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Tolerance Following Peanut Oral Immunotherapy (PNOIT2)

Primary Purpose

Peanut Allergy

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Peanut Flour
Oat Flour
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Peanut Allergy focused on measuring peanut, allergy, food, immunotherapy, tolerance, desensitization

Eligibility Criteria

7 Years - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Peanut Flour

Oat Flour

Arm Description

Oral Immunotherapy with peanut flour.

Oral Immunotherapy with oat flour.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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)
Clinical: Desensitization
- The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.
Clinical: Safety
- The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups.
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.
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.
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.
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.
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.

Full Information

First Posted
December 13, 2012
Last Updated
July 6, 2021
Sponsor
Massachusetts General Hospital
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01750879
Brief Title
Tolerance Following Peanut Oral Immunotherapy
Acronym
PNOIT2
Official Title
Clinical Desensitization and Tolerance Following Peanut Oral Immunotherapy and Subsequent Allergen Avoidance
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
July 11, 2017 (Actual)
Study Completion Date
July 11, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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. 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. To evaluate the safety of PN OIT. Mechanistic Objectives: 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. 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. 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. 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: 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peanut Allergy
Keywords
peanut, allergy, food, immunotherapy, tolerance, desensitization

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Peanut Flour
Arm Type
Active Comparator
Arm Description
Oral Immunotherapy with peanut flour.
Arm Title
Oat Flour
Arm Type
Placebo Comparator
Arm Description
Oral Immunotherapy with oat flour.
Intervention Type
Drug
Intervention Name(s)
Peanut Flour
Intervention Description
Peanut Flour
Intervention Type
Drug
Intervention Name(s)
Oat Flour
Intervention Description
Oat Flour
Primary Outcome Measure Information:
Title
Tolerance, Partial Tolerance, or Treatment Failure
Description
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
Time Frame
Average 515 days from DBPCFC1 to DBPCFC3
Secondary Outcome Measure Information:
Title
Clinical: Tolerance
Description
The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC3. (note: ED right censored to maximum dose for those without any clinical reactivity)
Time Frame
630 days
Title
Clinical: Desensitization
Description
- The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.
Time Frame
518 days
Title
Clinical: Safety
Description
- The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups.
Time Frame
630 days
Title
Mechanistic: TCR Clonal Diversity
Description
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.
Time Frame
630 days
Title
Mechanistic: Change Eliciting Dose of End-point Dilution.
Description
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.
Time Frame
518 days
Title
Mechanistic: Change in Basophil Eliciting Dose.
Description
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.
Time Frame
630 days
Title
Mechanistic: Change in Peanut Allergen-specific IgG4
Description
The change in peanut allergen-specific IgG4 in actively treated participants by the end of maintenance between clinical outcome groups.
Time Frame
518 days
Title
Mechanistic: Significant Gene Expression Changes by Transcriptional Profiling of Regulatory and Effector T Cell Populations
Description
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.
Time Frame
630 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wayne G Shreffler, MD, PhD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
de-identified data exported from REDCap
IPD Sharing Time Frame
upon request within the year and without planned time limitation
Citations:
PubMed Identifier
34813505
Citation
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.
Results Reference
derived

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Tolerance Following Peanut Oral Immunotherapy

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