Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/springer-journals/scit-with-ahigh-dose-house-dust-mite-allergoid-is-well-tolerated-OjJyarJoAt
- Publisher
- Springer Journals
- Copyright
- Copyright © 2018 by The Author(s)
- Subject
- Medicine & Public Health; Allergology; Dermatology; Environmental Health; Immunology
- eISSN
- 2197-0378
- DOI
- 10.1007/s40629-018-0059-x
- Publisher site
- See Article on Publisher Site
Abstract
original article Allergo J Int (2018) 27:131–139 https://doi.org/10.1007/s40629-018-0059-x SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and more than 10 years of daily practice analyzed in different subgroups Ludger Klimek · Gabriele-Cornelia Fox · Susanne Thum-Oltmer Received: 9 January 2018 / Accepted: 8 March 2018 © The Author(s) 2018 Abstract verse events (AEs) were observed with 1800 PNU in Background Efficacy of house dust mite (HDM) al- HDM-DBPC (31.2% PL, 35.5% HDM-ALL [1800 PNU]); lergen immunotherapy (AIT) in allergic rhinitis and the difference was primarily because of local reac- controlled allergic asthma has been documented in tions; there was no difference in systemic reactions controlled trials with adults and children. However, (10.9% PL, 11.2% HDM-DBPC, 11.2% HDM-ALL); one tolerability comparing clinical development and post out of 279 high-dose HDM allergoid-treated patients marketing data, particularly in different subgroups, is had a serious adverse event (SAE). missing. Children (n = 39)/adolescents (n = 26) had fewer re- Methods We performed an analysis of pooled safety lated AEs and local reactions compared to adults; sys- data for subcutaneous AIT (SCIT) with a high-dose temic reactions: children 12.8%, adults 11.2% ado- house dust mite allergoid from 6 randomized, con- lescents 7.7%. Females had slightly more AEs. Treat- trolled trials (RCT) in HDM allergic respiratory disease ment was well tolerated in asthmatic patients (n = 267; (ARD) and of post marketing safety data from more GINA I n = 32, II n = 104, III n = 17, 114 no classifica- than 10 years including different subgroups (age, gen- tion). der, asthma status). In more than 10 years more than 100,000 patients Results In all, 500 patients with ARD were treated were treated with high-dose HDM allergoid (1800 in RCTs: 279 received the marketed dose of 1800 PNU) under daily practice conditions. Adverse drug protein nitrogen units (PNU) high-dose HDM aller- reactions (ADRs) were reported in 0.5% of patients. goid AIT (214 double-blind placebo controlled [HDM- 94.6% of these ADRs were expected. DBPC], 65 children/adolescents usual care controlled Conclusion SCIT with the marketed dose of high-dose [HDM-RCT(UC)]), and 221 placebo (PL). 38.8% ad- HDM allergoid was well tolerated in clinical develop- ment and in daily practice. There was no increased risk for the investigated patient subgroups. Tolerabil- All authors concur with the submission. ity was comparable to HDM sublingual immunother- Author contributions G.-C. Fox,S.Thum-Oltmer, L.Klimek apy (SLIT) tablets. were involved in manuscript conception and interpretation of the data. G.-C. Fox performed the data analysis. Keywords Tolerability · Subcutaneous allergen im- S. Thum-Oltmer prepared figures and substantially munotherapy · Allergic rhinitis · Asthma · Children contributed to the manuscript from the first draft stage. L. Klimek supervised and participated in writing the Abbreviations manuscript. G.-C. Fox, S. Thum-Oltmer, L. Klimek reviewed, AA Allergic asthma commented and approved the final manuscript. ADR Adverse drug reaction Prof.L.Klimek, MD () AE Adverse event Center for Rhinology and Allergology, An den AIT Allergen immunotherapy Quellen 10, 65183 Wiesbaden, Germany AR Allergic rhinitis Ludger.Klimek@allergiezentrum.org ARD Allergic respiratory disease Dr.G.-C. Fox, PhD·Dr.S. Thum-Oltmer,VD DBPC Double-blind placebo controlled Allergopharma GmbH & Co. KG, Reinbek bei Hamburg, FEV Forced expiratory flow in 1 sec Germany K SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . 131 original article GINA Global Initiative for Asthma imum injection volume of 0.6 ml (1800 PNU; [8]). The HDM House dust mite major allergen content of the high-dose HDM aller- HDM-ALL HDM-DBPC plus HDM-RCT(UC) goid D. pteronyssinus is 12μq/ml Der p 1 and 10μg/ml PEF Peak expiratory flow Der p 2; for the high-dose HDM allergoid D. farinae it PL Placebo is 20μg/ml Der f 1 and 15μg/ml Der f 2 [9]. PNU Protein nitrogen units This HDM SCIT product has been shown to be ef- RCT Randomized, controlled trials fective in patients with mite-induced allergic asthma. SAE Serious adverse event Adding the mite allergoid SCIT to pharmacologic SCIT Subcutaneous immunotherapy treatment was an effective and safe strategy to re- SLIT Sublingual immunotherapy duce corticosteroid doses while maintaining disease SOC System organ class control and significantly improved bronchial aller- TRAE Treatment-related adverse event gen provocation (BAP; [6, 7]). There is however no UC Usual care data available comparing safety information for AIT products from clinical development and spontaneous safety reports from daily practice since launch, par- Introduction ticularly not in different patient subgroups [10]. Allergen immunotherapy (AIT) is a therapy with dis- The publication presents safety data of this high- ease-modifying effects and the only available treat- dose HDM allergoid in clinical development and ment to target the disease instead of the symptoms. from adverse drug reactions (ADRs) spontaneously By administering allergen extracts, specific blocking reported after launch, including subgroup analysis. antibodies, tolerance-inducing cells, and mediators SLIT is reported as having ADRs in 40–75% of the are activated. These prevent further exacerbation of cases as temporary local mucosal reactions (pruritus the allergen-triggered immune response, block the or dysesthesia in the oral cavity, swelling of the oral specific immune response, and attenuate the inflam- mucosa, throat irritation) and considered as having matory response in tissue [1, 2]. a better safety profile than SCIT, especially with re- House dust mite (HDM) allergy is strongly impli- spect to systemic reactions, anaphylaxis, and other cated in the pathogenesis of respiratory allergic dis- severe systemic reactions [1]. Therefore, the safety ease and a large proportion of patients with aller- data of this product were compared to the safety of gic rhinitis (AR), allergic asthma (AA), or both, are two different SLIT mite tablets as benchmark. sensitized to HDM, predominantly Dermatophagoides pteronyssinus and Dermatophagoides farinae [3]. Material and methods Efficacy of AIT in HDM allergy is documented by a number of controlled trials in adults and few Product controlled trials in children [1, 4]. Subcutaneous immunotherapy (SCIT) has been well investigated The high-dose HDM allergoid (Acaroid ) consists for individual preparations in controlled bronchial of the HDM Dermatophagoides pteronyssinus alone asthma as defined by the Global Initiative for Asthma (used in Trials AL0104av (EudraCT: 2004-003892-35), (GINA) 2007 as well as in intermittent and mild per- 97-09 M, 97-09 UK, AL0106ac (EudraCT: 2006-000934- sistent asthma (GINA 2005). AIT is recommended as 11), and AL1009ac (EurdraCT: 2011-002248-29)) or in a treatment option, in addition to allergen avoidance 1:1 combination with Dermatophagoides farinae (used and pharmacotherapy in GINA 2017, provided there in Trial AL0400av; Table 1). 97-09 M, 97-09 UK, and is a clear causal link between respiratory symptoms AL0400av were performed before introduction of the and the relevant allergen [1, 4, 5]. EudraCT database. The drug product is a suspension The high-dose HDM allergoid is a depot formu- administered by subcutaneous injection. lation with aluminum hydroxide for subcutaneous The following strengths were used in Trials AIT. Formaldehyde and glutaraldehyde have been AL0104av, 97-09 M, 97-09 UK, AL0400av, and AL0106ac: used in combination to chemically modify an aque- strength B: 3000 PNU/mL; strength A: 300 PNU/mL ous extract of purified HDM bodies and to produce (obtained by a 1:10 dilution of strength B). In the dose a stable allergoid. The allergen extract consists of range finding trial AL1009ac 4 different doses were the HDM Dermatophagoides pteronyssinus or Der- tested: 600 PNU/mL, 1800 PNU/mL, 3000 PNU/mL matophagoides farinae alone or in combination. The and 5400 PNU/mL. product is manufactured at two different strengths, which enables a low initial dose and increasing con- Study population centration of allergens in the further course of treat- ment. In maintenance therapy, intervals of up to This publication presents safety information from 8 weeks are very convenient and allow for flexibility. 6 completed, randomized, controlled clinical tri- The marketed dose is 3000 protein nitrogen units als conducted between 2000 and 2015 in patients (PNU)/mL in strength B (strength A: 300 PNU/mL with allergic rhinitis/rhinoconjunctivitis (97-09 M, obtained by a 1:10 dilution of strength B) with a max- 97-09 UK, AL0400av, and AL0106ac), patients with al- 132 SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . K original article Table 1 Summary of the high-dose HDM allergoid clinical trials included in the pooled safety analysis Study Population Treatment n Included in safety set of Indication Age (years) HDM-ALL HDM-DBPC HDM-RCT(UC) Placebo (n = 279) (n = 214) (n = 65) (n = 221) 97-09 M Allergic rhinitis/rhinoconjunctivitis 18–58 1800 PNU 20 Yes Yes – – Placebo 20 – – – Yes 97-09 UK Allergic rhinitis/rhinoconjunctivitis 22–54 1800 PNU 15 Yes Yes – – Placebo 15 – – – Yes AL0106ac Allergic rhinitis/rhinoconjunctivitis 19–46 1800 PNU 51 Yes Yes – – EudraCT: Placebo 57 – – – Yes 2006-000934-11 Al0400av Allergic rhinitis/rhinoconjunctivitis 18–54 1800 PNU 69 Yes Yes – – Placebo 66 – – – Yes Al1009ac Controlled allergic bronchial asthma 18–40 600 PNU 24 – – – – EurdraCT: and rhinitis/rhinoconjunctivitis 1800 PNU 31 Yes Yes – – 2011-002248-29 3000 PNU 28 – – – – 5400 PNU 31 – – – – Placebo 32 – – – Yes AL0104av Allergic asthma with or without 6–406–40 – – – – – – EudraCT: allergic rhinitis/rhinoconjunctivitis ≥18 1800 PNU 28 Yes Yes – – 2004-003892-35 ≥18 Placebo 31 – – – Yes <12 1800 PNU 39 Yes – Yes – 12–17 1800 PNU 26 Yes – Yes – 6–17 Usual care 32 – – – – Performed before introduction of the EudraCT database HDM house dust mites, HDM-DBPC high-dose HDM allergoid AIT double-blind placebo controlled, HDM-RCT(UC) high-dose HDM allergoid AIT usual care controlled, HDM-ALL HDM-DBPC plus HDM-RCT(UC), PNU protein nitrogen units lergic asthma and allergic rhinitis/rhinoconjunctivitis Subgroups: The following subgroups were per- (Trial AL1009ac), or subjects with allergic asthma formed: with or without allergic rhinitis/rhinoconjunctivitis Age group (<12, 12–17, ≥18 years) (Trial AL0104av). Demographic details are shown Gender (female/male) in Table 2. We present safety information from pa- Subjects with asthmatic symptoms (Global Initia- tients treated with the marketed dose of 1800 PNU tive for Asthma classification >0, GINA, 2006). Clas- (n = 279) as maintenance dose (100% D. pteronyssinus sification was assessed in Trials AL1009ac, AL0104av, or 50%/50% D. pteronyssinus/D. farinae allergens/ AL0106ac, and AL0400av. mixtures). The maximum treatment duration was 3 years and 2 years with placebo, respectively; the Spontaneous safety reports: For the period after maximum double-blind, placebo-controlled treat- launch of the product (01 July 2005) to 31 March ment phase was 2 years (97-09 M, 97-09 UK, AL0400av, 2016, ADRs were calculated in relation to the number and AL0106ac, AL0104av adults). In study AL0104av, of products sold and patients treated and classified children and adolescents (n = 65; 6–17 years) with according to expectedness. For unexpected ADRs, the asthma were treated for up to 3 years with this HDM system organ classes (SOCs) were reported. AIT (Group: HDM-RCT(UC)). Coding of treatment-related AEs (TRAEs): Safety sets AEs were coded using the MedDRA version 15.0. AEs Subjects of the double-blind placebo controlled with onset during or after the first administration of (DBPC) safety set who received at least 1 dose of the trial drug were defined as TRAEs. An AE was de- the trial drug during the double-blind treatment pe- fined as being related to the trial drug if the causal riod with 1800 PNU or placebo were combined (Trials relationship of the AE was assessed as “at least possi- AL1009ac, AL0104av, 97-09 M, 97-09 UK, AL0106ac, ble”. and AL0400av) in group HDM-DBPC (n = 214). The safety set HDM-ALL consists of patients from the DBPC phase plus patients from the asthma versus usual care trial (n = 279; Table 1). K SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . 133 original article Table 2 Demographics and baseline characteristics Statistics 97-09 M 97-09 UK AL0104av AL0106ac AL0400av AL1009ac Total (n = 20) (n = 15) (n = 93) (n = 51) (n = 69) (n = 114) (n = 362) Age (years) Mean (SD) 29.4 (10.0) 36.9 (10.4) 15.2 (8.9) 29.6 (8.0) 27.6 (9.3) 27.3 (6.6) 25.1 (10.3) Min–Max 18.0–58.0 22.0–54.0 6.0–40.0 19.0–46.0 18.0–54.0 18.0–40.0 6.0–58.0 Gender (n [%]) Female 5 (25.0) 10 (66.7) 33 (35.5) 24 (47.1) 29 (42.0) 49 (43.0) 150 (41.4) Male 15 (75.0) 5 (33.3) 60 (64.5) 27 (52.9) 40 (58.0) 65 (57.0) 212 (58.6) Age group (n [%]) <12 0 (0.0) 0 (0.0) 39 (41.9) 0 (0.0) 0 (0.0) 0 (0.0) 39 (10.8) 12–17 0 (0.0) 0 (0.0) 26 (28.0) 0 (0.0) 0 (0.0) 0 (0.0) 26 (7.2) ≥18 20 (100.0) 15 (100.0) 28 (30.1) 51 (100.0) 69 (100.0) 114 (100.0) 297 (82.0) Smoking status (n [%]) Smoker 4 (20.0) 0 (0.0) 0 (0.0) 5 (9.8) 18 (26.1) 1 (0.9) 28 (7.7) Nonsmoker 16 (80.0) 15 (100.0) 93 (100.0) 46 (90.2) 51 (73.9) 113 (99.1) 334 (92.3) Asthma (n [%]) Yes – – 93 (100.0) 26 (51.0) 34 (49.3) 114 (100.0) 267 (73.8) No – – 0 (0.0) 25 (49.0) 35 (50.7) 0 (0.0) 60 (16.6) GINA classification GINA I – – 0 (0.0) 14 (27.5) 18 (26.1) – 32 (8.8) (n [%]) GINA II – – 76 (81.7) 12 (23.5) 16 (23.2) – 104 (28.7) GINA III – – 17 (18.3) 0 (0.0) 0 (0.0) – 17 (4.7) GINA IV – – 0 (0.0) 0 (0.0) 0 (0.0) – 0 (0.0) No asthma – – 0 (0.0) 25 (49.0) 35 (50.7) – 60 (16.6) FEV or PEF 1 n – – 93 51 69 61 274 (% of predicted value) Mean (SD) – – 93.1 (10.6) 101.8 (15.2) 104.2 (14.2) 98.7 (9.8) 98.8 (13.1) Min–Max – – 80.0–139.0 80.1–135.7 75.0–147.0 82.2–123.8 75.0–147.0 Duration of allergic n 20 15 77 51 69 114 346 rhinoconjunctivitis Mean (SD) 5.8 (3.2) 21.1 (10.1) 5.7 (5.1) 12.5 (8.6) 8.6 (7.8) 8.2 (5.8) 8.8 (7.4) (years) Min–Max 2.0–13.0 2.0–40.0 1.0–20.0 2.0–39.0 1.0–45.0 0.0–24.0 0.0–45.0 GINA Global Initiative for Asthma, FEV Forced Expiratory Flow in 1 sec, PEF Peak Expiratory Flow all, 148 patients received 1800 PNU for >2 years. Over- Results all, 267 patients in the clinical development program of this HDM AIT had asthma: GINA I n = 32, GINA II Clinical development n = 104, and GINA III n = 17 (114 patients without GINA In all, 362 subjects (children, adolescents, adults) classification). Patients had rhinoconjunctivitis for have received at least 1 dose of active treatment in a mean of 8.8 (SD 7.4) years, min. 2–max. 45 years. the completed trials of the high-dose HDM allergoid A total of 65 patients were less than 18 years of age clinical development program (Table 1)—114 subjects (only included in the asthma trial, Trial AL0104av): in the dose finding trial, 93 subjects in the allergic <12 years (n = 39), 12–17 years (n = 26; Table 1). asthma trial, and 155 subjects in the allergic rhinitis/ rhinoconjunctivitis trials. A total of 297 patients were Safety of marketed dose in clinical development treated with this HDM AIT during the DBPC period of the trials, 221 subjects with placebo. In children/ In all, 214 patients received the 1800 PNU during adolescents, the trial drug was administered in an the DBPC phase of the different trials and 65 in the open-label design and usual care was used as control asthma versus usual care trial (RCT(UC); Table 1), instead of placebo (n = 65). whereby 38.8% of patients treated with HDM AIT had an adverse event related to the trial drug, compared to 31.2% with placebo and 35.5% of the HDM AIT Marketed dose in clinical development patients in the HDM-ALL group (Fig. 1). The dif- A total of 279 subjects received the marketed dose of ference in adverse events related to the study drug 1800 PNU (0.6 ml strength B). The median number of was primarily because of local reactions; there was injections administered in the 1800 PNU group was no difference in the share of patients with systemic st 15 injections during the 1 treatment year (placebo: reactions (10.9% placebo, 11.2% HDM-DBPC, 11.1% nd 15 injections), 12 injections during the 2 treatment HDM-All). One out of 279 patients in the HDM- year (placebo: 12 injections), and 8 injections during All group experienced a serious adverse event (SAE): rd the 3 treatment year. The reasons for the difference hospitalization because of erythema, conjunctivitis, in injection numbers are the up-dosing phase in year asthma, cough, cyanosis, urticaria, and wheezing oneand thepossible prolongation of treatment inter- 15 min after administration of the trial drug during rd vals up to 8 weeks during maintenance treatment. In the 3 treatment year. The event resolved on the 134 SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . K original article Fig. 1 Percentage of patients reporting treatment-related HDM-All n= 279). HDM-DBPC high-dose HDM allergoid AIT adverse events related to study drug: a in the different treat- double-blind placebo controlled, HDM-RCT(UC) high-dose ment groups: placebo, HDM-DBPC, and HDM-All. b Distribu- HDM allergoid AIT usual care controlled, HDM-ALL HDM- tion according to local, systemic and serious adverse event DBPC plus HDM-RCT(UC), AE adverse event (AE). (DBPC Phase: placebo n= 221, HDM DBPC n= 214; Table 3 Treatment-related Number (%) subjects adverse events related to DBPC Phase DBPC plus RCT(UC) the trial drug reported in Placebo HDM DBPC HDM-All >2% of subjectsbyPT in decreasing frequency (N = 221) (N = 214) (N = 279) Subjects with related treatment-emergent AE 69 (31.2) 83 (38.8) 99 (35.5) Injection site swelling 51 (23.1) 61 (28.5) 71 (25.4) Injection site pruritus 11 (5.0) 25 (11.7) 31 (11.1) Injection site erythema 4 (1.8) 16 (7.5) 17 (6.1) Injection site pain 5 (2.3) 9 (4.2) 15 (5.4) Rhinitis 5 (2.3) 7 (3.3) 8 (2.9) Pruritus 0 (0.0) 7 (3.3) 7 (2.5) Cough 2 (0.9) 6 (2.8) 8 (2.9) Sneezing 6 (2.7) 1 (0.5) 1 (0.4) Rhinitis allergic 3 (1.4) 2 (0.9) 6 (2.2) Fatigue 1 (0.5) 5 (2.3) 5 (1.8) DBPC double-blind placebo controlled, RCT(UC) usual care controlled, HDM-DBPC high-dose HDM allergoid AIT double-blind placebo controlled, HDM-RCT(UC) high-dose HDM allergoid AIT usual care controlled, HDM-ALL HDM-DBPC plus HDM-RCT(UC), AE adverse event same day. Exacerbations of asthma were mentioned Subgroup analysis in the medical history. The patient was treated with an inhaled corticosteroid dose of 200 µg fluticasone A summary of TRAEs by subgroups—age (a, b), gender as asthma controller medication that was reduced to (c, d), asthma status (e, f)—is presented in Fig. 2.Chil- 100 µg 4 weeks before the SAE. No SAEs were observed dren and adolescents had fewer related adverse events in placebo or HDM-DBPC group. and local reactions compared to adults; systemic re- An overview about the TRAEs related to the trial actions were slightly more frequent in children (12.8% drug and reported in >2% of patients is presented in versus 11.2% in adults), but much lower in adoles- Table 3. cents (7.7%). Females had more adverse events in all Clinical laboratory measurements (biochemistry, 4 groups compared to males (see Fig. 2c, d). Treat- hematology, and urinalysis) were analyzed in most ment was well tolerated in asthmatic patients and the of the trials. A shift of normal at baseline to abnor- number of related adverse event, local reactions, and mal after treatment was reported for >5% of subjects systemic reactions were low (see Fig. 2e, f), but one in any group only for eosinophils and neutrophils SAE occurred. (14 subjects with HDM AIT). There were no other noteworthy differences between the groups. K SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . 135 original article Table 4 Safety overview of the high-dose HDM allergoid were in patients with asthma and 0.5% in non-asth- versus SLIT mite tablets matics. Product ADRs with at least possible relationship to study drug (%) Discussion Rhinoconjunctivitis ± AsAsth thmma a Pediatrics with asthma In recent years, publications on HDM immunother- (12–17 years) apy focused on sublingual treatment. Several multina- HDM allergoid tional, randomized, placebo-controlled clinical trials 1800 PNU high- 38.8 23.9 19.2 of high quality standards in different patient popula- dose HDM allergoid tions and subgroups are available. In addition, this Placebo 31.2 18.0 – treatment route is known to be safe, which is why HDM SLIT tablet [12, 14–16] we compared our data with relevant data of sublin- 6SQ-HDM 48 39 55 gual products recently published in international lit- 12 SQ-HDM 53/50 46 50 erature. Placebo 15/16 17 32 HDM SLIT tablet [13] Rhinoconjunctivitis 300 IR 66.8 – – In our observation of patients with rhinoconjunctivi- 500 IR 73.1 – – tis with/without asthma, adverse events with at least Placebo 18.6 – – possible relationship to the high-dose HDM allergoid ADR adverse drug reactions, PNU protein nitrogen units, HDM house dust were 38.8% compared to 31.2% with placebo. This mites, SLIT sublingual immunotherapy is lower than the, at least possibly, related adverse events seen in allergic rhinitis patients treated with HDM SLIT tablet (48.0% 6 SQ-HDM, 53.0% 12 SQ- Spontaneous safety reports HDM, 15.0% placebo; [12]; Table 4). The related AEs In the period from the first market launch (01 July were primarily local reactions (33.6%) in HDM SCIT 2005) to 31 March 2016 more than hundred thou- (injection site swelling 28.5%, -pruritus 11.7%, -ery- sand patients were treated with HDM AIT 1800 PNU thema 7.5%, -pain 4.2%). This is comparable to the as maintenance dose. ADRs were reported in 0.5% of safety profile of HDM SLIT where the most common patients compared to 38.8% (HDM-DBPC) and 35.5% AEs are reported as being related to the investigational (HDM-ALL) in clinical development; 94.6% of these medicinal product (IMP) by the investigator were oral ADRs were expected. The unexpected events were pruritus, throat irritation, and mouth edema (20.0, primarily reported in the SOCs: nervous system dis- 14.0, and 8.0% of subjects on active treatment, respec- orders (headache, hypoesthesia, paresthesia); muscu- tively; [12]). In a recently published double-blind trial, loskeletal and connective tissue disorders (arthralgia, evaluating the efficacy and safety of HDM tablets in myalgia, pain in extremity); general disorders and ad- 968 adolescent and adult patients (aged 12–64 years) ministration site conditions (pyrexia); gastrointestinal with HDM-induced AR with or without intermittent disorders (oral mucosal blistering, nausea, gastroin- asthma over 52 weeks, the number of subjects with testinal pain); and skin and subcutaneous tissue dis- any adverse drug reaction was 66.8% with the recom- orders (alopecia, eczema). No special patient group mended dose 300 IR (73.1% with 500 IR), and 18.6% could be identified to be at higher risk, and no safety with placebo [13]. In two pooled RC clinical trials with concern has arisen from this received post marketing 1215 subjects (12 SQ HDM tablet n = 600, 615 placebo) safety data. with a clinical history of HDM allergic rhinitis, and 863 (71%) with additional HDM allergic asthma 50% of subjects on active treatment reported TRAEs com- Subgroup analysis of spontaneous safety reports pared to 16% of subjects on placebo [14]. In the period from the first market launch to 31 March 2016 several ten thousand children and adolescents Asthma were also treated with HDM AIT 1800 PNU. ADRs were reported in 0.9% of children (0–11 years of age), HDM is the most common allergen associated with 0.6% of adolescents (12–17 years) compared to 0.3% asthma and more than 40% of adult asthmatics are in adults (≥18 years). atopic with a positive skin prick test result for the If we assume that 50% female and 50% male pa- HDM allergens [15]. Adverse events related to the tients were treated after launch, the number of ADRs high-dose HDM allergoid were 23.9% in the group were comparable irrespective of gender (female 0.4%, of patients with asthma compared to 46.7% in pa- male 0.5%). The same was true for asthma. Asthma tients without asthma, placebo 18%; subjects with is found in up to 38% of patients with allergic rhinitis TRAEs were 47.9% compared to 51.6% with placebo. [11]. With this HDM AIT SCIT 0.4% of ADR reports In a recently published study of asthma patients with a sublingual HDM tablet, AIT TRAEs occurred in 136 SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . K original article Fig. 2 Percentage of pa- tients reporting treatment- related adverse events re- lated to study drug an- alyzed in different sub- groups: age (a, b), gen- der (c, d), asthma status (e, f). a Data are shown for HDM- DBPC (≥18 years) and HDM- RCT(UC) (12–17 years and <12 years). b Distribu- tion according to local, systemic and serious AE. c Percentage of female and male patients in HDM- All reporting a treatment- related AE. d Distribution according to local, systemic and serious AE. e Percent- age of patients with and without asthma reporting a treatment-related AE and f Distribution according to local, systemic and serious AE. (Age (a, b): ≥18 years n= 214, 12–17 years n= 26, <12 years n= 39; Gender (c, d): female n= 115, male n= 164; Asthma status (e, f): no asthma symptom n= 60, any asthma symptom n= 184). HDM-DBPC high-dose HDM allergoid AIT double-blind placebo controlled, HDM- RCT(UC) high-dose HDM allergoid AIT usual care controlled, HDM-ALL HDM- DBPC plus HDM-RCT(UC), AE adverse event, yrs years 39.0% in the 6 SQ-HDM group, 46.0% in the 12 SQ- Pediatrics HDM group, and 17.0% with placebo [14]. A possibly treatment-related serious adverse event was reported There is little data available about the safety of HDM for the 12 SQ-HDM tablet: asthma (moderate, alterna- AIT in children and adolescents. In a recently pub- tive etiology was “recently viral infection”; [15]). With lished multicenter, double-blinded, randomized trial the high-dose HDM allergoid a serious adverse event in adolescents (12–17 years old) with HDM allergic (erythema, conjunctivitis, asthma, cough, cyanosis, rhinitis with and without conjunctivitis and with or urticaria, wheezing) was reported in an asthmatic without asthma, patients received placebo, HDM child 15 min after administration of trial drug. Exac- SLIT tablet 6SQor12SQoncedaily for 28days. erbations of asthma were mentioned in the medical The proportion of subjects who experienced TRAEs history and the corticosteroid dose was reduced from was 25.0%, 45.0%, and 52.0% for the placebo, 6 SQ- 200 µg fluticasone to 100 µg 4 weeks before the SAE. HDM, and 12 SQ-HDM groups, respectively [16]. With These examples show how important it is that asthma the high-dose HDM allergoid, TRAEs were observed is controlled, especially when an AIT is performed in 19.2% of adolescents (12–17 years old). There and guidelines are followed. was a greater incidence of TRAEs in adolescents with asthma receiving the HDM SLIT tablet compared with placebo (asthma: 32.0%, 55.0%, 50.0%, placebo, 6-SQ, K SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . 137 original article 12-SQ respectively; without asthma: 21.0%, 40.0%, Conclusion 54.0%; [16]). In the high-dose HDM allergoid group of adolescents, all had asthma and received the trial Subcutaneous treatment with the high-dose HDM al- drug for up to two years (28 days for HDM SLIT). lergoid was well tolerated in HDM respiratory allergic disease in clinical development. The observed differ- ence to placebo was primarily driven by local reac- Gender tions; there was no difference in systemic reactions. No literature is available about safety differences of The high-dose HDM allergoid was also well tolerated HDM immunotherapy in females versus males. In the in daily practice. As 95% of ADRs were expected, no clinical development program of the HDM SCIT aller- safety concern has arisen from the post marketing goid we observed a few more related AEs in females safety data. The product was well tolerated in all age (39.1%) compared to males (32.9%), but more data are groups (children, adolescents, and adults), in asth- needed. matics and non-asthmatics. Furthermore, the safety profile was comparable to HDM SLIT tablets. Spontaneous safety reports Acknowledgements The authors like to thank Annemie Narkus, MC Narkus Medical Consulting + Services, Bleckede, The safety of a medicinal product after launch in daily Germany for medical writing and Jacqueline Alig, Aller- practice with much higher numbers of treated pa- gopharma GmbH & Co. KG, for intensive discussions on tients and a broad range of different patients treated the results and the way of their presentation. adds to the safety information of a product. Very rare Funding Financial support for the development of this arti- side effects might be seen for the first time and unex- cle was provided by Allergopharma GmbH & Co. KG. Aller- pected side effects might be reported. With the HDM gopharma GmbH & Co. KG designed and provided funding SCIT product presented in this publication, adverse for the studies described in this article. drug reactions were reported in 0.5% of patients com- Conflict of interest L. Klimek has received research grants pared to 38.8% (HDM-DBPC) and 35.5% (HDM-ALL) from ALK-Abelló, Denmark; Allergopharma, Germany; Bio- in clinical development, whereby 94.6% of these ADRs norica, Germany; Biomay, Austria, Boehringer Ingelheim, were expected, and there was no major concern about Germany, Circassia, USA; Stallergenes, France; HAL, Nether- the unexpected ADRs related to the safety of this SCIT lands; Allergy Therapeutics/Bencard, Great Britain/Germany; Hartington, Spain; Lofarma, Italy; MEDA, Sweden; Novartis, product in daily routine. Switzerland, Leti, Spain; ROXALL, Germany; Glaxo-Smith- Kline (GSK), Great Britain; Cytos, Switzerland; Curalogic, Pediatric data analyzed from spontanous safety Denmark; and/or has served on the speaker’s bureau or was reports consulting for the above mentioned pharmaceutical com- panies. G.-C. Fox and S. Thum-Oltmer are employees of Compared to adults slightly more children and adoles- Allergopharma GmbH & Co. KG, Reinbek, Germany. cents (0.9% children, 0.6% adolescents, 0.3% adults) Open Access This article is distributed under the terms of experienced an ADR. This is based on a great database the Creative Commons Attribution 4.0 International License of several thousand treated patients and possibly (http://creativecommons.org/licenses/by/4.0/), which per- a higher reporting rate of ADRs in younger age groups. mits unrestricted use, distribution, and reproduction in any No new safety information has arisen concerning sys- medium, provided you give appropriate credit to the origi- nal author(s) and the source, provide a link to the Creative tem organ classes or preferred terms of the reported Commons license, and indicate if changes were made. ADRs. References Gender data analyzed from spontanous safety reports 1. PfaarO,BachertC,BufeA,BuhlR,EbnerC,EngP,etal. Guide- line on allergen-specific immunotherapy in IgE-mediated According to post marketing safety data no gender allergicdiseases: S2kGuidelineoftheGermanSocietyforAl- specific safety difference could be identified (female lergologyandClinicalImmunology(DGAKI),theSocietyfor 0.4%, male 0.5%), and the high-dose HDM allergoid is Pediatric Allergy and Environmental Medicine (GPA), the well tolerated in asthmatic as well as non-asthmatic Medical Association of German Allergologists (AeDA), the patients (0.4% asthma, 0.5% non-asthma patients with Austrian Society for Allergy and Immunology (OGAI), the Swiss Society for Allergy and Immunology (SGAI), the Ger- ADR). man Society of Dermatology (DDG), the German Society of On the basis of more than hundred thousand Oto-Rhino-Laryngology, HeadandNeck Surgery (DGHNO- treated patients with the high-dose HDM allergoid in KHC), the German Society of Pediatrics and Adolescent daily routine and a broad range of different patient Medicine (DGKJ), the Society for Pediatric Pneumology groups, no special patient group could be identified (GPP), the German Respiratory Society (DGP), the German to be at higher risk, no safety concern has arisen from Association of ENT Surgeons (BV-HNO), the Professional the unexpected ADRs and the safety was comparable Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the to what was already known from clinical development. 138 SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . K original article German Dermatologists Association (BVDD). Allergo J Int. 11. Brozek JL, Bousquet J,AgacheI,Agarwal A, Bachert C, 2014;23:282–319. Bosnic-Anticevich S, et al. Allergic Rhinitis and its Impact 2. Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, on Asthma (ARIA) guidelines-2016 revision. J Allergy Clin Gerth van Wijk R, et al. EAACI guidelines on allergen Immunol. 2017;140:950–8. immunotherapy: allergic rhinoconjunctivitis. Allergy. 12. Demoly P, Emminger W, Rehm D, Backer V, Tommerup 2017; https://doi.org/10.1111/all.13317. L, Kleine-Tebbe J. Effective treatment of house dust mite- 3. Calderon MA, Kleine-Tebbe J, Linneberg A, De Blay F, Her- induced allergic rhinitis with 2 doses of the SQ HDM nandez Fernandez de Rojas D, Virchow JC, et al. House dust SLIT-tablet: results from a randomized, double-blind, mite respiratory allergy: an overview of current therapeutic placebo-controlled phase III trial. J Allergy Clin Immunol. strategies. J Allergy Clin Immunol Pract. 2015;3:843–55. 2016;137:444–451.e8. 4. Global strategy for asthma management and prevention. 13. Okamoto Y, Fujieda S, Okano M, Yoshida Y, Kakudo S, https://www.ginasthma.org. 2017. Accessed02/01/2018 Masuyama K. House dust mite sublingual tablet is effec- 5. DhamiS,NurmatovU,Agache I,Lau S, Muraro A, Jutel M, tive and safe in patients with allergic rhinitis. Allergy. etal. Allergen immunotherapy for allergic asthma: protocol 2017;72:435–43. for a systematicreview. Clin Transl Allergy. 2015;6:5. 14. Emminger W, Hernandez MD, Cardona V, Smeenk F, Fogh 6. Zielen S, Kardos P, Madonini E. Steroid-sparing effects with BS, Calderon MA, et al. The SQ house dust mite SLIT-tablet allergen-specific immunotherapy in children with asthma: is well toleratedin patients with housedustmiterespiratory a randomized controlled trial. J Allergy Clin Immunol. allergicdisease. IntArch Allergy Immunol. 2017;174:35–44. 2010;126(5):942–9. 15. Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen 7. Rosewich M, Arendt S, El Moussaoui S, Schulze J, Schubert HH, et al. Efficacy of a house dust mite sublingual allergen R,ZielenS.Bronchialallergenprovocation: ausefulmethod immunotherapy tablet in adults with allergic asthma: a toassesstheefficacyofspecificimmunotherapyinchildren. randomizedclinical trial. JAMA. 2016;315:1715–25. Pediatr Allergy Immunol. 2013;24:434–40. 16. Maloney J, Prenner BM, Bernstein DI, Lu S, Gawchik S, 8. Allergopharma. Summary of product characteristics, Berman G, et al. Safety of house dust mite sublingual Acaroid Milbenpräparate. 2017. immunotherapy standardized quality tablet in children 9. Brehler R, Kahlert H, Thum-Oltmer S. Hypoallergene Prä- allergic to house dust mites. Ann Allergy Asthma Immunol. paratein der SCIT. Allergo J Int. 2010;19:477–84. 2016;116:59–65. 10. van der Valk JP, de Jong NW, Gerth van Wijk R. Review on immunotherapy in airway allergen sensitised patients. Neth J Med. 2015;73:263–9. K SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and. . . 139
Journal
Allergo Journal International – Springer Journals
Published: Jul 25, 2018