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…
ID
Source
Brief title
Condition
- Allergic conditions
- Upper respiratory tract disorders (excl infections)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome of the study is the reactivity, cellular composition and
detailed characterization of antigen-presenting cells (APC) and T cells in the
PBMC, using proliferation, cell surface marker expression, and cytokine
production in response to polyclonal and allergen-specific stimulation at
start and 4 weeks of treatment.
Secondary outcome
Immunological secondary endpoints are 1) cell surface markers measured by FACS
to characterize the cellular composition with respect to T-cell subsets (Th1,
Th2, Th17, Th22, Treg), B-cells and APC, 2) measurement of T-cell proliferation
and cytokine production (ELISA) in PBMC stimulated by allergen (Bet v 1) and
polyclonally (*CD3/*CD28), and 3) intracellular cytokine measurements (by FACS)
upon stimulation of PBMC by PMA/ionomycin, and 4) IgE responses to birch pollen
measured in serum by ImmunoCAP.
The safety and tolerability (local and systemic reactions / [serious] adverse
events) of the VD3 analogue Zemplar® administered via the subcutaneous route
will be evaluated. Systemic reactions will be classified in accordance with the
WAO-grading system for systemic reactions42 (see appendix 16.1). The onset of
local reactions (redness, itching, swelling, pain and bruising) will be checked
30 minutes after injection. If the diameter of the swelling exceeds 5 cm, the
investigator will record this as AE in the CRF. Late local reactions (swelling
exceeding 5 cm) within 24 hrs are measured and recorded by subjects at home. At
the next visit the investigator will document this as AE in the CRF.
Monitoring of AEs will be done throughout the study, focusing on date of onset,
occurrence, duration, intensity, action taken, outcome and relationship to
study medication.
In addition to the evaluation of cellular immune responses at week 4 (V4),
these will also be evaluated at the start of treatment and after 4 weeks
follow-up to allow assessing how persistent observed immune skewing effects
are.
Background summary
Low Vitamin D3 (VD3) levels have been reported to be associated with the risk
of allergic diseases like asthma. In addition, VD3 has been demonstrated in
vitro, ex vivo (skin-explants) and in animal models to program the immune
system towards anti-inflammatory immune responses, dominated by regulatory
T-cells (Treg) producing IL-10. In response to allergens, healthy individuals
by default have such a protective immune response against innocuous allergens,
whereas allergic subjects develop an inflammatory Th2-type response. VD3
co-administered with allergen may be a promising adjuvant to improve the onset
and efficacy of allergen immunotherapy (AIT), by helping the allergic immune
system to divert towards an allergen-specific response dominated by Treg and
IL-10. A clinical trial will be performed to compare the immune effects, the
tolerability and safety of multiple doses of a VD3 analogue (Zemplar® 5 µg/ml *
Abbvie, registered for the intravenous route) administered by the subcutaneous
(s.c.) route in subjects with allergic rhinitis and healthy controls. Primary
and secondary outcomes will be compared at baseline and at several time points
during the study to investigate whether 1) the healthy controls at baseline
have a more anti-inflammatory systemic cellular immune response to polyclonal
stimuli and to allergens compared to birch pollen allergic subjects, and 2)
whether s.c.VD3 analogue can skew these responses in allergic subjects towards
a profile more resembling the one observed in healthy controls. The overall aim
is to provide additional (in vivo) support for the use of VD3 as an adjuvant in
allergen-specific immunotherapy, on top of the existing pre-clinical evidence
demonstrating that antigen-presenting cells educate the adaptive immune system
towards an anti-inflammatory response when allergen is seen in the presence of
VD3.
Study objective
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 and age matched healthy control
subjects.
To this end, the primary outcome of the study is the measurement of 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.
Study design
This is a randomized, double-blind, placebo-controlled, parallel group study.
A total of 24 subjects and 24 healthy-individuals, matched by gender and age
will be randomized to four treatment groups as follows: 12 subjects receiving
active treatment, 12 subjects receiving placebo, 12 healthy controls receiving
active treatment, 12 healthy controls receiving placebo. An age matched control
is defined as the age of the subject ± 5 years, but not above 60 years or
younger than 18 years of age.
Inclusion will start at least 12 weeks before the start of the birch pollen
season (treatment: October-January). Subjects will be treated for 21 days, have
a treatment evaluation visit 7 days after the last application (V4) and a
follow up visit (V5) will take place 4 weeks after the treatment evaluation
visit. Treatments will include 4 weekly injections of 2.5 µg or placebo.
Efforts will be made to have exactly 7 days between each injection, if a
subject is unable to come to the clinic they are allowed to come 3 days in
advance or after the planned visit. The treatment review visit (V4) may not be
before day 28.
Intervention
Subjects will be treated with 2.5 µg VD3 analogue or with placebo. VD3 analogue
or placebo will be administered subcutaneously once a week for four times (day
0, 7, 14, 21).
Eligible birch pollen allergic subjects will be randomly assigned to one of the
two treatment groups in a 1:1 manner:
VD 3 in birch-pollen allergic subjects OR placebo in birch-pollen allergic
subjects.
Eligible gender and age matched healthy controls will be randomly assigned to
one of the two treatment groups in a 1:1 manner:
VD 3 in healthy controls OR placebo in healthy controls.
Study burden and risks
The VD3 analogue Zemplar® is registered for intravenous administration. In the
current study the VD3 analogue will be administered subcutaneously instead of
intravenously (i.e. off-label), leading to a lower exposure. In an earlier
study, subcutaneous administration of active VD3 (Calcijex / not anymore on the
market) in grass pollen allergic subjects was found to be safe and well
tolerated (AMC data on file). Based on the observations with active VD3, and
the less invasive route, the risk of the proposed study with Zemplar® is
assessed to be low.
Based on epidemiological studies, low VD3 levels have been associated with
increased risk of developing allergic asthma. Therefore the evaluation of the
immune skewing potency (away from allergic immune responses) of a VD3 analogue
in subjects compared to healthy controls is of potential benefit for allergic
subjects. A possible effect of administration of VD3 analogue in healthy
controls may have potential relevance from a preventive perspective in healthy
controls not being allergic but at risk of becoming allergic. From a more
general perspective, such an immune-skewing potency may have broader
application in the treatment of other chronic inflammatory disorders. Together
therefore, the observations made in this trial may have relevance for both
allergic subjects and non-allergic controls.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
Protocol page: 20
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.
Exclusion criteria
Protocol page: 20
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- * 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003202-16-NL |
| CCMO | NL54090.018.15 |