Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 5U19AI095261-02 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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).
Clinical Objectives:
Mechanistic Objectives:
Exploratory Objectives:
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Peanut Flour | Active Comparator | Oral Immunotherapy with peanut flour. |
|
| Oat Flour | Placebo Comparator | Oral Immunotherapy with oat flour. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Peanut Flour | Drug | Peanut Flour |
| |
| Oat Flour |
| Measure | Description | Time Frame |
|---|---|---|
| Tolerance, Partial Tolerance, or Treatment Failure |
| Average 515 days from DBPCFC1 to DBPCFC3 |
| 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 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Wayne G Shreffler, MD, PhD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34813505 | Derived | 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. |
Not provided
Not provided
de-identified data exported from REDCap
upon request within the year and without planned time limitation
Not provided
Not provided
113 screened, 72 excluded (3 Lost to follow-up pre-randomization; 8 Re-screened following protocol change; 21 Screen Fail no objective symptoms on DBPCF1; 29 Screen Fail prior to DBPCFC; and 11 Voluntary withdrawal pre-randomization)
Participants recruited from a specialty clinic, college campus clinic, and community outreach (including advertisements on Boston MBTA) between May 2013 and January 2016. The first participant was enrolled in August 2013.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Peanut Flour | Participants will be randomly assigned by study statistician to treatment or placebo groups at a ratio of 3:1 following a double-blind placebo controlled food challenge, DBPCFC1, on 2 separate days. One challenge will consist of 5 doses of peanut in increasing amounts up to a total of 443 mg of peanut protein masked in vehicle food. The second day will consist of placebo material given similarly. Participants with an eliciting dose of 443mg or less will receive daily escalating dosages of peanut flour OIT in a blinded fashion, as described in the modified rush phase, until a daily dose of 4000 mg is reached. Following treatment, a 2nd challenge will occur DBPCFC2, identical to DBPCFC1, but with additional doses of 1000 mg and 3000 mg for a cumulative dose of 4443 mg peanut protein. After 12 weeks of complete peanut avoidance, participants will undergo a third challenge, DBPCFC3, which will follow a slightly different schedule of doses for a cumulative dose of 4430 mg peanut protein. |
| FG001 | Placebo (Oat) Flour | Participants in the placebo arm will follow the same protocol except they receive daily escalating dosages of placebo oat flour, and they will not participate in DBPCFC3. Following DBPCFC2, assignment will be unblinded and placebo participants will be offered open-label active treatment under a separate protocol. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Active | Participants will be randomly assigned by study statistician to treatment or placebo groups at a ratio of 3:1 following a double-blind placebo controlled food challenge, DBPCFC1, on 2 separate days. One challenge will consist of 5 doses of peanut in increasing amounts up to a total of 443 mg of peanut protein masked in vehicle food. The second day will consist of placebo material given similarly. Participants with an eliciting dose of 443mg or less will receive daily escalating dosages of peanut flour OIT in a blinded fashion, as described in the modified rush phase, until a daily dose of 4000 mg is reached. Following treatment, a 2nd challenge will occur DBPCFC2, identical to DBPCFC1, but with additional doses of 1000 mg and 3000 mg for a cumulative dose of 4443 mg peanut protein. After 12 weeks of complete peanut avoidance, participants will undergo a third challenge, DBPCFC3, which will follow a slightly different schedule of doses for a cumulative dose of 4430 mg peanut protein. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Tolerance, Partial Tolerance, or Treatment Failure |
| Posted | Count of Participants | Participants | Average 515 days from DBPCFC1 to DBPCFC3 |
|
August 2013 to January 2016 (2 years and 5 months)
Build up AEs, At home AEs, DBPCFC2 AEs
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Peanut Flour | Oral Immunotherapy with peanut flour. Peanut Flour: Peanut Flour |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal Ideation, unrelated | Psychiatric disorders | MedDRA 19.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaphylactic Reaction | Immune system disorders | MedDRA 19.0 | Systematic Assessment | Build up AEs; Moderate to severe AEs reported |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Wayne Shreffler | Massachusetts General Hospital | 617-726-6147 | WSHREFFLER@mgh.harvard.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 29, 2015 | Jul 11, 2018 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D021183 | Peanut Hypersensitivity |
| D006967 | Hypersensitivity |
| ID | Term |
|---|---|
| D000074924 | Nut and Peanut Hypersensitivity |
| D005512 | Food Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D007154 | Immune System Diseases |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Drug |
Oat Flour |
|
- 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 |
| Withdrawal by Subject |
|
| Did not complete per protocol |
|
| BG001 | Placebo | Participants in the placebo arm will follow the same protocol except they receive daily escalating dosages of placebo oat flour, and they will not participate in DBPCFC3. Following DBPCFC2, assignment will be unblinded and placebo participants will be offered open-label active treatment under a separate protocol. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Peanut-specific IgE | Mean | Standard Deviation | kU/L |
|
| OG001 | Placebo | Participants in the placebo arm will follow the same protocol except they receive daily escalating dosages of placebo oat flour, and they will not participate in DBPCFC3. Following DBPCFC2, assignment will be unblinded and placebo participants will be offered open-label active treatment under a separate protocol. |
|
|
| Secondary | 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) | Per protocol, subjects were unblinded after DBPCFC2 and those on placebo were not subjected to DBPCFC3 | Posted | Median | Full Range | mg | 630 days |
|
|
|
| Secondary | Clinical: Desensitization | - The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2. | 30 active and 11 placebo had baseline challenge (DBPCFC1); 20 active and 8 placebo had first post-treatment challenge (DBPCFC2). Change in median eliciting dose restricted to the 20 and 8 who competed DBPCFC2 (i.e., per protocol) | Posted | Median | Full Range | mg | 518 days |
|
|
|
| Secondary | Clinical: Safety | - The rate of reported adverse advents due to accidental ingestions in the active versus placebo groups. | Posted | Count of Participants | Participants | 630 days |
|
|
|
| Secondary | 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. | 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). | Posted | Mean | 95% Confidence Interval | percentage of clones | 630 days |
|
|
|
| Secondary | 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. | skin test quality was poor | Posted | 518 days |
|
|
| Secondary | 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. | basophil time points inadequate for analysis | Posted | 630 days |
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | mg/mL | 518 days |
|
|
|
| Secondary | 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. | Subjects as defined per protocol. All 5 placebo were 'treatment failure -- non-desensitized' and per protocol, none were eligible for avoidance or DBPCFC3. Total RNA from CD154+ and CD154-CD69- T cells was used for cDNA synthesis and amplification. Read depth of approximately 30 million per sample (Illumina HiSeq) and aligned to the hg19 human reference genome with the ensemble version 75 annotation. Differential expression analysis was performed using DESeq2 v 1.30.1 (R v 4.04). | Posted | Number | number of differentially expressed genes | 630 days |
|
|
|
| 0 |
| 30 |
| 1 |
| 30 |
| 30 |
| 30 |
| EG001 | Oat Flour | Oral Immunotherapy with oat flour. Oat Flour: Oat Flour | 0 | 11 | 0 | 11 | 11 | 11 |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | Build up AEs; Moderate to severe AEs reported |
|
| Nausea/Vomting | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | Build up AEs; Moderate to severe AEs reported |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment | At home AEs; Moderate to severe AEs reported |
|
| Anaphylactic Reaction | Immune system disorders | MedDRA 19.0 | Systematic Assessment | At home AEs; Moderate to severe AEs reported |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | At home AEs; Moderate to severe AEs reported |
|
| Nausea/Vomiting | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | At home AEs; Moderate to severe AEs reported |
|
| Asthma Exacerbation | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment | At home AEs; Moderate to severe AEs reported |
|
| Skin/oral pruritis | Immune system disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Angiodema | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Anaphylactic Reaction | Immune system disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Reflux | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Nausea/Vomiting | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Other | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
| Wheeze/SOB | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment | DBPCFC2 AEs; 20 subjects on peanut; 9 subjects on placebo |
|
Not provided
Not provided
| genes up at avoidance versus baseline |
|
| genes down at maintenance versus baseline |
|
| genes down at avoidance versus baseline |
|