Intralymphatic Immunotherapy for House Dust Mite, Dog, and Cat Allergy Using Tyrosine S® in Allergic Rhinitis (ILIT-T)

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

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).

Study Overview

• Status: Completed
• Conditions: Allergic Rhinitis
• Intervention / Treatment: Biological: ILIT with extract of causal allergen; Drug: Rescue medication for allergic rhinitis; Biological: ILIT with normal saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Incheon, Korea, Republic of, 405-760
    • Gachon University Gil Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

1. Sensitization should be verified by skin prick test and the level of serum specific IgE measured by ImmunoCAP® (Thermo Fisher Scientific, Uppsala, Sweden).
2. Subjects should complain of AR symptoms during exposure of house dust, dog and/or cat in daily life.

Exclusion Criteria:

1. 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
2. Significant cardiovascular, hepatic, renal, hematologic, oncologic, or infectious diseases
3. Administration of beta blocker, angiotensin converting enzyme inhibitor, tricyclic antidepressant, immunosuppressant including systemic glucocorticosteroid within last 2 weeks
4. AR caused by other perennial or seasonal allergen
5. Prior history of allergen-specific immunotherapy
6. Rejection or low compliance,
7. Pregnancy or lactation
8. Vulnerable volunteer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active group; 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; 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.; Other Names: Active ILIT; Drug: Rescue medication for allergic rhinitis; 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.; Other Names: Rescue medication
Placebo Comparator: Placebo group; In placebo group, normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.	Drug: Rescue medication for allergic rhinitis; 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.; Other Names: Rescue medication; Biological: ILIT with normal saline; 0.5 ml of normal saline will be injected into inguinal lymph node through guidance by ultrasonography three times with 4-week interval.; Other Names: Placebo ILIT

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gachon University Gil Medical Center
• Collaborators: Korea Research Foundation
• Investigators: Principal Investigator: Sang Min Lee, MD, PhD, Gachon University Gil Medical Center

Publications and helpful links

General Publications

• Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, Simard JJ, Wuthrich B, Crameri R, Graf N, Johansen P, Kundig TM. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17908-12. doi: 10.1073/pnas.0803725105. Epub 2008 Nov 10.
• Hylander T, Latif L, Petersson-Westin U, Cardell LO. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis. J Allergy Clin Immunol. 2013 Feb;131(2):412-20. doi: 10.1016/j.jaci.2012.10.056.
• Witten M, Malling HJ, Blom L, Poulsen BC, Poulsen LK. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? J Allergy Clin Immunol. 2013 Nov;132(5):1248-1252.e5. doi: 10.1016/j.jaci.2013.07.033. Epub 2013 Sep 13. No abstract available.
• Senti G, Johansen P, Kundig TM. Intralymphatic immunotherapy. Curr Opin Allergy Clin Immunol. 2009 Dec;9(6):537-43. doi: 10.1097/ACI.0b013e3283310ff7.
• Kundig TM, Johansen P, Bachmann MF, Cardell LO, Senti G. Intralymphatic immunotherapy: time interval between injections is essential. J Allergy Clin Immunol. 2014 Mar;133(3):930-1. doi: 10.1016/j.jaci.2013.11.036. Epub 2014 Jan 15. No abstract available.
• Zaleska A, Eiwegger T, Soyer O, van de Veen W, Rhyner C, Soyka MB, Bekpen C, Demiroz D, Treis A, Sollner S, Palomares O, Kwok WW, Rose H, Senti G, Kundig TM, Ozoren N, Jutel M, Akdis CA, Crameri R, Akdis M. Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine. Allergy. 2014 Sep;69(9):1162-70. doi: 10.1111/all.12461. Epub 2014 Jul 12. Erratum In: Allergy. 2016 Jan;71(1):129.
• Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn LA, Gronlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H, Kundig TM. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012 May;129(5):1290-6. doi: 10.1016/j.jaci.2012.02.026. Epub 2012 Mar 30.
• Senti G, Johansen P, Kundig TM. Intralymphatic immunotherapy: from the rationale to human applications. Curr Top Microbiol Immunol. 2011;352:71-84. doi: 10.1007/82_2011_133.
• Johansen P, Kundig TM. Intralymphatic immunotherapy and vaccination in mice. J Vis Exp. 2014 Feb 2;(84):e51031. doi: 10.3791/51031.
• Graf N, Dinkel B, Rose H, Hothorn LA, Gerhard D, Johansen P, Kundig TM, Klimek L, Senti G. A critical appraisal of analyzing nasal provocation test results in allergen immunotherapy trials. Rhinology. 2014 Jun;52(2):137-41. doi: 10.4193/Rhino13.145.
• Senti G, Kundig TM. Intralymphatic immunotherapy. World Allergy Organ J. 2015 Mar 7;8(1):9. doi: 10.1186/s40413-014-0047-7. eCollection 2015.
• Hjalmsdottir A, Wackerle-Men Y, Duda A, Kundig TM, Johansen P. Dosing intervals in intralymphatic immunotherapy. Clin Exp Allergy. 2016 Mar;46(3):504-7. doi: 10.1111/cea.12657. No abstract available.
• Patterson AM, Bonny AE, Shiels WE 2nd, Erwin EA. Three-injection intralymphatic immunotherapy in adolescents and young adults with grass pollen rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2016 Feb;116(2):168-70. doi: 10.1016/j.anai.2015.11.010. Epub 2015 Dec 17. No abstract available.
• Park HJ, Kim SH, Shin YS, Park CH, Cho ES, Choi SJ, Park SH, Jung JH, Kang IG, Lee MS, Kim DW, Lee SM, Yang MS, Lee SP. Intralymphatic immunotherapy with tyrosine-adsorbed allergens: a double-blind, placebo-controlled trial. Respir Res. 2021 Jun 4;22(1):170. doi: 10.1186/s12931-021-01766-0.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: January 10, 2016
• First Submitted That Met QC Criteria: January 24, 2016
• First Posted (Estimate): January 28, 2016

Study Record Updates

• Last Update Posted (Actual): February 11, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Immunotherapy; Allergic rhinitis; Injection, intralymphatic; Dermatophagoides farinae; Dermatophagoides pteronyssinus; Dogs; Cats
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Otorhinolaryngologic Diseases; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Rhinitis; Rhinitis, Allergic
• Other Study ID Numbers: GBIRB2016-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO