Safety and Tolerability of an Intra-seasonal Initiation of the SQ-Standardised Grass Allergy Immunotherapy Tablet: A Non-interventional Observational Study Investigating the Feasibility During Routine Administration

In this non-interventional, open-label, uncontrolled observational study the treatment of patients who started grass-AIT administration within the summer grass pollen season between June and August 2010 in Germany was planned to be documented by 286 allergologically trained physicians distributed across Germany.

For treatment with grass AIT GRAZAX^® (Phleum pratense 75,000 SQ-T/2,800 BAU, ALK, Hørsholm, Denmark) was applied.

Centres were asked to participate in the study according to regional random lists of allergists applying SIT and were asked to record data on two to three patients in consecutive order, dependent on the patient’s willingness to participate in the study, in order to avoid a selection bias. Physicians were asked to document all patients who were potentially eligible to be included in a patient log.

Data on patients with a diagnosis of grass pollen-induced rhinitis and/or conjunctivitis (according to symptoms, skin prick test or RAST) with or without asthma with clinically relevant symptoms who had no contraindications to a prescription of grass AIT according to the Summary of Product Characteristics for GRAZAX^® [18] were eligible to be documented in this study. Contraindications included hypersensitivity to any of the excipients of the AIT, malignancy or systemic diseases affecting the immune system, e.g. autoimmune diseases, immune complex diseases or immune deficiency diseases; inflammatory conditions in the oral cavity with severe symptoms such as oral lichen planus with ulcerations or severe oral mycosis; and patients with uncontrolled or severe asthma (forced expiratory volume in 1 second <70 % of predicted value after adequate pharmacological treatment in adults and <80 % in children). The study plan was approved by the Ethics Committee of the Landesärztekammer Baden-Württemberg and patient consent for the collection of their data was obtained.

The time schedule and the major observations of the study are illustrated in Fig. 1.

At visit 1 (V1), when the patient was included in the study, demographic data and data on the allergy history including age at first appearance of symptoms, clinical manifestation of the allergy (rhinitis/conjunctivitis/asthma/atopic dermatitis), other allergies, the diagnostics performed, any previous treatment by SIT, and concomitant treatments by SIT or other medications due to concomitant diseases were recorded. Symptoms and medication use in the previous grass pollen season were recorded retrospectively. Symptoms were recorded as nasal, ocular, bronchial and skin symptoms assessed on a scale from 0 to 3 (no/mild/moderate/severe) and the different types of symptomatic medication that had been used (topical nasal and eye drops/oral antihistamines/oral corticosteroids/bronchial β-sympathomimetics/bronchial corticosteroids/other) were recorded. The first administration of the grass AIT was performed in the clinic, where an eventual anti-allergic pre-medication was recorded as well as any AEs that occurred while the patient was under observation for 30 min. An AE was defined as any untoward medical occurrence in a patient who was administered grass AIT and which did not necessarily have a causal relationship with treatment. AEs that were possibly related to treatment were classified as adverse drug reactions (ADRs). For the first 2 weeks of therapy, patients were asked to enter the administration of the grass AIT and all AEs and the respective actions they had taken (medication taken/physician contacted) in a diary. AEs were specified by the physician in the case report form (CRF) as diagnosis or description and assessed by intensity (mild/moderate/severe), causality (possible/unlikely), change of treatment (no change/interruption/discontinuation), treatment by medication (yes/no), outcome (recovered/improved/recovered with sequelae/not recovered/fatal/unknown) and whether it was serious (yes/no). An AE was assessed as severe when the event considerably interfered with the patient’s daily activities. A serious AE (SAE) was defined as any medical occurrence or effect that was life-threatening, required hospitalization or prolongation of hospitalization, resulted in persistent or significant disability or incapacity, resulted in death, congenital abnormalities or birth defect, or any other event judged medically important.

The patients came back to the clinic after 1–3 months [visit 2 (V2)] for a new prescription, depending on whether 30 or 100 tablets of grass AIT had been prescribed. At V2 the physician interviewed the patients about AEs that occurred between V1 and V2 during home treatment and recorded all AEs in the CRF, including his assessment. Furthermore, the overall compliance of the patient during the observation period was assessed by the physician according to overall compliance rates of <50, 50 to <80 or ≥80 %: with a rate of ≥80 % the patient was considered to be compliant with grass AIT. Symptoms and medication after 1–3 months of treatment with grass AIT were recorded and compared with data obtained at V1 and the well-being of the patient with grass AIT compared with previous years (much better/better/unchanged/worse/much worse) was assessed. Patients and physicians rated their satisfaction with grass AIT (very satisfied/satisfied/unsatisfied/very unsatisfied) and globally assessed the tolerability (very good/good/moderate/poor) and overall effectiveness of therapy (very good/good/moderate/no effect/not assessable). Finally, the continuation or discontinuation of treatment and its reasons were recorded.

Data for 662 patients from 286 sites who had their first intake of grass AIT in the clinic and had been treated for 51.6 days on average could be evaluated. In a small proportion of these patients treatment had been started after the end of the grass pollen season (later than August). Therefore, patients were stratified according to the start of treatment into the following subgroups: intra-seasonal start of treatment (until 31 August 2010, n = 620; 93.7 %) and post-seasonal start of treatment (after 31 August 2010, n = 42; 6.3 %). The patients’ demographic data at start of grass AIT (V1) are summarised in Table 1.

After the first administration in the clinic, 53 patients did not return for the follow-up visit, but 18 patients sent their diary to the physician by mail, so 627 patients in total could be evaluated with respect to the tolerability of the second and further administrations of grass AIT. Diaries were evaluable for 510 (77.0 %) patients. The flow of patients through the study is shown in Fig. 2.

During the entire observation period AEs were observed in 345 (52.1 %) of the 662 total patients, and in 320 (51.6 %) of 620 patients who started grass AIT intra-seasonally and 25 (59.5 %) of 42 patients who started grass AIT post-season. Data on AEs observed during the study are displayed in Table 2.

During first administration of grass AIT, AEs were recorded in 236 (35.6 %) of the total patients, and in 215 (34.7 %) patients who started grass AIT intra-seasonally and in 21 (50.0 %) patients who started grass AIT post-season.

Most AEs were assessed as possibly related to grass AIT and were, therefore, ADRs. The majority of the reactions were of mild or moderate intensity. Severe reactions were recorded in 48 (7.7 %) patients with intra-seasonal start of grass AIT and in 5 (11.9 %) patients with post-seasonal start; 10.9 % of patients were treated with medication due to AEs and 7.7 % discontinued treatment with grass AIT due to AEs.

Throat irritation (21.3 % of patients), paraesthesia oral (19.9 %), oral pruritus (14.0 %), ear pruritus (10.3 %) and oedema mouth (6.9 %) were recorded with the highest frequency; all other AEs were observed in less than 5 % of patients (Fig. 3).

SAEs were reported in four patients. In two patients the SAEs were unrelated to treatment (meniscus lesion and bladder surgery) and in two patients the SAEs were considered possibly related; both had started grass AIT intra-seasonally. In a 44-year-old male patient an asthma attack, dyspnoea, swollen lips and tongue, and loss of voice for 2 h was reported on day 5 of treatment and was treated with antihistamines, corticosteroids and β-sympathomimetics. In a 73-year-old female patient nausea, fainting, hypotension, bradycardia, diarrhoea, vomiting and stomach pain for less than 1 day were reported 5 h after first administration and 1.75 h after dinner. Symptoms disappeared within 2 h without treatment. In both patients the reaction was considered medically important and the patients discontinued treatment.

The results of the evaluation of the patient diary for the first 14 days of treatment are shown in Fig. 4. The rate of AEs recorded by the patients decreased continuously from 44.7 % of patients who recorded AEs on day 1 of treatment to 26.9 % with AEs on day 14. On average, about 5 % of patients reported having forgotten to take their daily tablet during the 14-day diary period.

Global tolerability was assessed as “good” or “very good” by 519 of 595 patients (87.2 %) and by the physicians in 542 of 593 patients (91.4 %) who had an evaluable assessment.

Effectiveness parameters could be evaluated in a total of 586 patients; 551 started treatment with grass AIT intra-seasonally.

Overall, 77.7 % of patients who started grass AIT intra-seasonally responded to treatment (as being “free of symptoms” or “improved”) with respect to nasal symptoms, 74.8 % with respect to eye symptoms, 66.4 % with respect to bronchial symptoms, and 69.0 % with respect to skin symptoms in the grass pollen season with grass AIT compared with the previous season before grass AIT. The use of symptomatic medication by patients decreased from 79.8 % in the previous season to 40.6 % in the season with grass AIT. Well-being was assessed to be “better” or “much better” by 67.4 % of patients who started grass AIT intra-seasonally. More than 90 % of patients and physicians were “satisfied” or “very satisfied” with treatment for patients who started grass AIT intra-seasonally. The global effectiveness of treatment was assessed as “very good” or “good” by 355 of 436 patients (81.4 %) and by the physicians in 386 of 450 (85.8 %) patients.