E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen (with or without concomitant mild to moderate persistent asthma) |
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E.1.1.1 | Medical condition in easily understood language |
moderate to severe allergic rhinitis/rhino-conjunctivitis caused by birch pollen (with or without mild to moderate persistent asthma) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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)
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This will be determined at every visit according to the reports of the patient. |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |