1/Placebo2 throughout the pre-seasonal treatment course. This will be determined at every visit according to the reports of the patient.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This will be determined at every visit according to the reports of the patient.
    E.5.2Secondary end point(s)
    1) Reduction of upper airway response to allergen compared to baseline evaluation as assessed by a TNPT after the first maintenance shot.
    2) Improvement in nasal patency compared to baseline evaluation (Visit 1) as assessed by Peak Nasal Inspiratory Flow (PNIF) after TNPT after the first maintenance shot.
    3) Furthermore, clinical efficacy will be investigated by analyzing the reduction in a combined symptom and medication score (CSMS) in the BM41/VD3 treatment group compared to BM41/Placebo2, VD3/Placebo1 and Placebo1/Placebo2 as assessed during the birch pollen season.
    The following definition will be used to calculate the CSMS:
    CSMS = (daily) Symptom Score (dSS) + (daily) Medication Score (dMS)
    The dSS comprises of six individual symptom scores: four nasal symptoms (Itchy Nose, Sneezing, Runny Nose, Blocked Nose) and two ocular symptoms (Itchy/red eyes, Watery eyes), all daily scored (by patients in e-diaries in the birch pollen season) on a scale from 0-3. The dSS will be calculated as mean of all non-missing daily SS during the birch pollen season (range 0-18) divided by the number of individual symptoms (6 symptoms). As such the dSS has a range from 0-3.
    The dMS is based on the following scores: 0 = no rescue medication, 1 = antihistamines (oral and topical), 2 = nasal corticosteroids, 3 = oral corticosteroids . The dMS will be scored as the average of the daily MS during the birch pollen season. As such, the dMS has a range from 0-3. Therefore, the corresponding CSMS (dSS + dMS) has a range from 0-6.
    4) A self questionnaire for assessing the control of allergic rhinitis based on 5 standardized questions as being scored from 1 to 5 points (on a Likert-scale) reporting the severity of AR over the previous 2 weeks. Averages of this ‘control-score’ will be compared between the treatment groups.
    5) The “Mini-Rhinoconjunctivitis Quality of Life Questionnaire (mini-RQLQ)” will be assessed. This self-administered questionnaire assesses (the disease specific) patients’ quality of life (QoL) .
    The m-RQLQ comprises five domains (activity limitation, practical problems, nose symptoms, eye symptoms and non-nose/eye symptoms) based on 14 standardized questions. The Quality of Life Total Score will be assessed based on subject's self-filled Mini-RQLQ. Averages of the m-RQLQ will be compared between the treatment groups.
    6) Based on the dSS and the dMS, the percentage of ‘well days’ (=days with no intake of rescue mediation and a symptom score ≤ 2) and ‘severe days’ (a symptom score of 3 for any of the rhinoconjunctivitis symptoms) will be compared between the treatment groups.
    7) Changes of serum specific immunoglobulin levels (total IgE, rBet v 1- and birch pollen-specific IgG, rBet v 1- and birch pollen-specific IgG4) (all centers) and cellular immunology (two centers) compared to baseline evaluation.
    8) Average of Asthma Control Score, obtained during the birch pollen season.
    9) Nasal brushing and analysis of basal nasal cells and nasal microbiom (two centers) will be compared between the treatment groups.

    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Visit (V1),V6, V10 and at V12 (after grass/weed pollen seasons).
    2) V1,V6, V10 and a at V12 (after grass/weed pollen seasons).
    3) Patients will be asked to keep a daily e-diary to collect the CSMS during the birch pollen season
    4) The standardized 5 questions will be assessed at baseline V1, during birch pollen-season 2018 at V11 and at the end of the trial (V12).
    5) The mini-RQLQ at baseline,during birch pollen-season 2018 and at the end of the trial. The Quality of Life Total Score at baseline, during birch pollen-season 2018 at V11 and at the end of the trial (V12).
    6) Daily Diary
    7) At V6, V10, V11 and V12 compared to baseline evaluation (V1).
    8) At V1, V11 and V12
    9) At V1, V6, V10 and V12
    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 Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    immunological response
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.1.7.1Other trial design description
    double dummy
    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 EEA4
    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 months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months1
    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: 160
    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.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 160
    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 Decision2017-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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