The aim of this clinical phase IIa randomized, double-blind, placebo-controlled study is to investigate tolerability/ safety and clinical and immunological effects of the addition of a subcuteaneous injection of a VD3 analogue in the vicinity of the…
ID
Source
Brief title
Condition
- Upper respiratory tract disorders (excl infections)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Amongst the immunological outcomes, IL-10 production by PBMCs in response to
allergen-specific stimulation after 5 weeks of treatment with VD3 analogue
Zemplar® compared to placebo was chosen as primary end-point (visit 7). The
rationale behind this is that 1) IL-10 is the key cytokine in the mechanism of
SCIT [22, 23] and 2) the hypothesis is that IL-10 induction is more rapid in
the presence of VD3 than without, hence visible already after 5 weeks of
treatment. At 11 weeks the postulated difference may already not be as
significant anymore.
Secondary outcome
* The IL-10 production by PBMCs in response to allergen-specific stimulation
after 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo
(visit 10).
* 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 6 and 12 weeks of treatment (visit 7 and 10).
* 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 6 and 12 weeks of
treatment (visit 7 and 10).
* Determination of the difference between PBMC proliferation and cytokine
production in response to polyclonal stimuli (*CD3/*CD28) induced by SCIT with
VD3 compared to SCIT alone in patients with moderate to severe allergic
rhinitis/rhino-conjunctivitis caused by birch pollen after 6 and 12 weeks of
treatment (visit 7 and 10).
* 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 6 and 12 weeks of treatment (visit 7 and 10).
* 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 6 and 12 weeks of treatment (visit 7 and 10).
* 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 6 and 12 weeks of treatment (visit 7
and 10).
* The identification of predictive and efficacy-associated biomarkers by
transcriptomics on nasal brushing taken at after 6 and 12 weeks of treatment
(visit 7 and 10).
* 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 6 and 12 weeks of treatment (visit 7 and 10).
* 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.
Background summary
For decades, allergen immunotherapy (AIT) is being 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. Vitamin D3 (VD3) is a promising
adjuvant to more rapidly skew the allergic immune response towards a protective
anti-inflammatory immune status.
Study objective
The aim of this clinical phase IIa randomized, double-blind, placebo-controlled
study is to investigate tolerability/ safety and clinical and immunological
effects of the addition of a subcuteaneous injection of a VD3 analogue in the
vicinity of the SCIT administration site in birch pollen allergic patients with
moderate-severe allergic rhinitis.
A total of 40 birch pollen allergic patients with allergic rhinitis
(AR)/allergic rhinoconjunctivitis (ARC) with/without concomitant controlled
allergic asthma (AA) will be included. The treatment will be performed as a
pre-seasonal course of 12 weeks with a total of 13 injections with Alutard and
9 injections with VD3/Placebo.
Study design
This trial is planned as a randomized, double-blind, placebo-controlled Phase
IIa study.
Intervention
A total of 40 patients will be randomized to 2 treatment groups in a 1:1 manner
as follows: 20 patients receiving SCIT/VD3, 20 patients receiving SCIT/placebo
(=placebo matching VD3).
Study burden and risks
Venapunction 4 times 57 ml
Subcutaneous injection 22 times 0.5-1 ml
Nasal provocation 3 times
Nasal brush 3 times
Titrated skin prick test 3 times
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
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 ImmunoCAP (>0.7 kU/L) for birch pollen
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.
For the rest of the exclusion criteria see protocol
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 | EUCTR2018-001339-33-NL |
| CCMO | NL65758.018.18 |