Intralymphatic Immunotherapy for House Dust Mite, Dog, and Cat Allergy Using Tyrosine S® in Allergic Rhinitis

Study Overview
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Brief Summary
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The investigators will perform double-blinded placebo-controlled randomized clinical trial which evaluates the efficacy and safety of allergen-specific intralymphatic immunotherapy (ILIT) for allergens including Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), cat, and dog that are sensitized and provoke rhinitis-related symptoms in patients with allergic rhinitis (AR), using allergen extracts for allergen-specific immunotherapy (Tyrosine S, Allergy Therapeutic, West Sussex, UK).

Detailed Description
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After informed consent, subjects will be randomly assigned to ILIT group or placebo group in double-blind manner. In both group, causal allergen or placebo will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval. In ILIT group, initial dose of allergen will be 1,000-fold diluted solution from maximal concentration of allergen extract for subcutaneous immunotherapy (Tyrosine S, Allergy Therapeutic, West Sussex, UK) in volume of 0.1ml. If skin is highly reactive in skin prick test, the initial dose will be 10-fold dilution from maximal concentration where diameter of wheal is less than that of histamine. After the first dose, allergen concentration will be escalated 3-fold at second dose, and 10-fold at third dose if there are no (or mild) local or systemic hypersensitivity reaction. The allergen concentration will not change at second or third dose if there is moderate local or systemic reaction. The allergen concentration will decrease by 10 or 100-fold from previous concentration or further injection will be held if there is severe local or systemic reaction after sufficient explanation and discussion with subjects. The investigators will evaluate allergic rhinitis symptom score before and 4, 12 months after the initial treatment. Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and Sino-Nasal Outcome Test (SNOT-20) will be used. Visual analogue scale (VAS) of symptoms including rhinorrhea, sneezing, nasal obstruction, postnasal drip, eye/nose/ear/palate itching, dyspnea, wheezing, chest discomfort as well as urticaria, angioedema, and itching on exposed skin during exposure to causal allergen in daily life will be also evaluated. Skin prick test (SPT), intradermal test (IDT), blood sampling for serum total immunoglobulin E (IgE), allergen-specific IgE, and allergen-specific immunoglobulin G4 (IgG4), nasal lavage for Th1, Th2, and Treg cytokines, and nasal provocation test (NPT) with Df and/or Dp allergen (in subjects whose AR symptoms are provoked by Df and/or Dp) will be also performed before and 4, 12 months after the initial treatment. In addition, the investigators evaluated the change of subjects' recognition of causal allergens, their avoidance, and AIT during this study. Using VAS, subjects were requested to score the rate of agreement with Allergen provokes allergic symptoms in daily life, Allergen avoidance can reduce allergic symptoms, Allergen-specific Immunotherapy (AIT) can reduce allergic symptoms, I can pay 50,000 Korean Won (KRW)/month for allergen avoidance, I can pay 100,000 KRW/month for allergen avoidance, I can pay 200,000 KRW/month for allergen avoidance, I can pay 150,000 KRW for each injection of ILIT, I can pay 300,000 KRW for each injection of ILIT, I can pay 600,000 KRW for each injection of ILIT before and after SPT/IDT, after NPT, 4 months and 1 year after ILIT. Adverse events will be recorded and graded according to Muller classification and Ring and Meissner classification.

Official Title
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The Efficacy and Adverse Effect of Intralymphatic Immunotherapy With Tyrosine S®, Allergen Extract for Immunotherapy, in Patients With Allergic Rhinitis Induced by House Dust Mite, Dog, and Cat Allergen

Conditions
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Allergic Rhinitis

Intervention / Treatment
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* Biological: ILIT with extract of causal allergen
* Biological: ILIT with normal saline
* Drug: Rescue medication for allergic rhinitis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: We enrolled subjects who suffered from AR, symptoms of which were provoked by Dp, Df, dog, and/or cat allergen. Concretely, two inclusion criteria should be met. Sensitization should be verified by skin prick test and the level of serum specific IgE measured by ImmunoCAP® (Thermo Fisher Scientific, Uppsala, Sweden). Subjects should complain of AR symptoms during exposure of house dust, dog and/or cat in daily life. Exclusion Criteria: Uncontrolled or severe asthma according to Global Initiative of Asthma (GINA) guideline including a case in which forced expiratory volume in 1 s (FEV1) was less than 50% of predicted value Significant cardiovascular, hepatic, renal, hematologic, oncologic, or infectious diseases Administration of beta blocker, angiotensin converting enzyme inhibitor, tricyclic antidepressant, immunosuppressant including systemic glucocorticosteroid within last 2 weeks AR caused by other perennial or seasonal allergen Prior history of allergen-specific immunotherapy Rejection or low compliance, Pregnancy or lactation Vulnerable volunteer

Ages Eligible for Study
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Minimum Age: 19 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active group<br>In active group, extract of causal allergen will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval. | Biological: ILIT with extract of causal allergen<br>* 0.5 ml of allergen extract from D. farinae, D. pteronyssinus, cat, and/or dog for allergen specific immunotherapy (Tyrosine S, Allergy Therapeutic, UK) will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.<br>* Other names: Active ILIT;Drug: Rescue medication for allergic rhinitis<br>* Subjects are requested to administer oral antihistamine (cetirizine) or nasal glucocorticosteroid (ciclesonide) as rescue medication for allergic rhinitis in accordance with severity and frequency of allergic rhinitis symptoms according to Allergic Rhinitis and its Impact on Asthma (ARIA) guideline.<br>* Other names: Rescue medication;|
| Placebo Comparator: Placebo group<br>In placebo group, normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval. | Biological: ILIT with normal saline<br>* 0.5 ml of normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.<br>* Other names: Placebo ILIT;Drug: Rescue medication for allergic rhinitis<br>* Subjects are requested to administer oral antihistamine (cetirizine) or nasal glucocorticosteroid (ciclesonide) as rescue medication for allergic rhinitis in accordance with severity and frequency of allergic rhinitis symptoms according to Allergic Rhinitis and its Impact on Asthma (ARIA) guideline.<br>* Other names: Rescue medication;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RQLQ | Rhinoconjunctivitis Quality of Life Questionnaires | 4 months after the day of first injection of ILIT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SNOT-20 | Sinonasal Outcome Test-20 | before and 4, 12 months after the day of first injection of ILIT | 
| Allergic symptoms provoked by causal allergen in daily life | Rates scored by subjects using visual analogue scale regarding allergic symptoms provoked by causal allergen in daily life | before and 4, 12 months after the day of first injection of ILIT | 
| Rhinitis symptom in nasal provocation test | Rhinitis symptom (visual analogue scale: 0 100) during nasal provocation test with allergen of D. farinae and/or D. pteronyssinus in subjects in whom D. farinae and/or D. pteronyssinus is causal allergen. | before and 4, 12 months after the day of first injection of ILIT | 
| Skin reactivity in skin prick test | Mean diameters of wheal caused by 1- to 10^7- fold dilution of causal allergen in skin prick test and their allergen histamine ratio | before and 4, 12 months after the day of first injection of ILIT | 
| Skin reactivity in intradermal test | Mean diameters of wheal caused by 10^2- to 10^7- fold dilution of causal allergen in intradermal test and their allergen saline ratio | before and 4, 12 months after the day of first injection of ILIT | 
| Serum total IgE level | Serum total IgE level using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden) | before and 4, 12 months after the day of first injection of ILIT | 
| Allergen-specific IgE for causal allergen | Allergen-specific IgE for causal allergen of D. farinae, D. pteronyssinus, cat, and/dog using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden) | before and 4, 12 months after the day of first injection of ILIT | 
| Cytokines in nasal lavage fluid before and after nasal provocation test | Cytokines of Th1, Th2, and Treg immunity including interleukin-4 (IL-4), IL-5, IL-10, IL-12, IL-13, interferon-gamma (IFN-g), and tumor growth factor-beta (TGF-b) in nasal lavage fluid | before and 4, 12 months after the day of first injection of ILIT | 
| Subjects' score (0 100) regarding agreement to Allergen provokes allergic symptoms in daily life | Subjects' score regarding agreement to Allergen provokes allergic symptoms in daily life using visual analogue scale (0 100). | before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT | 
| Subjects' score (0 100) regarding agreement to Allergen avoidance can reduce allergic symptoms | Subjects' score regarding agreement to Allergen avoidance can reduce allergic symptoms using visual analogue scale (0 100). | before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT | 
| Subjects' score (0 100) regarding agreement to Allergen-specific immunotherapy can reduce allergic symptoms | Subjects' score regarding agreement to Allergen-specific immunotherapy can reduce allergic symptoms using visual analogue scale (0 100). | before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT | 
| Willingness to pay for allergen avoidance | Agreement% scored by subjects using visual analogue scale to I am willing to pay 50,000, 100,000 or 200,000 Korean Won per month for allergen avoidance | before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT | 
| Willingness to pay for intralymphatic immunotherapy | Agreement% scored by subjects using visual analogue scale to I am willing to pay 150,000, 300,000 or 600,000 Korean Won for each injection of intralymphatic immunotherapy | before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT | 
| Nasal mucosal inflammation | Inflammatory cell count in nasal mucosal biopsy (/high power field, x400) | before and 4, 12 months after the day of first injection of ILIT | 
| RQLQ | Rhinoconjunctivitis Quality of Life Questionnaires | 12 months after the day of first injection of ILIT | 
| Nasal cavitary volume decrease in nasal provocation test | Nasal cavitary volume decrease (basal%) measured by acoustic rhinometry during nasal provocation test with allergen of D. farinae and/or D. pteronyssinus in subjects in whom D. farinae and/or D. pteronyssinus is causal allergen. | before and 4, 12 months after the day of first injection of ILIT | 
| Allergen-specific IgG4 for causal allergen | Allergen-specific IgG4 for causal allergen of D. farinae, D. pteronyssinus, cat, and/dog using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden) | before and 4, 12 months after the day of first injection of ILIT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allergic rhinitis, Injection, intralymphatic, Immunotherapy, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Dogs, Cats