Clinical trial NCT02665754: Intralymphatic Immunotherapy for House Dust Mite, Dog, and Cat Allergy Using Tyrosine S® in Allergic Rhinitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Allergic Rhinitis
Keywords: Allergic rhinitis
Injection, intralymphatic
Immunotherapy
Dermatophagoides farinae
Dermatophagoides pteronyssinus
Dogs
Cats
Lead sponsor: Gachon University Gil Medical Center
Sponsor class: OTHER
Collaborators: name: Korea Research Foundation
First posted: 2016-01-28
Enrollment: 32
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: RQLQ
timeFrame: 4 months after the day of first injection of ILIT
Secondary outcomes:
measure: SNOT-20
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Allergic symptoms provoked by causal allergen in daily life
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Rhinitis symptom in nasal provocation test
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Skin reactivity in skin prick test
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Skin reactivity in intradermal test
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Serum total IgE level
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Allergen-specific IgE for causal allergen
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Cytokines in nasal lavage fluid before and after nasal provocation test
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Subjects' score (0~100) regarding agreement to "Allergen provokes allergic symptoms in daily life"
timeFrame: before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT
measure: Subjects' score (0~100) regarding agreement to "Allergen avoidance can reduce allergic symptoms"
timeFrame: before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT
measure: Subjects' score (0~100) regarding agreement to "Allergen-specific immunotherapy can reduce allergic symptoms"
timeFrame: before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT
measure: Willingness to pay for allergen avoidance
timeFrame: before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT
measure: Willingness to pay for intralymphatic immunotherapy
timeFrame: before skin prick test / intradermal test, nasal provocation test, and 4, 12 months after the day of first injection of ILIT
measure: Nasal mucosal inflammation
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: RQLQ
timeFrame: 12 months after the day of first injection of ILIT
measure: Nasal cavitary volume decrease in nasal provocation test
timeFrame: before and 4, 12 months after the day of first injection of ILIT
measure: Allergen-specific IgG4 for causal allergen
timeFrame: before and 4, 12 months after the day of first injection of ILIT
Other outcomes:
Locations:
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
Study officials:
affiliation: Gachon University Gil Medical Center
name: Sang Min Lee, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Senti G, Johansen P, Kundig TM. Intralymphatic immunotherapy. Curr Opin Allergy Clin Immunol. 2009 Dec;9(6):537-43. doi: 10.1097/ACI.0b013e3283310ff7.
citation: 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.
citation: 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.
citation: Johansen P, Kundig TM. Intralymphatic immunotherapy and vaccination in mice. J Vis Exp. 2014 Feb 2;(84):e51031. doi: 10.3791/51031.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.