Long-Term Effects of Sublingual Grass Therapy

Study Overview
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Brief Summary
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The purpose of this research study is to investigate whether sublingual immunotherapy (SLIT, grass pollen tablets under the tongue) has long term effects in severe hay fever.

Detailed Description
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This is a randomized, double-blind, single-center, placebo-controlled, three-arm study comparing SLIT with placebo and SCIT with placebo. The main comparison will be between SLIT and placebo. Individuals with severe grass pollen hay fever, with or without associated seasonal asthma, will be recruited during the pollen season of March through September 2011. Eligible participants will be randomized to one of the following three treatment arms administered in a double-blind (masked), double-dummy fashion in a 1:1:1 ratio: SLIT + SCIT placebo SCIT + SLIT placebo SLIT placebo + SCIT placebo Participants will receive treatment over a 2-year period followed by a 1-year blinded (masked) withdrawal phase. Participants will be provided with anti-allergic rescue medications (antihistamine, topical intranasal corticosteroids, and short-acting beta agonists) throughout the study. Clinical endpoint assessments will be performed at prior to initiating their assigned treatment, after 1 and 2 years of treatment, and after the 1-year withdrawal period at 3 years.

Official Title
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A Randomized, Double-blind, Single-center, Placebo Controlled Study of Sublingual Immunotherapy and Subcutaneous Immunotherapy in Adults With Seasonal Allergic Rhinitis (ITN043AD)

Conditions
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Rhinitis, Allergic, Seasonal

Intervention / Treatment
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* Biological: Sublingual immunotherapy (SLIT)
* Biological: Subcutaneous immunotherapy (SCIT)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A clinical history of grass pollen-induced allergic rhinoconjunctivitis for at least 2 years with peak symptoms in May, June, or July; A clinical history of moderate to severe rhinoconjunctivitis symptoms interfering with usual daily activities or with sleep as defined according to the Allergic Rhinitis and its Impact on Asthma (ARIA) classification of rhinitis; A clinical history of rhinoconjunctivitis for at least 2 years requiring treatment with either antihistamines or nasal corticosteroids during the grass pollen season; Positive skin prick test response, defined as wheal diameter greater than or equal to 3 mm, to Phleum pratense (e.g., Timothy grass); Positive specific IgE, defined as greater than or equal to IgE class 2 (0.7 kU/L), against Phleum pratense; A positive response to nasal allergen challenge with Phleum pretense, defined as an increase in TNSS greater than or equal to 7 points above baseline; For women of childbearing age, a willingness to use an effective form of contraception for the duration of the trial; and The ability to give informed consent and comply with study procedures. Exclusion Criteria: Prebronchodilator forced expiratory volume at 1 second (FEV1) less than 70% of predicted value at either screening or baseline visit; A clinical history of moderate to severe allergic rhinitis, according to the ARIA classification, due to tree pollen near or overlapping the grass pollen season; A clinical history of persistent asthma and/or requiring regular inhaled corticosteroids for > 4 weeks per year outside of the grass pollen season; A clinical history of moderate- severe allergic rhinitis, according to the ARIA classification, caused by an allergen to which the participant is regularly exposed; History of emergency visit or hospital admission for asthma in the previous 12 months; History of chronic obstructive pulmonary disease; History of significant recurrent acute sinusitis, defined as 2 episodes per year for the last 2 years, all of which required antibiotic treatment; History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12 weeks that includes 2 or more major factors or 1 major factor and 2 minor factors. Major factors are defined as facial pain or pressure, nasal obstruction or blockage, nasal discharge or purulence or discolored postnasal discharge, purulence in nasal cavity, or impaired or loss of smell. Minor factors are defined as headache, fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, or fullness. At randomization, current symptoms of, or treatment for, upper respiratory tract infection, acute sinusitis, acute otitis media, or other relevant infectious process; serous otitis media is not an exclusion criterion. Participants may be re-evaluated for eligibility after symptoms resolve. Any tobacco smoking within the last 6 months or a history of ≥ 10 pack years; Previous treatment by immunotherapy with grass pollen allergen within the previous 5 years. Any history of grade 4 anaphylaxis due to any cause as defined by the World Allergy Organization (WAO) grading criteria for immunotherapy; History of bleeding disorders or treatment with anticoagulation therapy; History of anti-IgE monoclonal antibody treatment; Ongoing systemic immunosuppressive treatment; History of intolerance to the study therapy, rescue medications, or their excipients; For women of childbearing age a positive serum or urine pregnancy test with sensitivity of less than 50 mIU/mL within 72 hours before the start of study therapy; The use of any investigational drug within 30 days of the screening visit; or The presence of any medical condition that the investigator deems incompatible with participation in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCIT + Placebo<br>Subcutaneous immunotherapy (SCIT) + sublingual immunotherapy (SLIT) placebo | Biological: Subcutaneous immunotherapy (SCIT)<br>* Participants randomized to receive subcutaneous injection immunotherapy with placebo tablets. Subcutaneous immunotherapy was included as a positive control.<br>* Other names: Alutard SQ Grass Pollen®;Other: Placebo<br>* Participants randomized to double-placebo tablets and injections. This group was included as a negative control.<br>|
| Experimental: SLIT + Placebo<br>Sublingual immunotherapy (SLIT) + subcutaneous immunotherapy (SCIT) placebo | Biological: Sublingual immunotherapy (SLIT)<br>* Participants randomized to receive sublingual allergen tablet immunotherapy with placebo injections.<br>* Other names: Grazax®;Other: Placebo<br>* Participants randomized to double-placebo tablets and injections. This group was included as a negative control.<br>|
| Placebo Comparator: Placebo + Placebo<br>Sublingual immunotherapy (SLIT) placebo + subcutaneous immunotherapy (SCIT) placebo | Other: Placebo<br>* Participants randomized to double-placebo tablets and injections. This group was included as a negative control.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasal Response to Allergen Challenge | Defined as the average of the Total Nasal Symptom Score (TNSS) area under the curve (AUC) measured at 0 to 1 hours and the AUC measured at 1 to 10 hours after allergen challenge. The primary outcome consists of the comparison of SLIT + SCIT placebo versus SLIT placebo + SCIT placebo. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Late Phase Response (LPR) to Intradermal Testing | Recorded as the mean diameter of the swelling measured at the specified time points after allergen challenge at 1, 2, and 3 years. The analysis of this outcome will compare the mean diameter of the swelling at 1, 2, and 3 years separately, adjusting for baseline diameter using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1,-2, and -3 years | 
| Skin Early Phase Response (EPR) to Intradermal Testing | Recorded as the mean diameter of the swelling measured at the specified time points after allergen challenge at 1, 2, and 3 years. The analysis of this outcome will compare the mean diameter of the swelling at 1, 2, and 3 years separately, adjusting for baseline diameter using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1, -2, and -3 years | 
| Nasal LPR | Defined as the TNSS AUC over the specified time periods after allergen challenge at 1, 2, and 3 years. The analysis of these this outcome will compare the mean TNSS AUC at 1, 2, and 3 years separately, adjusting for baseline LPR using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1, -2, and -3 years | 
| Nasal EPR | Defined as the TNSS AUC over the specified time periods after allergen challenge at 1, 2, and 3 years. The analysis of these this outcome will compare the mean TNSS AUC at 1, 2, and 3 years separately, adjusting for baseline EPR using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1, -2, and -3 years | 
| Peak Total Nasal Symptom Score (TNSS) EPR | Maximum TNSS score measured between 0 and 1 hour after challenge. | Baseline (Time 0) and 1, -2, and -3 years | 
| Peak Nasal Inspiratory Flow (PNIF) LPR | Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1, -2, and -3 years | 
| Peak Nasal Inspiratory Flow (PNIF) LPR Area Under the Curve (AUC) | Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance. | Baseline (Time 0) and 1, -2, and -3 years | 
| Peak Nasal Inspiratory Flow (PNIF) EPR Area Under the Curve (AUC) | Defined as PNIF AUC over the specified time periods after allergen challenge at 1, 2 and 3 years. The analyses for this outcome will compare the mean PNIF AUC at 1, 2, and 3 years separately, adjusting for baseline PNIF using ANCOVA at the 0.05 level of significance. AUC measured hourly between 1 and 10 hours after challenge. | Baseline (Time 0) and 1, -2, and -3 years | 
| Skin Prick Test Endpoint Titration | Assessed as the mean wheal diameters (mm) in response to skin prick tests in duplicate with 1000 SQ, 10,000 SQ and 100,000 SQ units of grass pollen allergen. | Baseline (Time 0) and 1, -2, and -3 years | 
| Use of Rescue Medications During the Pollen Season | A composite rescue medication score will be derived using a pre-defined scoring algorithm. | 1, -2, and -3 years | 
| Mini Rhinoconjunctivitis Quality-of-Life Questionnaire Score | Mini Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ) scores will be collected pre-, peak-, and post-pollen season at 1, 2, and 3 years. | 1, -2, and -3 years | 
| Hay Fever Severity Score | Measured at the end of each pollen season at 1, -2, and -3 years. | 1, 2 and 3 years | 
| Weekly Visual Analog Symptom (VAS) Scores | Weekly Visual Analogue Scale scores will be summarized descriptively by group and year. | 1, -2, and -3 years | 
| EXPLORATORY: Mechanistic Assessments of Local Immune Responses | Measured in the nasal mucosa before and after nasal allergen challenge. Nasal secretions will be assayed for inflammatory mediators and local antibodies. | 1, 2, and 3 years | 
| EXPLORATORY: Mechanistic Assessments of Peripheral Blood Subsets | Peripheral blood mononuclear cells (PBMCs) samples will be analyzed. | 1, 2, and 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sublingual immunotherapy, subcutaneous immunotherapy