Tolerance Following Peanut Oral Immunotherapy

NCT ID: NCT01750879

Last Updated: 2021-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2017-07-11

Brief Summary

The unifying objective of this project is to determine whether peanut oral immunotherapy (PN OIT) induced clinical tolerance in the context of food allergy is significantly associated with the expansion of a specific regulatory T cell subset (CD45RA- CD25++ FoxP3++) that is thought to be inducible in the gut-associated lymphoid compartment and associated with immunological tolerance.

The hypothesis of the study is that the induction of Treg cells will be associated with clinical tolerance.

The investigators will measure the change from baseline of induced Treg cells as a frequency of total CD4 T cells during active treatment and compare that between participants who achieve significant clinical tolerance (Tolerance and Partial Tolerance Groups as defined below) and those who do not (Treatment Failure Group).

Detailed Description

Clinical Objectives:

1. To evaluate whether PN OIT induces increased tolerance, defined as a statistically significant increase in the median eliciting dose (ED) from a double-blind placebo-controlled food challenge (DBPCFC) before and after treatment with PN OIT and after subsequent allergen avoidance.

2. To evaluate whether PN OIT induces clinical desensitization, defined as 1) a median 10-fold or greater increase in ED at DBPCFC before and after PN OIT treatment period 2) a statistically significant higher median ED at DBPCFC following treatment period between active and control treatment; and 3) a significantly lower frequency of accidental ingestion reactions in active versus control treatment.

3. To evaluate the safety of PN OIT.

Mechanistic Objectives:

1. To determine whether PN OIT induces a statistically significant increase in the TCR clonal diversity of Treg populations during active treatment among participants who achieve increased clinical tolerance (Tolerance and Partial Tolerance Groups as defined in clinical endpoints) versus the Treatment Failure Group.

2. To determine whether PN OIT suppresses mast cells by inducing a significant suppression of the median ED on end-point dilution skin testing in actively treated participants by the end of maintenance therapy.

3. To determine whether PN OIT suppresses basophils as defined by a 10-fold suppression of peanut-specific basophil ED in actively treated participants by end of a maintenance period.

4. To determine whether either mast cell or basophil suppression at the end of maintenance therapy is significantly associated with clinical outcomes following avoidance.

Exploratory Objectives:

1. To describe the gene expression profiles and clonal diversity of regulatory and effector T cell subsets before and after OIT to better understand the phenotype and ontogeny of these subsets and potentially discover new therapeutic pathways.

2. To engineer human MHC class II tetramers on common HLA backgrounds and map T cell epitopes of the dominant peanut allergens for use in validating earlier findings and for future studies of peanut-specific immune responses in humans.

Conditions

Peanut Allergy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

Peanut Flour

Oral Immunotherapy with peanut flour.

Group Type: ACTIVE_COMPARATOR

Peanut Flour

Intervention Type: DRUG

Peanut Flour

Oat Flour

Oral Immunotherapy with oat flour.

Group Type: PLACEBO_COMPARATOR

Oat Flour

Intervention Type: DRUG

Oat Flour

Interventions

Peanut Flour

Peanut Flour

Intervention Type: DRUG

Oat Flour

Oat Flour

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Diagnosis of peanut allergy by a positive skin prick test to peanut (reaction wheal at least 5 mm larger than saline control) and by medical history or Serum peanut-specific IgE >5 kU/L at screening visit.
• Ara h 2 specific IgE >0.35 kU/L at screening visit
• Ability to provide informed consent.
• Males and females of all ethnic/racial groups aged 7-55 years old who are otherwise healthy.
• React to less than 443 mg of peanut protein during DBPCFC1

Exclusion Criteria

• History of severe anaphylaxis as defined by hypoxia (cyanosis or SpO2 <92% during reaction), documented hypotension (documented systolic BP >30% below predicted normal for sex, height, weight or from known baseline), neurological compromise (confusion, loss of consciousness), or incontinence.
• Severe or Moderate asthma as defined using the severity criteria of the current NHBLI Guidelines for the Diagnosis and Management of Asthma (http://www.nhlbi.nih.gov/guidelines/asthma/).
• Poorly-controlled asthma as defined by FEV1 <80% or any of the following symptoms: nighttime awakening >2 days/week or rescue medication use >2 days / week.
• Diagnosis of other severe or complicating medical problems, including autoimmune or chronic immune inflammatory conditions or gastrointestinal inflammatory conditions, including Celiac Disease, Inflammatory Bowel Disease and Eosinophilic Gastrointestinal Disorders
• Inability to cooperate with and/or perform oral food challenge procedures.
• Primary Immune Deficiency
• Allergy to oat confirmed by skin prick testing and history
• Current use of beta blockers, angiotensin converting enzyme inhibitors, or monoamine oxidase inhibitors
• Women of childbearing potential who are pregnant, planning to become pregnant, or breastfeeding
• Hemoglobin level less than 12.5 gm/dL at screening. Weight <23 kg
• Use within the past 6 months of other systemic immunomodulatory treatments including allergen immunotherapy, or use of biologics with an immune target, including omalizumab.
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study may also exclude a participant from the study.

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Wayne G. Shreffler, MD, PhD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wayne G Shreffler, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Countries

United States

References

Monian B, Tu AA, Ruiter B, Morgan DM, Petrossian PM, Smith NP, Gierahn TM, Ginder JH, Shreffler WG, Love JC. Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells. J Clin Invest. 2022 Jan 18;132(2):e150634. doi: 10.1172/JCI150634.

Reference Type: DERIVED

PMID: 34813505 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

5U19AI095261-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2012P002153

Identifier Type: -

Identifier Source: org_study_id