Allergen immunotherapy trials
The confirmatory trial of an allergen immunotherapy product runs under natural allergen exposure, which varies with region, year and patient. Its primary endpoint counts rescue medication alongside symptoms, and the efficacy claim it can support depends on how many years it lasted. European requirements fix the controlled design and the guideline the trial follows, and the class has its own conventions for controlling allergen exposure, selecting patients, scoring symptoms and medication, and grading safety.
The European regulatory framework
Allergen immunotherapy products were previously marketed mainly on expert opinion, with limited regulatory oversight, and in the twenty years before 2018 clinical data became increasingly necessary for market access. Since 1993 an EU marketing authorisation has been granted only if at least one double-blind placebo-controlled trial has been successfully completed, except for bee and wasp venom preparations. More stringent requirements for allergen immunotherapy trials have significantly improved the quality of the data. Many randomised double-blind placebo-controlled trials of allergen immunotherapy products were conducted in the years before 2018. Because many allergic diseases are seasonal and the immunological changes the therapy induces are lasting, allergen immunotherapy trials can be very time-consuming and costly, especially where a disease-modifying effect is the intended claim.
Since 2008 allergen immunotherapy trials must be designed according to the CHMP guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases (CHMP/EWP/18504/2006). The guideline addresses efficacy and safety measures for products based on active substances such as allergen extracts, recombinant allergens, purified native allergens and modified allergens, and it applies to allergen immunotherapy trials whatever the affected organ system, allergen source, allergen product or route of administration.
Efficacy claims and trial duration
Efficacy in allergic rhinoconjunctivitis can be evaluated in a single pollen season for seasonal allergies, or after one or two control periods for perennial ones. A persistent effect due to changes in the immune system, however, can only be demonstrated in a long-term trial, so the claims of efficacy a trial can support differ with its duration.
| Claim | Efficacy parameter |
|---|---|
| Treatment of allergic symptoms | Short-term trials showing efficacy in the first pollen season after immunotherapy starts, or efficacy in perennial allergies after some months of treatment |
| Sustained clinical effect | Maintenance of significant and clinically relevant efficacy during two to three treatment years |
| Long-term efficacy and disease-modifying effect | Sustained significant and clinically relevant efficacy in the post-treatment years |
| Curing allergy | Sustained absence of allergic symptoms in the post-treatment years |
Phase I and dose-finding trials
In phase I, allergen immunotherapy products should only be tested in patients with allergies, because healthy individuals do not react to allergens and are not put at risk by exposure to them.
Dose-finding studies have several arms, each given short-term treatment at a different dose, for example for two to four months. The primary efficacy measure can be a provocation test, such as a conjunctival, nasal or bronchial test or whole-body exposure in an allergen challenge chamber, or another clinical endpoint assessing allergy severity.
For seasonal allergies, exposure to the relevant allergen must be documented for the baseline and evaluation periods, and a minimum pollen count must be defined. For perennial allergies, such as to house dust mites, variation in indoor allergen levels must be minimised; for example, the patient's home should be cleaned before the trial starts and before baseline symptoms are measured. Allergen exposure should also be documented for each patient.
Confirmatory trials under natural allergen exposure
A confirmatory trial should be double-blind and placebo-controlled, and statistical superiority over placebo or another comparator must generally be demonstrated. Because local allergic adverse events are frequent with allergen immunotherapy, a placebo preparation containing histamine should be considered to maintain blinding. The trial should include a prospective baseline period with controlled collection of symptoms and allergen exposure, to avoid the effects of variable allergen exposure, for example during pollen seasons.
In one example of a pollen trial, screened patients record their symptoms and medication use in a diary during a baseline pollen season, and those with a defined minimum level of allergic symptoms are selected for randomisation. Active therapy or placebo is given before the following pollen season, and symptoms and medication use, the efficacy measures, are recorded in a diary during that season.
Phase 3 trials must be performed under natural allergen exposure, and they are also called field trials. The outcome of allergen immunotherapy trials can be influenced by variation in pollen counts between regions and across years, by an individual patient's exposure during the season, and by interfering aeroallergens. A patient's symptoms also depend on their sensitivity to the investigated allergen, and often more on the allergen content than on the total pollen load.
Allergen challenge chambers have been used in dose-finding trials and may also be an option for confirmatory trials of allergens with unpredictable pollination and allergen content. They may be particularly useful in trials running over several years or in years with low pollen counts. Their results, however, must be validated in studies assessing effects under natural exposure, and how measurement within or outside the pollen season compares must be evaluated.
Patient selection
Patients with allergic disease are usually sensitised to more than one allergen group, so selecting those sensitised to a single group is difficult. Trials should therefore include patients sensitised to a limited number of allergens, which must be identified and documented. Patients with concurrent allergies should be excluded so that they do not bias the outcome for the allergy under study, although not all cosensitisations are clinically relevant. One concurrent allergy that may bias results is allergic rhinoconjunctivitis caused both by pollen, a seasonal allergen, and by animal dander from a pet, a perennial one. Patients should also be excluded if they have received allergen immunotherapy for the investigational allergen or a cross-reacting one in the previous five years, or are receiving it for any allergen.
Confirmatory trials should enrol only patients with mild symptoms before randomisation. A baseline period before enrolment is recommended for patients with allergic airway disease, to ensure minimal symptoms at the start of treatment.
Symptom and medication scores
In phase 3 trials the primary endpoint must include both symptom and medication scores. In confirmatory trials on allergic rhinoconjunctivitis the primary endpoint reflects both symptom severity and the intake of rescue medication, and several combined scores have been developed that include both. Whichever primary endpoint is chosen, the endpoint and what constitutes a clinically relevant effect should be pre-specified and justified in the protocol. Secondary endpoints of confirmatory trials can include the total symptom score, the total medication score, individual symptom scores, health-related quality of life on a validated questionnaire, symptom load on a visual analogue scale, and symptom-free days.
Symptom severity is often assessed through patient self-reported symptom scores recorded daily over a defined period. There is no single harmonised symptom score for allergic rhinoconjunctivitis, although most trials use a four-point rating scale for nasal itching, sneezing, rhinorrhoea, nasal obstruction, ocular itching, grittiness, redness and ocular tearing. On one such scale, severity is rated from 0 to 3 for nasal symptoms (sneezing, running, blocked), conjunctival symptoms (itching, tear flow, redness) and bronchial symptoms (cough, wheezing, asthma with dyspnoea), giving a possible maximum daily score of 27.
| Score | Severity | Definition |
|---|---|---|
| 0 | Absent | No symptom evident |
| 1 | Mild | Clearly present; minimal awareness of symptom; easily tolerated |
| 2 | Moderate | Definite awareness of symptom; bothersome but tolerable |
| 3 | Severe | Poorly tolerated symptom; interferes with daily activities or sleeping |
Medication use should be scored according to the medication needed to relieve the magnitude and duration of symptoms. The medication score rates the daily consumption of additional anti-allergic drugs according to their type, route and dose or number of applications.
| Type of medication | Unit | Score |
|---|---|---|
| Levocabastine nasal spray | 1 puff | 0.5 |
| Levocabastine eye drops | 1 drop | 0.5 |
| Loratadine or cetirizine tablets | 10 mg | 6 |
| Oral corticosteroid | 5 mg prednisolone or equivalent | 4 |
| Salbutamol | 100 µg | 1 |
| Inhaled corticosteroids | 400 µg budesonide or equivalent | 6 |
The combined symptom medication score is the daily sum of the documented symptoms and the intake of additional anti-allergic medication.
Safety assessment
Adverse events in allergen immunotherapy trials are coded with MedDRA, and they are usually graded as mild, moderate or severe and assessed for relatedness to the trial medication. Serious adverse events, especially treatment-related ones, must be described in detail. Expected allergic side-effects are classified by their timing, immediate or delayed, and by the site of appearance, local or systemic. Systemic reactions are graded using the European Academy of Allergy and Clinical Immunology or the World Allergy Organisation grading systems. Other safety parameters collected include vital signs, routine blood and biochemical tests, and urinalyses.