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Tolerance Following Peanut Oral Immunotherapy (PNOIT2)

6. juli 2021 oppdatert av: Wayne G. Shreffler, MD, PhD, Massachusetts General Hospital

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).

Studieoversikt

Status

Fullført

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

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.

Studietype

Intervensjonell

Registrering (Faktiske)

41

Fase

  • Fase 2
  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • Massachusetts
      • Boston, Massachusetts, Forente stater, 02114
        • Massachusetts General Hospital

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

7 år til 55 år (Barn, Voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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.

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Grunnvitenskap
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Trippel

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Aktiv komparator: Peanut Flour
Oral Immunotherapy with peanut flour.
Legemiddel: Peanut Flour
Peanut Flour
Placebo komparator: Oat Flour
Oral Immunotherapy with oat flour.
Legemiddel: Oat Flour
Oat Flour

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Tolerance, Partial Tolerance, or Treatment Failure
Tidsramme: Average 515 days from DBPCFC1 to DBPCFC3
  1. Tolerance: Ingestion of 4430 mg of peanut protein at DBPCFC3 without symptoms.
  2. Partial Tolerance: ED at DBPCFC3 <4430 mg but =>430 mg AND >10-fold more than at DBPCFC1.
  3. 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.
  4. Treatment Failure - withdrawal
Average 515 days from DBPCFC1 to DBPCFC3

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Clinical: Tolerance
Tidsramme: 630 days
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
Tidsramme: 518 days
- The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.
518 days
Clinical: Safety
Tidsramme: 630 days
- The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups.
630 days
Mechanistic: TCR Clonal Diversity
Tidsramme: 630 days

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.
Tidsramme: 518 days
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.
Tidsramme: 630 days
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
Tidsramme: 518 days
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
Tidsramme: 630 days

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

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Massachusetts General Hospital

Samarbeidspartnere

National Institute of Allergy and Infectious Diseases (NIAID)

Publikasjoner og nyttige lenker

Den som er ansvarlig for å legge inn informasjon om studien leverer frivillig disse publikasjonene. Disse kan handle om alt relatert til studiet.

Generelle publikasjoner

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. august 2013

Primær fullføring (Faktiske)

11. juli 2017

Studiet fullført (Faktiske)

11. juli 2017

Datoer for studieregistrering

Først innsendt

13. desember 2012

Først innsendt som oppfylte QC-kriteriene

14. desember 2012

Først lagt ut (Anslag)

17. desember 2012

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

28. juli 2021

Siste oppdatering sendt inn som oppfylte QC-kriteriene

6. juli 2021

Sist bekreftet

1. juli 2021

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 2012P002153
  • 5U19AI095261-02 (U.S. NIH-stipend/kontrakt)

Plan for individuelle deltakerdata (IPD)

Planlegger du å dele individuelle deltakerdata (IPD)?

Ja

IPD-planbeskrivelse

de-identified data exported from REDCap

IPD-delingstidsramme

upon request within the year and without planned time limitation

IPD-deling Støtteinformasjonstype

  • Studieprotokoll
  • Statistisk analyseplan (SAP)
  • Informert samtykkeskjema (ICF)
  • Analytisk kode

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

produkt produsert i og eksportert fra USA

Nei

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