Tolerance Following Peanut Oral Immunotherapy (PNOIT2)

Clinical Desensitization and Tolerance Following Peanut Oral Immunotherapy and Subsequent Allergen Avoidance

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).

Study Overview

• Status: Completed
• Conditions: Peanut Allergy
• Intervention / Treatment: Drug: Peanut Flour; Drug: Oat Flour

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Peanut Flour; Oral Immunotherapy with peanut flour.	Drug: Peanut Flour; Peanut Flour
Placebo Comparator: Oat Flour; Oral Immunotherapy with oat flour.	Drug: Oat Flour; Oat Flour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance, Partial Tolerance, or Treatment Failure	Tolerance: Ingestion of 4430 mg of peanut protein at DBPCFC3 without symptoms.; Partial Tolerance: ED at DBPCFC3 <4430 mg but =>430 mg AND >10-fold more than at DBPCFC1.; Treatment Failure - non desensitized: Failure to achieve the minimum maintenance dose (600 mg) of peanut protein by 12 months, or an ED <1443 mg at DBPCFC2, or ED at DBPCFC3 <443 mg OR <10-fold more than at DBPCFC1.; Treatment Failure - withdrawal	Average 515 days from DBPCFC1 to DBPCFC3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical: Tolerance	The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC3. (note: ED right censored to maximum dose for those without any clinical reactivity)	630 days
Clinical: Desensitization	- The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.	518 days
Clinical: Safety	- The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups.	630 days
Mechanistic: TCR Clonal Diversity	The change in the TCR clonal diversity of in vitro allergen-expanded Treg cells and induced Treg cells measured by TCRB CDR3 sequence clonotyping of sorted cells 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. We conducted a nested case-control analysis of a subset of actively treated (by treatment outcome) versus placebo treated patients. Genomic DNA was used to amplify and sequence the complementarity-determining region 3 (CDR3) regions (immunoSEQ assay; Adaptive Biotechnologies). Enriched clonotypes in the CD154+ fraction (doi: https://doi.org/10.1101/2020.05.11.088286) were analyzed for differences by Rank Abundance Curve analysis (R package alakazam; Chao A, et al. Ecology. 2015 96, 11891201) to determine differences in clonal diversity.	630 days
Mechanistic: Change Eliciting Dose of End-point Dilution.	The change in eliciting dose of end-point dilution skin testing between actively treated and placebo treated participants following maintenance therapy and the change in ED of end-point dilution skin testing among actively treated participants following maintenance therapy and avoidance between clinical outcome groups.	518 days
Mechanistic: Change in Basophil Eliciting Dose.	The change in peanut-specific basophil ED in actively treated participants at the end of maintenance and the end of avoidance between clinical outcome groups.	630 days
Mechanistic: Change in Peanut Allergen-specific IgG4	The change in peanut allergen-specific IgG4 in actively treated participants by the end of maintenance between clinical outcome groups.	518 days
Mechanistic: Significant Gene Expression Changes by Transcriptional Profiling of Regulatory and Effector T Cell Populations	Statistically significant gene expression changes (as number of genes) by transcriptional profiling of regulatory and effector T cell populations before and after OIT between clinical outcome groups. Total RNA from CD154+ and CD154-CD69- T cells was used for cDNA synthesis and amplification. Libraries were prepared and sequenced to a read depth of approximately 30 million reads per sample (Illumina HiSeq) and aligned to the hg19 human reference genome with the ensemble version 75 annotation using STAR version 2.5.3a,(Dobin et al. Bioinformatics 2013) and gene expression was summarized using RSEM version 1.3.0 (Li et al. BMC Bioinform 2013). Differential expression analysis was performed using DESeq2 v 1.30.1 (R v 4.04). Significance level was set at an unadjusted P value less than .001.	630 days

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): July 11, 2017
• Study Completion (Actual): July 11, 2017

Study Registration Dates

• First Submitted: December 13, 2012
• First Submitted That Met QC Criteria: December 14, 2012
• First Posted (Estimate): December 17, 2012

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 6, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: immunotherapy; food; tolerance; allergy; peanut; desensitization
• Additional Relevant MeSH Terms: Immune System Diseases; Food Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Nut and Peanut Hypersensitivity; Peanut Hypersensitivity
• Other Study ID Numbers: 2012P002153; 5U19AI095261-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: de-identified data exported from REDCap
• IPD Sharing Time Frame: upon request within the year and without planned time limitation
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code

Drug and device information, study documents

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