Phase I study of subcutaneous allergen immunotherapy with ...alergialafe.org/descargas/revistas/IT ACAROS-FASE I - BIAL.pdf · the severity of local and systemic ARs (SARs) to SCIT

89Immunotherapy (2015) 7(2), 89–99 ISSN 1750-743X

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Research Article

10.2217/IMT.15.13 © 2015 Future Medicine Ltd

Immunotherapy

10.2217/IMT.15.13

Research Article

Hernández Fernández de Rojas, Antépara Ercoreca, Ponte Tellechea et al.Subcutaneous allergen immunotherapy for Dermatophagoides pteronyssinus allergic rhino-conjunctivitis

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Aim: A double-blind placebo-controlled study was conducted according to EMA guidelines, to evaluate safety, tolerability and short-term treatment effects of three updosing regimens of Dermatophagoides pteronyssinus subcutaneous allergen immunotherapy. Patients & methods: Forty-eight patients were randomized to groups: A (six weekly doses), B (eight weekly doses) or C (eight doses, two clustered doses over 3 weeks). Results: The most frequent adverse events were local reactions. No serious adverse events were found. Severe systemic reactions were reported more frequently in Group C. Decreased cutaneous responses and increased specific IgGs were shown in all active groups, even within the short-term. Conclusion: Dermatophagoides pteronyssinus subcutaneous allergen immunotherapy in depot presentation exhibited good safety and tolerability. Group A seemed to show the best profile for further clinical development.

Keywords: allergen • Dermatophagoides pteronyssinus • house dust mites • rhinoconjunctivitis • safety • subcutaneous allergen immunotherapy • tolerability

Rhinoconjunctivitis is the most common allergic condition, accounting for 55.5% of diagnoses in allergy clinics [1]. House dust mites (HDM) are complex organisms that are capable of producing thousands of dif-ferent proteins and macromolecules, with a number of them being potential allergens. Dermatophagoides pteronyssinus (DPT) is the most prevalent HDM in Europe. According to Heinzerling et al. [2], DPT sensitization is present in about 20% of patients with rhinoconjunctivitis in Spain.

Allergen immunotherapy (AIT) is particu-larly recommended for patients with moder-ate-to-severe allergy unsuccessfully controlled by symptomatic treatment [3,4].

AIT, a type of immunomodulation, causes a reduced hypersensitivity response to certain allergens [5] and has been shown to be effective in allergic rhinitis [4] as well as in selected patients with allergic asthma [6]. AIT has been used for more than a cen-tury, but only in recent decades have dou-ble-blind controlled trials been published to

prove its effects. Based on a comprehensive review, the WHO concluded that AIT was an effective and well-documented therapeu-tic option in allergic diseases [7]. The role of AIT was subsequently confirmed in an updated review [8].

Based on a review of more than 2700 ref-erences, an expert panel published Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines with a number of evidence-based recommendations on allergy therapy, includ-ing clinical trials showing that AIT results in clinical benefits in rhinitis and asthma [9].

Various routes of administration are avail-able for AIT, including subcutaneous, intra-nasal and sublingual. Although all so-called subcutaneous allergen immuno therapy (SCIT) therapies share some common fea-tures, such as using allergenic extracts, a range of different products are available. They are mainly adsorbed onto aluminum hydroxide in a matrix or gel, and allergens are slowly released. Such a procedure may result in a reduced incidence and severity

Phase I study of subcutaneous allergen immunotherapy with Dermatophagoides pteronyssinus in patients with allergic rhinoconjunctivitis with or without asthma

Dolores Hernández Fernández de Rojas1, Ignacio Antépara Ercoreca2, Ana Ponte Tellechea3, Ethel Ibáñez Echevarría1, Ignacio Jáuregui Presa2, Pedro Gamboa Setién2, Juan A Asturias3, Araitz Landeta Manzano*,3 & Begoña Madariaga Goirigolzarri31Allergy Department, IIS Hospital La Fe,

Valencia, Spain 2Allergy Department, Hospital

Universitario de Basurto, Bilbao, Bizkaia,

Spain 3Research & Development Department,

Bial Industrial Farmacéutica S.A.,

Zamudio, Parque Científico y Tecnológico

de Bizkaia, Edificio 401, E-48170

Zamudio, Bizkaia, Spain

*Author for correspondence:

Tel.: +34 94 4438000

Fax: +34 94 4438016

[email protected]

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90 Immunotherapy (2015) 7(2) future science group

Research Article Hernández Fernández de Rojas, Antépara Ercoreca, Ponte Tellechea et al.

of adverse effects (including local reactions, urticaria, asthma and others) [10].

The EMA guidelines do not recommend traditional Phase I trials with allergenic products in healthy volun-teers, because healthy individuals do not react in the same way as allergic patients; thus, they do not reflect the target population and no useful data on safety and tolerability are obtained [11]. Furthermore, a study using different dose schedules is recommended in order to collect preliminary data on safety and tolerability, and appropriate dose-escalation schedules for AIT. In the present clinical trial, an aluminum-adsorbed DPT extract for SCIT, a highly prevalent allergen in Spain, was used, and several accelerated schedules were investi-gated. The main objective was to compare the tolerabil-ity and safety when administered using three different dose-escalating schedules in adult patients with allergic rhinoconjunctivitis with/without asthma sensitized to DPT. Establishing the optimal administration sched-ule was a secondary study objective. Surrogate efficacy markers were also assessed, in terms of immuno globulin changes (specific IgE, IgG and IgG

4) and skin tests

(prick test dose response).

Patients & methodsA Phase I randomized, double-blind, placebo-controlled, trial was performed in two participating centers in Spain (Hospital Universitario La Fe, Valencia, and Hospital Basurto, Bilbao). The allergenic product used in this study was a sterile depot suspension with DPT native extract (Allergovac Depot®, Bial-Arístegui, Zamudio, Spain), which was adsorbed to 0.33% aluminum hydroxide to produce prolonged release of the allergen from the injec-tion site. The other components were phenol, sodium chloride and water for injection. The evaluated vaccine can be considered different to previously commercialized vaccines from Bial-Arístegui, so an early clinical phase was necessary in order to obtain orientation toward dose and escalation schedule. Raw material used to obtain the D. pteronyssinus allergen extract was of the mite isolated bodies type instead of the previous whole mite culture type used previously. Mite bodies were isolated by sieving a harvested culture which had been grown in nonaller-genic media, thus leading mainly to a different balance of the major allergens Der p 1 and Der p 2. whole mite culture raw materials give rise to extracts with a high Der p 1:Der p 2 ratio; the preparations obtained from mite isolated bodies present a similar allergen content. Batch L-101006 was used in the current study. The maximum concentration (vial 3) of depot DPT extract was 1000 treatment standardized unit/ml (TSU/ml), equivalent to 0.5 SPT/ml and with Der p 1 and Der p 2 concentra-tions of 4.68 and 4.50 μg/ml, respectively. A volume of 0.5 ml of vial number 3 was injected as the maximum

dose administered, resulting in doses of 2.34 and 2.25 μg of Der p 1 and Der p 2, respectively.

Selection criteria were defined according to ARIA and EMA guidelines. Patients aged 18–60 years with allergic rhinoconjunctivitis with or without asthma, sensitized to DPT at least 1 year before study onset, were selected. Main selection criteria included a DPT prick test ≥3 mm and a DPT-specific IgE > 0.7 kUA/L (CAP, Phadia, Uppsala, Sweden) during the past year; patients sensitized to other clinically rel-evant seasonal allergens having a pollination period not concurrent with the DPT SCIT administration period were eligible for the study. Patients sensitized to other clinically relevant perennial allergens show-ing serum IgE levels higher than 0.7 kUA/l were excluded. Patients with severe asthma or forced expi-ratory volume in 1 s (FEV

1) less than 70%, or with

asthma which required treatment with inhaled or systemic corticoids at the time of the study or in the 8 weeks immediately prior to the onset of treatment, were also excluded.

After a 4-week screening period, patients were openly randomized to three therapeutic schedules (A, B and C) in entrance order. In the same randomization, using a double-blind design, patients were allocated in each group (A, B and C) to active therapy or placebo in a 3:1 ratio (Figure 1). Doses administered ranged from 2 to 500 TSU; the content of major allergen for the maximum administered dose (500 TSU) was 2.34 μg (Der p1) and 2.25 μg (Der p2). Duration of therapy was 5, 7 and 3 weeks in A, B and C schedules, respec-tively. A matching placebo not containing allergen extract was used. Cumulative doses for the three arms are described in Figure 2. Patients were treated accord-ing to the schedules presented herein. Rescue drug use for symptoms was allowed over the study period:

• Group A: six weekly doses (over 5 weeks):

– Vial 2: 0.1, 0.2 and 0.5 ml

– Vial 3: 0.1, 0.2 and 0.5 ml

• Group B: eight weekly doses (over 7 weeks):

– Vial 1: 0.2 ml

– Vial 2: 0.1, 0.2 and 0.4 ml

– Vial 3: 0.1, 0.2, 0.4 and 0.5 ml

• Group C: eight doses, two doses in the same day in a 30-min period (over 3 weeks):

– Week 1: vial 2 – two 0.1 ml doses

– Week 2: vial 2 – 0.2 and 0.3 ml

– Week 3: vial 3 – two 0.1 ml doses

– Week 4: vial 3 – 0.2 and 0.3 ml

Baseline demographic and clinical data were recorded, including age, weight, height, previous

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Figure 1. Patient disposition and a representation of study design. Patients per group: active 12, placebo 4.

Screening period (4 weeks)n = 48

n = 48

Screening failures

n = 0

Randomized

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Group A: 6 injections (5 weeks)

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Group B: 8 injections (7 weeks)

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Group C: 4 double injection (3 weeks)

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Active

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Active

Consent withdrawaln = 1

Discontinued Discontinued Discontinued Discontinued Discontinued Discontinued

Completedn = 10

Completedn = 13

Completedn = 15

1 week follow-up

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Subcutaneous allergen immunotherapy for Dermatophagoides pteronyssinus allergic rhinoconjunctivitis Research Article

personal and family history and current symptoms. Allergic rhinitis was classified as intermittent versus persistent and mild versus moderate to severe. Medi-cation use for rhinoconjunctivitis/asthma in the last 3 months was recorded. Symptoms were assessed before and after each administration; lung func-tion tests (spirometry) were evaluated at baseline and whenever the investigator suspected an adverse reac-tion (AR). Prick tests, performed using four increasing doses of DPT extracts (0.005, 0.05, 0.5 and 5 mg/ml), as well as positive (histamine) and negative (saline) controls and specific IgE and specific IgG (IgG and IgG4) to DPT, were measured before and after treat-ment by ELISA technique [12] at the Protein Lab of Bial-Industrial Farmacéutica S.A.

Symptoms were assessed before and 30 min after AIT was administered. Newly appearing symptoms after administration were reported as adverse reac-tions (ARs) in case report forms. Between visits, symptoms were recorded by patients on diary cards. Concomitant drug and rescue medication use were also recorded.

All reported adverse events (AEs) were recorded, regardless of their relationship with study therapy. Safety was additionally assessed with baseline and final routine laboratory analyses.

The primary end points were the number of ARs and the severity of local and systemic ARs (SARs) to SCIT administration. Proportions were compared between study arms. The tolerability of SCIT was evaluated by early and late local reactions (i.e., local swelling and redness) and systemic reactions after each injection (any symptoms from organs distant from the location of the injection). Reactions were classified depending on the severity and onset of the reaction, according to the EAACI classification [8]:

• 0: no symptoms or nonspecific symptoms;

• I: mild systemic reactions, which may include symptoms like localized urticaria, rhinitis or mild asthma (PF <20% decrease from baseline);

• II: moderate systemic reactions, which may start greater than 15 min after the injection and may com-

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Figure 2. Cumulative doses for three different updosing regimens (groups A, B and C). TSU: Treatment standardized unit.



prise symptoms like generalized urticaria, and/or moderate asthma (PF <40% decrease from baseline);

• III: severe but not life-threatening systemic reac-tions, which may comprise generalized urticaria, angioedema or severe asthma (PF >40% decrease from baseline) of rapid onset (<15 min);

• IV: anaphylactic shock, which may include symptoms such as: immediate evoked reaction of itching, flushing, erythema, generalized urticarial, stridor (angioedema), immediate asthma, hypotension, etc;

• Secondary end points included immunoglobulin level determination (specific IgE, IgG and IgG4) and prick-test dose response.

Statistical analysisSample size estimation was based on a maximum dif-ference between therapy arms of 50% for AEs and a 10% dropout rate. Forty-eight patients were included so that a final sample size of 43 patients could be achieved. Statistical power for AE differences in study arms was 87%, with a p-value <0.05 represent-ing the significance level. Continuous variables were assessed with the Student’s t-test for independent samples to compare active therapy versus placebo and with the analysis of variance (ANOVA) with Bonfer-roni’s correction to compare therapy schedules. Cate-

gorical variables were assessed with Fisher’s exact test or the χ2 test. The Student’s t-test for paired samples was used to compare baseline versus final end points within active therapy or placebo groups.

ResultsPopulation characteristics & treatmentTable 1 presents details of patient demographic and characteristics. A total of 48 patients were randomized: 16 (12 active, 4 placebo) patients per treatment group. The mean age of patients was 31.4 years (95% CI: 28.8–34.1) with 54.2% of patients being female. The majority (81.3%) of patients were Caucasians (n = 39), 6.3% were Arabs and 12.5% Hispanics.

The time since diagnosis was 5.9 years (95% CI: 3 to 8.7), and the age of onset was 25.6 years (95% CI: 22.6 to 28.5). Rhinitis was intermittent in 41.7% of patients and persistent in 58.3%. Disease was mild in 4 (8.3%) patients and moderate-to-severe in 44 (91.7%) patients. Most patients (41 [85.4%]) had used drug therapy for rhinitis and/or asthma within the last 12 months. Previous AIT had been used by 9 (18.8%) of patients, in all cases ended more than 5 years before entering in the study, as stated in the exclusion crite-ria. A history of other forms of allergy was noted in 27 (56.3%) patients and intermittent mild asthma in 18 patients (37.5%). A family history of allergy was present in 27 (56.3%) patients. Symptoms were pres-ent in 72.9% (n = 35) of patients at the baseline visit.

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No differences were found between groups for socio-demographic and clinical parameters depending on sex, therapy schedule or randomization to active treatment or placebo. Thus, groups were homogeneous at baseline.

During follow-up, only eight patients did not take any concomitant drug. Concomitant drugs included rescue medication (45.6%) and other drugs (54.4%).

Overall, 331 doses were administered (98, 126 and 107 in arms A, B and C, respectively). All patients received at least one study drug dose, and were included in the primary analysis. Thirty-six (75%) patients completed the study and received all planned doses. Two out of 36 patients completed the follow-up period despite they reached their own maximum toler-ated dose, which was lower than the established dose. There was just one dropout, only one patient withdrew the consent (0.48%). This patient belonged to group A. In addition, nine patients did not complete therapy as planned due to ARs (six patients) or because of a concomitant disease (three subjects). All interruptions occurred in patients receiving active therapy. The pro-portion of patients receiving active therapy who com-pleted the study as planned was significantly higher in arm A (91.6%) than in arm B (58.3%) or C (50%). Reasons for withdrawals were as follows: arm B, ARs (three patients); arm C, ARs (three patients) and other concomitant diseases (three patients). A flowchart of the study population is shown in Figure 1.

Adverse eventsAt least one AE was reported by 42 (87.5%) patients during the trial, including 11/12 (91.7%) patients receiving placebo and 31/36 (86.1%) patients receiv-ing active therapy. All patients in arm B showed at least one AE. Overall, 216 AEs were reported, which included 169 AEs in 36 patients in the active group and 47 AEs in 12 patients in the placebo group. The mean duration of reported AEs was 1.5 days (range 0–19; 95% CI: 1.1–1.9), with no difference between groups or therapies.

Adverse reactionsOut of 216 AEs, 76 ARs (local and systemic) related to therapy were observed (23%), six of them in the pla-cebo group. The number of ARs per group was 17.3% (17/98) in patients in group A, 23.8% (30/126) in group B and 21.5% (23/107) in group C.

The proportion of patients having ARs was signif-icantly higher (p < 0.05) for arm B, with no differ-ences between arms A and C. The mean number of ARs per patient was 1.6 (95% CI: 1–2.2); the median number per patient was 1.4 (range 0–13). The number of ARs was significantly higher in patients receiving active therapy (p = 0.001). No differences were found in the number of ARs per patient across study arms. The mean duration of AR was 0.6 days (95% CI: 0.34–0.9; range 0–6); no differences were observed across study arms. In relation to severity, ARs were

Variable Parameter Group A active (n = 12)

Group B active (n = 12)

Group C active (n = 12)

Placebo (n = 12)

Age (years) Mean (SD) 30 ± 8.5 29 ± 9.29 31 ± 8.84 34 ± 9.5

Sex % Male 33.33 66.67 41.67 50

% Female 66.67 33.33 58.33 50

CAP/PHADIA Class 2 (%) 1 (8.33%) 2 (16.67%) 0 (0%) 2 (16.67%)

Class 3 (%) 6 (50%) 2 (16.67%) 3 (25%) 4 (33.33%)

Class 4 (%) 1 (8.33%) 4 (33.33%) 5 (41.67%) 3 (25%)

Class 5 (%) 2 (16.67%) 2 (16.67%) 2 (16.67%) 3 (25%)

Class 6 (%) 2 (16.67%) 2 (16.67%) 2 (16.67%) 0 (0%)

IgE V0 (absorbance 492 nm)

Mean (SD) 0.81 ± 0.59 0.77 ± 0.66 1.01 ± 0.86 0.70 ± 0.64

FEV1 (%) Mean (SD) 116 ± 13.15 113 ± 13.88 103 ± 13.05 115 ± 13.51

Time since diagnosis (years)

Mean (SD) 1.35 ± 2.43 5.41 ± 10.41 4.19 ± 9.47 11.82 ± 11.79

Previous AIT % No 100 83.33 66.67 75

% Yes 0 16.67 33.33 25

AIT: Allergen immunotherapy; CAP/PHADIA: CAP IgE specific System (Phadia, Uppsala, Sweden); FEV1: Forced expiratory volume in 1 s;

SD: Standard deviation.

Table 1. Patient demographics and characteristics.

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mild in 37 cases (52.0%), moderate in 26 (37.1%) and severe in 7 (10%) with no differences across study arms. Most ARs required no action to be taken (49, 70%); 8 (11.4%) ARs required additional therapies; 6 (8.6%) required dose changes; and 7 (10%) resulted in withdrawal from the study. All ARs subsided by the end of the study.

Local & systemic ARsThere were 62 (18.7%) local ARs and 14 (4.2%) SARs among the 331 doses administered. Dose changes due to local ARs were required for two late local reactions in group A (same patient) and one late local reaction in group B, indicating that local reactions were clini-cally relevant in only 1% of administered doses. More than half of all patients (28 [58.3%]) had at least one local or systemic AR related to therapy, whereas 20 (41.7%) had no ARs. At least one AR was reported in 4/12 (33.3%) patients receiving placebo and in 24/36 (66.7%) receiving active therapy.

The highest proportion of patients receiving active therapy that developed local ARs was observed in arm B (p < 0.05).

A total of 14 cases of SARs were observed in ten patients (4, 6 and 4 SARs in arms A, B and C, respec-tively). In arm A, the severity of most SARs was grade I, as opposed to prevailing grade II or III events in arms B and C. The highest proportion of patients having SARs was observed in arm B (40%); no differ-ences were found between arms A and C (both 30%). The mean number of SARs per patient was 1.3 (95% CI: 0.95–1.65), and the median number was 1 per patient (range 1–2). Although no significant differ-ences were found across study arms, the mean number of SARs per patient was numerically higher in arm B.

The proportion of active doses associated with SARs was similar for the three groups (arm A: 4/98 [4.08%], arm B: 6/126 [4.76%] and arm C:4/107 [3.74%]). The severity of SARs appeared to be lower in arm A, with three grade I and one grade II SARs (3.06, and 1% in 98 doses) compared with both arm B, with one grade I, four grade II and one grade III SARs (0.8, 3.17 and 0.8% in 126 active doses) and arm C, with one grade I, one grade II and two grade III SARs (0.93, 0.93 and 1.9% in 107 total administered doses per group).

ImmunoglobulinsSpecific IgG for DPT and IgG4 increased significantly in all active groups (arms A and B, p < 0.0001; arm C, p = 0.001 vs placebo). Data for IgG4 and IgG levels are shown in Figures 3 & 4, respectively, after 5, 7 and 3 weeks of treatment for arms A, B and C, respectively. There were no significant differences in IgG and IgG4 increases between active groups. DPT-specific IgE

was reduced (not statistically significant) in all active groups (Figure 5).

Skin prick testReductions in skin reactivity (wheal area) were only observed in patients receiving active treatment but not in the placebo group. Skin prick test dose response in all active therapy groups is shown in Figure 6. In group A, reduction of the wheal area was statistically signifi-cant for vial 2 (p = 0.002), vial 3 (p = 0.005) and vial 4 (p = 0.001), but not for vial 1 (p = 0.071). In group B, wheal area reductions were not statistically significant for any of the allergen concentrations tested, whereas in group C, a statistically significant reduction in wheal area was observed for vial 1 (p = 0.005).

DiscussionAIT has been used since the beginning of the 20th century. However, guidelines on the clinical develop-ment of AIT (EMA guidelines) have only been effec-tive in recent years. According to EMA guidelines, the first step for developing a product for specific AIT is to provide data on safety and tolerability with regards to the maximum tolerated dose and suitable dose-escalation scheme. That reinforces the fact that there are not many published Phase I trials on AIT; whereas, it is more feasible to find papers on the effi-cacy and safety of AIT [13–15], including modifica-tion in allergic disease progression from rhinitis to asthma articles [16]. At present, there is good evidence for HDM-SCIT efficacy and its long-term effects in adults and children [17].

The present Phase I study with a depot DPT extract, which was designed as a randomized, double-blind, placebo-controlled trial and conducted accord-ing to EMA recommendations [12], provides evidence of the short-term safety and tolerability of SCIT in adult patients with allergic rhinoconjunctivitis and/or asthma.

A few Phase I studies of SCIT with HDM extracts in allergic patients have been reported. A single cen-ter, open-label Phase I/IIa study evaluated the safety, tolerability and clinical efficacy of A-type CpG oli-godeoxynucleotide (QbG10) as an adjuvant to AIT with a subcutaneous HDM allergen extract in patients with HDM allergy [18]. Twelve out of 21 study subjects (57.1%) reported a total of 41 AEs, of which 59% were rated as mild, 41% as moderate and none as severe. Recently, Corzo et al. [19] investigated the tolerability and acceptable dose range of an orodispersible HDM sublingual AIT tablet for the treatment of HDM-induced asthma, with or without rhinoconjunctivitis in adults and children in two Phase I trials. Doses up to 12 development units (DU) were tolerated in the

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Figure 3. Increased immunoglobulin IgG4 levels with active treatment. High basal IgG4 levels of Placebo A group could be due to the fact that one of the patients received previous immunotherapy.

Figure 4. Increased immunoglobulin IgG levels with active treatment.

2.0Changes in sIgG levels

Baseline End of the trial

Active A (n = 12)

Placebo A (n = 4)

Active B (n = 12)

Placebo B (n = 4)

Active C (n = 12)

Placebo C (n = 4)

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selected populations, and thus considered suitable for further clinical investigation. No serious AEs were reported. In trial 1 (maximum dose, 32 development

units [DU]), 1 patient in the 16 DU group discontin-ued due to AEs. The entire 32 DU group was discontin-ued as one patient had a severe adverse reaction. In trial

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Figure 5. Specific immunoglobulin IgE level changes in all groups: active and placebo.

Figure 6. Changes in skin prick test response: changes in wheal area (mm2) per group of treatment (groups A, B and C) between final visit and basal visit versus its placebo.



2 (maximum dose, 12 DU), no patients discontinued prematurely. Mild AEs related to the administration site (oral pruritus, stomatitis, oral paresthesia, mouth edema, throat irritation) were the most frequent. Data from these studies [18,19], regarding the occurrence of ARs, are difficult to be compared with the present findings because of differences in the extracts tested, QbG10 as adjunct to HDM in one study [18] and the use of an orodispersible HDM sublingual tablet in the other [19].

The aim of the current study was to find the most suitable updosing scheme in terms of safety and tol-erability. Different dose schedules were tested in our study with the same maximum dose (500 TSU) but different cumulative doses in each group. Besides this, exploratory trial was designed to provide a trend to select the most adequate dose-escalation scheme to continue with the clinical development of our vac-cine, thus, no statistically significant between-group differences results were anticipated. The overall rate

Baseline

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of ARs was 23% (with six cases occurring in the pla-cebo group). Most ARs were local and only 14 SARs (4.2%) were reported in ten patients. Local reactions, mainly caused by IgE antibody, are common during the course of AIT. These local reactions are usually mild and not worrisome for patients. In a retrospective analysis of an electronic AIT database over a 12-month period, including 360 patients who received a total of 9678 injections, it was concluded that local reactions do not predict subsequent local reactions [20]. In addi-tion, another review reported that local reactions do not predict future systemic reactions [21].

The incidence of SARs found in our study was simi-lar to data reported previously in a Cochrane review of SCIT for seasonal allergic rhinitis [4]. Thus, based on data of systemic ARs, treatment schedule of group A seems to be associated with the most favorable profile in terms of safety and tolerability.

Apparently, the more doses that are administered, the higher the expected risk of ARs; however, this is not the only factor that interferes with the number of ARs. In addition to the type of build-up schedule, the dose increasing steps may also influence the number of ARs. In fact, although the number of administered doses of conventional and cluster therapy was the same, the number of adverse reactions was 6 and 4, respectively. This confirmed that there are many fac-tors, apart from the number of administered doses, which affect the number of ARs.

In all study arms, after treatment with DPT extract, allergen-specific IgG and IgG4 levels increased signifi-cantly only in the active therapy groups but not in the placebo group. However, changes in specific IgE levels were not significant in all three study regimens. It is worth to mention that IgG4 basal levels for patients in placebo allocated to group A were significantly higher than other groups. It could have been because one of

the patient received AIT for 3 years, 5 years before entering in the study.

Studies with allergen SIT generally provide immuno logic data at 1 year of treatment [13,15] but, in this study, immunologic changes were assessed over a short time period, which represents a novel aspect of the current study. Furthermore, as occurs with the immuno globulin changes, most of the published stud-ies provide data on skin reactivity to 1 year [13]. Present study results showed that in active groups A and B, skin sensitivity was reduced, with the arm A dose escalation scheme showing significant differences.

ConclusionBased on our results, SCIT with a DPT extract in a depot preparation has shown a good safety and tol-erability profile for all tested dosing schedules. How-ever, the arm A schedule appears preferable based on the following findings: safety results showed that grade II–III SARs only occurred in arms B and C; the number of withdrawals was lower in arm A; prick test dose-response results demonstrated a significant wheal area reduction with all but one of the tested doses. Immune efficacy was achieved by all three schedules, with statistically significant increases in IgG and IgG4 compared with placebo.

Future perspectiveAlthough AIT for allergic disease has developed over more than a century, only recently have solid evidence-based data been available, with the achievement of sub-stantial improvements in the quality of clinical studies. In the near future, it is anticipated that existing inter-nationally agreed guidelines for AIT and evidence-based recommendations will be used more extensively and will undoubtedly improve therapeutic outcomes in specific clinical scenarios.

Executive summary

• This randomized, double-blind, placebo-controlled study, conducted according to EMA guidelines, provides preliminary data on the safety and tolerability of different dose-escalation schedules of subcutaneous allergen immunotherapy (SCIT) with Dermatophagoides pteronyssinus (DPT).

• A total of 48 patients (16 [12 active/four placebo] per treatment group) received 331 doses of SCIT DPT.• Overall, 76 (23%) adverse reactions were reported (six with placebo administration), most of which were local

(18.7%), and 1% were clinically relevant, and only 14 systemic adverse reactions (4.2%) were observed in ten patients receiving active therapy.

• After treatment with DPT extract, allergen-specific immunoglobulin IgG and IgG4 levels increased significantly in patients receiving active therapy in all groups.

• Reductions in wheal area were only observed in patients receiving active treatment but not in the placebo group and achieved statistical significance in group A.

• Short-term effects of SCIT with DPT extract in a depot form demonstrated a good safety and tolerability profile, and induced significant changes in both humoral and skin-prick dose response. Group A showed less severe adverse reactions compared with groups B and C.

• Among the tested schedules, arm A showed the best tolerability and efficacy profile compared with arms B and C.

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ReferencesPapers of special note have been highlighted as:•ofinterest

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• Recentstudythatdemonstratedgoodevidenceforhousedustmitessubcutaneousallergenimmunotherapyefficacyanditslong-termeffectsinchildrenandadults.

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At the same time, clinical trial designs based on regulatory agency recommendations will help to define the best dose, formulation, composition, release form and route of administration for SCIT products. SCIT products have become a very promising therapeutic tool in the management of allergic diseases and it is anticipated that their acceptance and use will continue to increase in the coming years.

Financial & competing interests disclosureThis study was supported by Bial Industrial Farmacéutica S.A.

A Landeta Manzano, A Ponte Tellechea, B Madariaga Goirigol-

zarri and JA Asturias are employees of Bial Industrial Farma-

céutica S.A. The authors have no other relevant affiliations or

financial involvement with any organization or entity with a fi-

nancial interest in or financial conflict with the subject matter or

materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this man-

uscript. The authors thank Content Ed Net, Madrid, for provid-

ing editorial assistance in the preparation of this manuscript,

with funding from Bial Industrial Farmacéutica S.A.

Ethical conduct of researchThe authors state that they have obtained appropriate institu-

tional review board approval or have followed the principles

outlined in the Declaration of Helsinki for all human or animal

experimental investigations. In addition, informed consent

was obtained from the participants involved.

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www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf

http://emedicine.medscape.com/article/1588289-overview#aw2aab6b2b1aa



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• Despitethefactthatthisstudyevaluatedallergenimmunotherapyusingsublingualtablets,ratherthansubcutaneousallergenimmunotherapy,thisisan

importantstudybecauseitisoneofthefewpublishedPhaseIstudiesevaluatingallergenimmunotherapyforallergicdisease.

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21 Coop CA. Local reactions from subcutaneous allergen immunotherapy. Immunotherapy 5, 1339–1345 (2013).

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