Desensitization and Cross-Desensitization During Oral Grass or Ragweed Pollen Immunotherapy

The purpose of this study is to determine if sublingual allergen immunotherapy tablets work by inducing a state of desensitization in mast cells and basophils.

Study Overview

• Status: Terminated
• Conditions: Immunologic Desensitization
• Intervention / Treatment: Drug: allergen extract tablet; Drug: Placebo tablet

Detailed Description

To induce clinical tolerance, a failure to respond to an allergen to which one was previously responsive, is an important objective for physicians, one that plays a significant role in the primary prevention of allergic reactions in the clinical practice of Allergy & Immunology. The tolerance resulting after standard subcutaneous immunotherapy to aeroallergen and insect venom allergens is long lasting and allergen-specific, and may involve antigen-specific T regulatory cells. In contrast, tolerance resulting from drug desensitization protocols is short-lived, and postulated to target mast cells and basophils. Research into the cellular and biochemical processes by which desensitization occurs has revealed that mast cells desensitized to one antigen in vitro, under certain conditions, lose the ability to degranulate to unrelated antigens or to direct FcεRI cross-linking. Preliminary data suggests that this cross-desensitization can happen in patients undergoing incremental desensitization, depending in part on the percentage of IgE targeted to the allergen used for desensitization. This proposal therefore aims to explore desensitization and cross-desensitization in human volunteers undergoing standard sublingual (SL) immunotherapy to grass or ragweed pollen.

Subjects will undergo SL immunotherapy with either Timothy or Short Ragweed tablets, taking one tablet per day, or will take a placebo tablet. Titration skin testing to Timothy or Short Ragweed, to one or preferably two additional allergens to which the subject is sensitive, and to codeine as a control for mast cell activation capability through a non-IgE-dependent pathway will be performed to determine the PC3 value (see below). Skin testing, including histamine and diluent controls, will be performed prior to and at one and four weeks after initiation of immunotherapy. At each time point, blood will be obtained to measure total and antigen-specific IgE levels, tryptase and cytokine levels, and basophil activation with the relevant allergens and C5a as a non-IgE-mediated control for basophil activation.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Verified allergic sensitivity to either Timothy Grass or Short Ragweed pollen (primary allergen)
• Verified allergic sensitivity to at least one allergen in addition to the primary allergen

Exclusion Criteria:

• Negative skin testing to Timothy Grass or Short Ragweed pollen and at least one other environmental allergen
• Dermatographism
• Severe dermatologic condition that may interfere with skin testing
• Pregnancy
• H1 receptor antihistamine taken within 7 days of testing
• Systemic steroids
• Omalizumab taken at any time in the past
• Receiving or received allergen immunotherapy
• Desensitized to any drug within 6 months
• Current uncontrolled or severe asthma
• Eosinophilic esophagitis
• Significant pulmonary, cardiovascular, renal, hepatobiliary, or neurological diseases, or another disease process felt to put a subject at increased risk for adverse events
• Hypersensitivity to any of the inactive ingredients in the allergen extract tablets
• History of mental illness or drug or alcohol abuse that could interfere with the ability to comply with study requirements
• Inability or unwillingness to give written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sublingual allergen tablets; Subjects will be administered a sublingual allergen tablet customized to their individual allergic sensitization.	Drug: allergen extract tablet; 1 allergen extract tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet; Other Names: Ragwitek; Grastek
Placebo Comparator: Placebo; Subjects will be administered placebo sublingual tablets	Drug: Placebo tablet; 1 placebo tablet, placed under the tongue until dissolved, taken daily; do not swallow for 1 minute after placing tablet; do not eat or drink for 5 minutes after placing tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PC3	Change in the dose of allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3)	Assessed at 2 weeks and at the end of the study (2 months)
Change in Basophil Activation	Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls	Assessed at 2 weeks and at the end of the study (2 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cross-desensitization - PC3	Change in the dose of an unrelated allergen eliciting a wheal 3 mm greater than negative control upon skin prick testing (PC3)	Assessed at 2 weeks and at the end of the study (2 months)
Cross-desensitization - Basophil Activation	Change in the dose of allergen eliciting a 50% increase in number of basophils positive for CD63 and/or CD203c relative to negative and positive controls	Assessed at 2 weeks and at the end of the study (2 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Allergen-specific IgE	The percent of total serum IgE that is specific for the primary allergen will be compared to the degree (if any) of cross-desensitization seen by skin prick or basophil activation testing	Assessed at enrollment, at 2 weeks, and at the end of the study (2 months)

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Investigators: Principal Investigator: Lawrence B Schwartz, M.D.,Ph.D., Virginia Commonwealth University

Publications and helpful links

General Publications

• Cockcroft DW, Davis BE, Boulet LP, Deschesnes F, Gauvreau GM, O'Byrne PM, Watson RM. The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen. Allergy. 2005 Jan;60(1):56-9. doi: 10.1111/j.1398-9995.2004.00612.x.
• Zhao W, Gomez G, Macey M, Kepley CL, Schwartz LB. In vitro desensitization of human skin mast cells. J Clin Immunol. 2012 Feb;32(1):150-60. doi: 10.1007/s10875-011-9605-8. Epub 2011 Oct 19.
• Maloney J, Bernstein DI, Nelson H, Creticos P, Hebert J, Noonan M, Skoner D, Zhou Y, Kaur A, Nolte H. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014 Feb;112(2):146-153.e2. doi: 10.1016/j.anai.2013.11.018. Epub 2013 Dec 21.
• Creticos PS, Maloney J, Bernstein DI, Casale T, Kaur A, Fisher R, Liu N, Murphy K, Nekam K, Nolte H. Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults. J Allergy Clin Immunol. 2013 May;131(5):1342-9.e6. doi: 10.1016/j.jaci.2013.03.019.
• Niederberger V, Laffer S, Froschl R, Kraft D, Rumpold H, Kapiotis S, Valenta R, Spitzauer S. IgE antibodies to recombinant pollen allergens (Phl p 1, Phl p 2, Phl p 5, and Bet v 2) account for a high percentage of grass pollen-specific IgE. J Allergy Clin Immunol. 1998 Feb;101(2 Pt 1):258-64. doi: 10.1016/s0091-6749(98)70391-4.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): January 18, 2018
• Study Completion (Actual): January 18, 2018

Study Registration Dates

• First Submitted: February 3, 2016
• First Submitted That Met QC Criteria: February 3, 2016
• First Posted (Estimate): February 8, 2016

Study Record Updates

• Last Update Posted (Actual): March 18, 2022
• Last Update Submitted That Met QC Criteria: February 21, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Allergic rhinitis; Sublingual Immunotherapy; Immunotherapy, Allergen
• Other Study ID Numbers: HM20006291; MISP 52707 (Other Grant/Funding Number: Merck)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No