Tolerance Following Peanut Oral Immunotherapy (PNOIT2)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Massachusetts General Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Wayne G. Shreffler MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01750879
First received: December 13, 2012
Last updated: April 29, 2014
Last verified: April 2014
  Purpose

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).


Condition Intervention Phase
Peanut Allergy
Drug: Peanut Flour
Drug: Oat Flour
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: Clinical Desensitization and Tolerance Following Peanut Oral Immunotherapy and Subsequent Allergen Avoidance

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • The change in the percentage of induced Treg cells (CD45RA- CD25++ FoxP3++ of CD4+ T cells) from baseline to the end of maintenance therapy. [ Time Frame: 518 days ] [ Designated as safety issue: No ]

    Clinical outcomes will be defined as follows:

    • Treatment Failure: Failure to achieve the minimum maintenance dose (600 mg) of peanut protein by 12 months, or an ED <1750 mg at DBPCFC2, or ED at DBPCFC3 <500 mg OR <10-fold more than at DBPCFC1.
    • Partial Tolerance: ED at DBPCFC3 <6000 mg but >500 mg AND >10-fold more than at DBPCFC1.
    • Tolerance: Ingestion of 6000 mg of peanut protein at DBPCFC3 without symptoms.


Secondary Outcome Measures:
  • Clinical: Tolerance [ Time Frame: 630 days ] [ Designated as safety issue: No ]
    The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC3.

  • Clinical: Desensitization [ Time Frame: 518 days ] [ Designated as safety issue: No ]
    • The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.
    • The frequency of accidental ingestion reactions in active versus control treatment.

  • Clinical: Safety [ Time Frame: 630 days ] [ Designated as safety issue: Yes ]
    • Anaphylaxis requiring more than 1 administration of epinephrine; or hospitalization.
    • Death as a result of the investigational product.
    • The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups.

  • Mechanistic: TCR clonal diversity [ Time Frame: 630 days ] [ Designated as safety issue: No ]
    - 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.

  • Mechanistic: Change eliciting dose of end-point dilution. [ Time Frame: 518 days ] [ Designated as safety issue: No ]
    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. [ Time Frame: 630 days ] [ Designated as safety issue: No ]
    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 [ Time Frame: 518 days ] [ Designated as safety issue: No ]
    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 participants [ Time Frame: 630 days ] [ Designated as safety issue: No ]
    Statistically significant gene expression changes by transcriptional profiling of regulatory and effector T cell participants before and after OIT between clinical outcome groups.


Estimated Enrollment: 40
Study Start Date: May 2013
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.
  Eligibility

Ages Eligible for Study:   16 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 16-55 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 <50 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01750879

Contacts
Contact: Lauren E Tracy, BA 617-643-2262 letracy@mgh.harvard.edu
Contact: Christine K Elliott, BA 617-726-6376 ckelliott@mgh.harvard.edu

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Lauren E Tracy, BA    617-643-2262    letracy@mgh.harvard.edu   
Principal Investigator: Wayne G Shreffler, MD,PhD         
Sponsors and Collaborators
Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Wayne G. Shreffler MD, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01750879     History of Changes
Other Study ID Numbers: 2012P002153, 5U19AI095261-02
Study First Received: December 13, 2012
Last Updated: April 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
peanut
allergy
food
immunotherapy
tolerance
desensitization

Additional relevant MeSH terms:
Hypersensitivity
Peanut Hypersensitivity
Immune System Diseases
Food Hypersensitivity
Hypersensitivity, Immediate

ClinicalTrials.gov processed this record on July 29, 2014