Background
Allergic rhinoconjunctivitis and asthma are, frequently, concurrent disorders [
1,
2], which has led to the notion that these two conditions are different aspects of the same disease [
3,
4]. Results from the ONEAIR study, a prospective observational study conducted between 2004 and 2005 with 942 subjects from Spain, reinforced this idea, highlighting that almost 90 % of subjects suffering from asthma presented concomitant allergic rhinitis [
5].
The ability of olive pollen (
Olea europaea) to induce notorious symptoms of rhinitis and/or asthma in exposed populations through an IgE-mediated mechanism is amply documented in the Mediterranean areas [
6‐
12]. A study conducted in 4000 allergic subjects from all over Spain showed that 47 % of subjects suffering from allergic rhinoconjunctivitis and 51 % of asthmatics were sensitized to
Olea europaea, which emphasizes the importance of olive pollen allergen in Spain [
13].
Available treatment options in respiratory allergic conditions include allergen avoidance, symptomatic treatment and etiologic treatment. Olive pollen allergen avoidance is hardly applicable since only a limited reduction in exposure can be achieved by modifying life habits. Symptomatic treatment offers short-term symptomatic relief, but does not offer long-term benefit, as the natural course of the disease is not affected. Etiologic treatment with allergen-specific immunotherapy (AIT) has proven to be the most effective treatment option for allergic diseases. AIT involves administering specific allergens to patients suffering from IgE-mediated allergic diseases in order to ameliorate symptoms, induce sustained and long-term immunological tolerance to the causative allergen, and potentially alter the natural course of the disease [
14‐
16].
The subcutaneous route for the administration of AIT products has been proven to be clinically efficacious and well-tolerated in a number of studies [
17‐
19]. The standard schedule for the subcutaneous immunotherapy (SCIT) starts with an induction period or up-dosing phase, involving increasing weekly doses over a number of consecutive weeks (12–14 weeks) until the maintenance dose is reached; however, there has been growing interest in reducing the initiation period to facilitate AIT compliance [
20]. A new SCIT product containing allergen extract of
Olea europaea (AVANZ® Olive) has been developed based on previous SCIT products.
Therefore, all the above considerations prompted us to assess the tolerability and the immunological effect of the up-dosing phase of this new SCIT containing allergen extract derived from olive pollen.
Methods
Study design
This was an open-label, single-arm, phase II/III multicenter clinical trial conducted at 10 sites in Spain, where olive pollen is an important cause of rhinitis and/or bronchial asthma. The study was approved by the applicable ethics committees and by the Spanish Drug Agency, and written informed consent was obtained from all subjects before their inclusion in the study. The trial was conducted in accordance with the Declaration of Helsinki [
21] and in compliance with the Good Clinical Practice Guidelines [
22]. The trial was registered on ClinicalTrials.gov under identification number
NCT01674595.
Study population
The study population comprised adult subjects aged 18 to 65 years with a clinical history of olive pollen-induced allergic rhinoconjunctivitis and/or asthma at least 1 year prior to trial entry, a positive skin prick test (SPT) response to
Olea europaea (wheal diameter ≥ 3 mm), and a positive specific IgE against olive pollen (≥ IgE class 2; ≥ 0.70 KU/L) documented within the last 5 years. Subjects with forced expiratory volume in 1 s (FEV1) < 70 % of the predicted value at screening, uncontrolled or severe asthma, and a history of severe asthma exacerbation [
23] were not included in the study. Subjects were also excluded if they had had an emergency room visit/admission because of asthma within the previous 12 months, a history of anaphylactic shock due to food, insect venom, exercise or drug, or severe and recurrent angioedema, or previous treatment with olive AIT within the previous 5 years or other concomitant AIT.
Interventions
The trial was initiated after the olive pollen season of 2012. AVANZ® Olive injections were given by trained nurses and under supervision of expert allergists in Immunotherapy Units following national and international recommendations [
24].
Subjects were administered 5 weekly subcutaneous up-dosing injections (300 SQ+, 600 SQ+, 3000 SQ+, 6000 SQ+ and 15,000 SQ+), followed by the maintenance injection (15,000 SQ) 2 weeks after, as part of the short course of SCIT (6 weeks). Two days after each visit, subjects were contacted by telephone to record any adverse event.
Evaluations
Tolerability (primary endpoint) was assessed throughout the study as the incidence of adverse drug reactions (ADR) recorded during the 30 min waiting period after each injection, through phone calls 2 days after each injection and by reviewing the patients’ diaries issued to record any untoward experience. ADRs were defined as all noxious and unintended responses to any dose of the Investigational Medicinal Product (IMP) administered, and were classified as
immediate (within 30 min after the injection) or
delayed (>30 min after the injection). Likewise, ADRs were classified as
local (LR, reactions occurring at the injection site), or
systemic (SR, generalised signs/symptoms occurring away from the injection site). All LRs were recorded, regardless of size, including (diffuse) swelling, redness (erythema), pain, itching (pruritus) or injection site reaction (if two or more local symptoms occurred simultaneously); SRs were graded by the investigator according to the European Academy of Allergy and Clinical Immunology (EAACI) guidelines [
24]. Additionally, all AEs where coded according to the Medical Dictionary for regulatory Activities (MedDRA).
At SCIT initiation (visit 1) and 6 weeks after the beginning of SCIT (visit 6), SPT to 5-fold concentrations of
Olea europaea allergen extracts (12, 60 and 300 μg/ml Ole e 1) was performed and blood samples were taken for immunological assessments (secondary endpoint), including
Olea europaea-specific IgG
4 and IgE levels by ImmunoCAP (Phadia AB Uppsala). Changes in immediate skin response to
Olea europaea were analyzed using the parallel line assay (PLA) [
25], expressed as the cutaneous tolerance index (CTI), which indicates the difference in allergen concentration needed to elicit the same response.
Statistical considerations
Statistical analyses were performed on the full analysis set of subjects, using the available data without imputation of missing values. The tolerability profile was determined using descriptive analyses. Changes in specific IgG4 and IgE levels between visit 1 and visit 6 were performed using Student’s t-test for paired samples. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 17.
Discussion
Olive pollen is one of the most important causes of inhalant allergy in the Mediterranean countries [
26] and is becoming the main disease-eliciting pollen in some provinces of Southern Spain (i.e. Córdoba, Jaén). The aim of this study was to determine the tolerability profile of the up-dosing phase of the new SCIT with
Olea europaea allergen extract, measured as the incidence of ADRs. The trial was designed as non-controlled and as so, subjected to a certain degree of bias which may limit the interpretation of the results. However, regarding tolerability, the frequency of ADRs can be considered conservative, because all AEs with a temporary relation to the treatment with no other attributable cause have been related to the studied treatment. With regards to the immunological endpoints, the specificity of the immunological evaluations does not require a control group as it would be the case of a clinically-related endpoint.
The nature of the ADRs observed during treatment with this new SCIT was as expected. Over one-third of the study population suffered at least one ADR. All ADRs were mild in intensity, occurred at all dosing steps, most were related to the injection site and all participants achieved full recovery. Only one subject interrupted temporally the dosing schedule.
We have followed the current guidelines of the European Medicines Agency (EMA) on clinical development of AIT [
27] and all AEs have been coded with MedDRA. Consequently, all local ADRs have been reported, independently of their size. These two factors, together with the way AEs were registered, proactively with a phone call 2 days after each injection and with a subject diary, may explain the apparently higher rate of ADRs in this trial. Although it is difficult to compare the safety profile between trials due to these differences in the safety reporting methodology, the pattern of the ADRs observed in this trial seems to be in line with previous experience and with what has been observed in previous clinical trials with other AIT products [
28,
29].
A similar clinical trial led by Tabar AI [
30], conducted with 102 subjects with the same SCIT formulation containing a house dust mite (
Dermatophagoides mix)-derived allergen extract, showed similar results in terms of number and nature of the ADRs, with 4.9 % of the study population reporting mild, grade I SRs and a similar rate of LRs. In a randomised open controlled study of SCIT with a similar
Olea europaea standardised allergen extract quantified in mass units performed with a conventional up-dosing schedule in a province of the Southern region of Spain (Jaén), where pollen counts may reach 7000 grains/m
3, Gonzalez et al. [
28] reported similar results with a rate of SRs of 8.7 %, with 3 mild and 1 moderate reactions.
One of the secondary endpoints of our study was to determine the immunological effect of this new SCIT formulation by measuring the specific levels of IgE and IgG
4. Specific immunoglobulin levels are essential to establish the immune response of allergen immunotherapy, as the induction of IgG
4 potentially blocks the proportion of IgE-facilitated antigen to T cells and eosinophils, resulting in a reduction of IgE production and the inflammatory response [
29]. As might be expected, this new SCIT with olive pollen allergen extract induced immunological responses reflected as statistically significant increments of specific levels of IgE and IgG
4 within 6 weeks of therapy. AIT often induces a short-term increase in IgE levels followed by a long-term decrease and a rapid increase in IgG
4, [
19,
28,
31,
32] which can block the binding of IgE to allergens and B cells. The induction of T-regulatory cells (Treg) by AIT is central to the suppression of the allergic reaction: Treg produce IL-10 which is able to suppress IgE production by B cells and to induce IgG
4 [
33].
Several studies have evaluated the effect of SCIT on cutaneous reactivity to the causative allergen, showing continuous reduction in cutaneous response, which in some studies has been seen to correlate with clinical efficacy [
34]. In our study, we achieved progressive reduction in immediate skin reactivity to the different concentrations of olive allergen extract, expressed as the CTI, i.e. the factor by which the extract concentration has to be multiplied to obtain the same response as in the beginning in a linear dose–response relationship. Recently, Tabar AI et al. [
30] reported similar results, achieving a CTI of 1.44 (95 % CI, 1.04 - 1.98) after 6 weeks of immunotherapy. Likewise, clinical trials led by Martínez-Cocera [
35] and Vidal [
36] showed similar reductions in skin reactivity after a short course of AIT with allergen extract derived from
Phleum pratense and house dust mites, respectively.
Acknowledgements
The following principal investigators also participated in the trial: J. Borja (H. General Universitario de Ciudad Real), L. Alonso González (H. La Mancha Centro, Ciudad Real), J. González Cervera (H. Tomelloso, Ciudad Real), A. Vega (H. Universitario de Guadalajara) and P. Guardia (H. Universitario Virgen Macarena, Sevilla).
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Competing interests
Carmen Moreno, Blanca Sáenz De San Pedro, Carmen Millán, Carmen Panizo and Fernando Florido have received grant from ALK-Abelló for the participation in this trial. Santiago Martín is employee of ALK-Abelló.
Authors’ contributions
SM designed the trial. CMo acted as coordinating investigator and reviewed the trial design, protocol and assessments. All authors analysed the results and discussed the conclusions and actively participated in the elaboration of the manuscript. All authors have read and approved the final manuscript.