Grass Pollen Allergen Immunotherapy Tablet (AIT) Time Course Study
Condition: Allergic Rhinitis
MeSH terms: Rhinitis; Rhinitis, Allergic
Study type: Interventional
Phase: Phase 2

Summary: 
      About 45 million people in Europe have allergic rhinitis (hay fever) - inflammation of the
      nasal passages causing sneezing, runny nose, nasal congestion, itching and tearing of the
      eyes. In the United Kingdom (UK), seasonal hay fever due to grass pollen allergy accounts for
      approximately 7 times more doctors' appointments than asthma. The standard treatment for hay
      fever consists of treating the symptoms with a nasal spray and an antihistamine. However, in
      a survey taken in a UK general practice less than 40% of patients with hay fever reported
      good symptom control with this standard treatment. For those patients with hay fever whose
      symptoms are not well controlled by treatment with antihistamines and nasal sprays,
      subcutaneous immunotherapy (SCIT) - (monthly injections of a grass allergen extract for a
      period of 3-5 years) is an effective alternative, and is approved in the UK on a named
      patient basis. More recently, allergen immunotherapy tablets (AITs) have been developed,
      including grass pollen allergen tablets. These have been shown to be highly effective in the
      treatment of hay fever, with the additional benefit of being convenient for patients, given
      that they may be taken at home. Grazax® (manufactured by Allergologisk Laboratorium København
      (ALK)-Abello, Denmark) has UK and European Union (EU) license for use in the treatment of
      troublesome grass pollen induced hay fever. The aim of this research is to investigate the
      effects of the AIT treatment on the immune system over time - which changes are taking place
      and when in the course of treatment. This will provide insight into the complexities of the
      development of allergen-specific immune tolerance - how harmful allergic responses against
      innocuous substances such as grass pollen can be overridden.
    

Detailed description: 
      The study will be conducted over 44 months. We expect to screen 70 atopic patients in order
      to enroll up to 50 suitable atopic participants to ensure randomisation of at least 40 atopic
      participants following their baseline visit. Additionally, we shall recruit 20 healthy,
      non-atopic volunteers. Individuals with moderate to severe grass pollen hay fever, with or
      without associated seasonal asthma, will be recruited and screened after the pollen season
      from September through March 2014. Atopic Participants will undergo baseline assessments in
      December 2013 to March 2014. All screening assessments will be completed before eligible
      participants are randomized to active or placebo treatment. Atopic participants will then
      begin AIT treatment in February-March 2014 and continue treatment for 12 months. All atopic
      participants will be provided with anti-allergic rescue medications (antihistamine tablets,
      topical intranasal corticosteroids, and eye-drops) throughout the pollen season. Clinical
      surrogate endpoint assessments and on specific time Points blood, nasal fluid and nasal
      brushing sampling, will be performed at baseline (January-March 2014), at 4, 8, 12 and 16
      weeks after starting the AIT, and at 6 and at 12 months (January-March 2015) of treatment.
      Nasal mucosal biopsies will be taken at baseline, during the Peak pollen season, and 12
      months of treatment. After 12 months of treatment, unblinding will take place. Those atopic
      participants receiving active AIT treatment will continue therapy for another 12 months
      followed by a withdrawal phase of 12 months. Blood samples and nasal biopsies will be taken
      from these participants again at 24 and at 36 months from the initial start of treatment.
      Those atopic participants on placebo will be offered 24 months of active treatment after
      unblinding.

      20 healthy, non-atopic participants will also be recruited and studied on a single day before
      and after nasal challenge at one timepoint at 12 months. They will undergo the same clinical
      and immunological measurements as for the 46 randomised subjects participating in the
      clinical trial. The healthy subjects will undergo no therapeutic intervention and serve as
      controls for the immunological measurements.

      The study will receive monitoring by:

        -  the sponsor, Imperial College London

      and audits by:

        -  Medicines for human use (clinical trials) regulations authority (MHRA)

      We will assess the clinical data on paper case report forms and will use Inform as a database
      in order to verify completeness of data entry.

      The Inform database also includes normal ranges of parameters if relevant.

      Standard Operating Procedures are in place regarding clinical measures (e.g. nasal allergen
      challenges, nasal biopsies etc.) as well as data management (e.g. the Trial Master File),
      reporting of adverse events and data collection. All involved investigators are informed
      about these procedures and have current Good Clinical Practice (GMC) instructions.

      Statistical analysis will be with non-parametric statistics taking into account treatment
      effect baseline values and visit number. Inclusion of 20 participants per group will give
      greater than 90% power (p=0.05) to detect a 40% reduction in the early phase response (EPR)
      after nasal challenge (AUC of the TNSS in the first 60 minutes after challenge, a 40%
      reduction in the skin late phase response (LPR), and a 50% increase in grass pollen allergen
      specific immunoglobulin G4 (IgG4) for AIT vs. placebo.

      Based on more recent nasal allergen challenge studies (Scadding et al, unpublished data; mean
      4.63, standard deviation 1.65 for AUC 0-60 minutes post grass pollen nasal challenge in 14
      allergic volunteers), inclusion of 13 patients per group will provide 80% power to detect a
      40% reduction in AUC after challenge, whereas inclusion of 22 patients per group will provide
      80% power to detect a 30% reduction.

      Further based on a recent study (Scadding et al, unpublished data; mean 70.14, standard
      deviation 14.17 for cross-sectional area in cm2 at 8 hours for skin late phase response to
      intradermal grass pollen injection), inclusion of 7 participants per group will provide 80%
      power to detect a 30% reduction, whereas inclusion of 10 participants per group will provide
      90% power to detect a 30% reduction.

      Intent-to-treat (ITT) sample will be defined as all randomized participants. ITT participants
      will be analysed with the group to which they were randomized, regardless of the medication
      actually received. If participants drop out post randomisation, they will be invited to
      complete study assessments throughout the duration of the trial.

      Per-protocol (PP) sample will be defined as ITT sample participants who remain in the study
      for 12 months and in whom the primary endpoints were assessed. Participants in the PP sample
      must be compliant with study medication, defined as taking 75% or more of their study
      medication for the duration of the study. Compliance with study medication will be as
      assessed by pill count for returned AIT/placebo. Participants in the PP sample will be
      analysed with the group to which they were randomized. The non-atopics will also be included
      in the PP sample.

      Safety sample (SS) will be defined as all enrolled participants.

      Analysis of study data will be conducted to address all objectives of the trial and other
      interrelationships among all data elements of interest to the investigators and of relevance
      to the objectives of the study. Primary analysis of treatment effect will be conducted under
      the intention-to-treat (ITT) principle of eligible patients, whereby outcome data from all
      eligible patients will be included regardless of treatment compliance. In addition to the
      analyses described in sections below, summary descriptive statistics will be provided in the
      following manner: continuous data will be summarized descriptively by mean, standard
      deviation, median, and range; categorical data will be presented as enumerations and
      percentages.

      Analysis of primary endpoint:

      The primary endpoint will be analysed using the ITT and the PP sample. The analysis of the
      primary endpoint will compare the mean EPR to nasal challenge recorded by the TNSS during the
      first 60 minutes after the nasal challenge, at 12 months of therapy. Comparison between
      active and placebo groups will be assessed using ANOVA at the 0.05 level of significance.

      Analysis of secondary endpoint:

      All secondary analyses will be treated as supportive. P-values will be presented for the
      secondary endpoints but will not be adjusted for multiplicity and should be interpreted with
      caution. Findings will be evaluated in the context of the available body of knowledge and
      with respect to other findings.
    

Intervention name(s): Grazax; Grazax Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The active treatment arm will receive active grass pollen immunotherapy tablet (AIT), Grazax Oral Lyophilisate 75,000 SQ-T once daily.; This arm will receive Grazax placebo once daily which contains the same composition as in the active Grazax tablet with the only difference being the exclusion of the grass pollen allergen extract.
Other intervention name(s): Grazax 75,000 SQ-T oral lyophilisate; Allergen Immunotherapy Tablet; SQ Standardized Grass Allergy Immunotherapy; Grazax Placebo tablet
Intervention MeSH terms: Immunomodulating Agents; Immunologic Factors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: grass pollen allergy; hayfever; atopy; allergic rhinitis; sublingual immunotherapy tablets