Secondary objectives:The secondary objectives include demonstration of clinical efficacy of SCIT with BM41 alone, with BM41 plus VD3 and with VD3 alone, all three compared to placebo. Efficacy will be analysed for the upper airways by titrated nasal…
ID
Source
Brief title
Condition
- Upper respiratory tract disorders (excl infections)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
1) Reduction of upper airway response to allergen compared to baseline
evaluation (Visit 1) as assessed by a TNPT after the first maintenance shot,
before start birch-pollen season at Visit 10 and at end of trial at Visit 12
(after grass/weed pollen seasons).
Patients will receive incremental dosages of intranasal birch pollen extract
(100, 1,000 and 10,000 AU/ml, HAL Allergy B.V., Leiden, The Netherlands) at
baseline to determine the upper airways response and the threshold dose to
birch pollen. The upper airways response to intranasal birch pollen extract
will be quantified using the symptom score according to Lebel et al.. The mean
total symptom score is calculated from the response to the allergen dosage
which evoked a positive test. After the preseasonal treatment course before
birch-pollen season at Visit 10 and at end of trial at Visit 12 the TNPT will
be repeated with the same incremental allergen dosages as used at baseline. The
mean total symptom score to the allergen dosage which evokes a positive test at
Visit 10 (before birch-pollen season) and at end of trial at Visit 12 will be
compared to the baseline values. For a description of the TNPT and the Lebel
scores.
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, before birch-pollen season at Visit 10 and at end of trial at
Visit 12 (after grass/weed pollen seasons).
3) Furthermore, clinical efficacy will investigated by analyzing the reduction
in a combined symptom and medication score (CSMS) as assessed during the birch
pollen season. The BM41/VD3 (the combination treatment), the BM41/Placebo 2
(BM41 alone), and the VD3/Placebo1 (VD3 alone) treatment groups will be
compared to each other and to Placebo1/Placebo2. This clinical endpoint refers
to the recently published EAACI Position Paper on *Recommendations for the
standardization of clinical outcomes used in allergen immunotherapy trials for
allergic rhinoconjunctivitis* highlighting the CSMS as harmonized standard in
future clinical AIT trials for allergic rhinoconjunctivitis. For this, patients
will be asked to keep a daily e-diary to collect the CSMS 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 (anti-allergic) 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 has been
recently proposed and validated 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 week. This score showed a good correlation to the symptomatology
and QoL-related impairment caused by the disease. Moreover, it revealed to be
sensitive in demonstrating treatment effects of (anti-allergic)
pharmacotherapy. The standardized 5 questions will be assessed at baseline,
during birch pollen-season 2018 at Visit 11 and at the end of the trial (Visit
12, EoT). 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 at baseline, during birch pollen-season 2018 and at the end of
the trial. This self-administered questionnaire assesses (the disease specific)
patients* quality of life (QoL) and has been standardized and validated.
Moreover, validated translations are available in different languages which
will be used in the four different participating European countries.
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 at baseline, during birch pollen-season 2018 at Visit 11
and at the end of the trial (EoT) (Visit 12). 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 (anti-allergic) rescue mediation and a symptom score * 2) and
*severe days* (a symptom score of 3 for any of the rhinoconjunctivitis
symptoms, both reviewed in) will be compared between the treatment groups.
7) Changes of serum specific immunoglobulin levels (total IgE, rBet v 1- and
birch pollen-specific IgE, IgG, and IgG4) (all centers, see Appendix 8 in
manual and cellular immunology (two centers) at Visit 6, Visit 10, Visit 11 and
Visit 12 compared to baseline evaluation (Visit 1).
8) Average of Asthma Control Score, will be obtained during baseline and during
the birch pollen season (V 11) and at Visit 12 (eoT).
9) Nasal brushing and analysis of basal nasal cells and nasal microbiom (two
centers, at Visit 1, 6, 10 and Visit 12 will be compared between the treatment
groups.
Background summary
For decades, allergen immunotherapy (AIT) is used as a causal therapeutic
option in the treatment of IgE-mediated allergic diseases such as allergic
rhinitis (AR), allergic rhinoconjunctivitis (ARC) or allergic asthma (AA).
Efficacy of this therapeutic principle is well documented for allergen
extract-based products, but the required duration of the treatment of at least
three years of monthly injections and the (controlled) risk of severe
side-effects are experienced to be significant drawbacks. There is a need for a
treatment with a lower risk of side-effects and a more rapid onset of
longlasting efficacy, i.e. less injections. BM41 is a hypoallergenic (safer)
but hyper-immunogenic (more effective) recombinant variant of Bet v 1, the
major allergen of birch pollen, whereas vitamin D3 (VD3) is a promising
adjuvant to more rapidly skew the allergic immune response towards a protective
anti-inflammatory immune status.
Study objective
Secondary objectives:
The secondary objectives include demonstration of clinical efficacy of SCIT
with BM41 alone, with BM41 plus VD3 and with VD3 alone, all three compared to
placebo. Efficacy will be analysed for the upper airways by titrated nasal
provocation test (TNPT) including an objective read-out i.e. peak nasal
inspiratory flow (PNIF). Moreover, the clinical efficacy of SCIT with BM41
alone, with BM41 and VD3 and with VD3 alone, is further evaluated by recording
birch seasonal allergic symptoms and medication use, by control of rhinitis
symptoms, and by Health-Related Quality of Life and *well-days/severe days*,
compared to placebo. Further secondary objectives include the assessment of
serological and cellular immunological changes induced by SCIT with BM41 alone,
BM41 with VD3 and VD3 alone compared to placebo, the onset of clinical and
immunological changes induced by SCIT with with BM41 alone compared to BM41
with 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 titrated skin prick test
(tSPT). In a subset of patients, asthma control will be evaluated during birch
pollen season.
Study design
This trial is planned as a randomized, double-blind, placebo-controlled,
parallel group, double-dummy, multicentre (four European centres with three
additional satellite centres), Phase I/IIa study. A total of 160 patients will
be randomized to four treatment groups in a 1:1:1:1 manner as follows: 40
patients receiving BM41/VD3, 40 patients receiving BM41/Placebo 2 (=placebo
matching VD3), 40 patients receiving VD3/Placebo 1 (=placebo matching BM41) and
40 patients receiving Placebo1/Placebo2.
The whole pre-seasonal treatment course will comprise eight treatment visits
and 16 injections in total. It will begin between 15 Oct and 15 Dec 2017. SCIT
treatment will be administered as two separate subcutaneous injections within 1
cm of each other in a blinded double-dummy design. The treatment will be
scheduled with an initial phase of five simultaneous injections
(5xBM41/Placebo2 and 5x VD3/Placebo1) with increasing doses of BM41 in weekly
intervals followed by three simultaneous injections in 3 weeks intervals
(maintenance phase BM41). The whole treatment course will therefore be
approximately 13 weeks. The VD3 dosage will not be up-dosed, but be
administered at the maintenance dose level from the first treatment day
already.
Intervention
SCIT treatment will be administered in a blinded double-dummy design as two
separate subcutaneous injections (one BM41/Placebo 1, one VD3/Placebo 2) within
1 cm of each other to ensure that subcutaneous allergen presenting cells such
as e.g., dendritic cells are exposed to BM41 in the context of VD3.
The treatment will be scheduled with an initial phase of five simultaneous
injections (with increasing doses of BM41) in weekly intervals followed by
three simultaneous injections with maintenance dose in 3 weeks intervals. The
whole treatment course will therefore be approximately 13 weeks. The VD3 dosage
will not be up-dosed, but will be administered as a single dose level
throughout the treatment.
Study burden and risks
BM41 is developed for the causal treatment of immediate type allergic disorders
(IgE-mediated), such as allergic rhinitis, allergic conjunctivitis and allergic
bronchial asthma, triggered by sensitisation to allergenic substances from
birch pollen. This study will investigate if addition of VD3 enhances clinical
efficacy of BM41. The risk assessment is low. The potential benefit for
patients is that they will receive approximately 13 weeks of AIT treatment free
of charge during the study. The results of this study will indicate if BM41
and/or a combination of BM41/VD3 is safe and induces a more rapid onset and
enhancement of efficacy. In future, other patients with a birch pollen allergy
may benefit from this combined therapy.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
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 TNPT for birch pollen at screening (Lebel score *6)
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 *-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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004827-22-NL |
| CCMO | NL60701.000.17 |