Clinical Desensitization and Tolerance Following Peanut Oral Immunotherapy and Subsequent Allergen Avoidance
Phase: PHASE1
Conditions: Peanut Allergy
Sponsor: Massachusetts General Hospital

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Protocol 2012P002153
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ASTHMA AND ALLERGIC DISEASES COOPERATIVE RESEARCH CENTER
AADCRC IDENTIFYING NUMBER
AADCRC MGH–004
IRB PROTOCOL IDENTIFYING NUMBER
2012P002153
PROTOCOL TITLE
Clinical Desensitization and Tolerance Following Peanut
Oral Immunotherapy and Subsequent Allergen Avoidance
VERSION 8.0 / June 29, 2015
IND # 14478 (Peanut Flour)
IND Sponsor: Wayne G Shrefﬂer, MD, PhD
PRINCIPAL INVESTIGATOR
CO-INVESTIGATOR(S)
Wayne G Shrefﬂer, MD, PhD
Daniel Hamilos, MD
BIOSTATISTICIAN
INDEPENDENT SAFETY MONITOR
Agustin Calatroni, PhD
Aleena Banerji, MD
Conﬁdentiality Statement
The information contained within this document is not to be disclosed in any way without the prior permission of the Principal Investigator and the
Division of Allergy, Immunology and Transplantation of the National Institute of Allergy and Infectious Diseases.
!
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INVESTIGATOR SIGNATURE PAGE
Protocol
Version/Date:
2012P002153
8.0 / June 29, 2015
IND Number
Principal Investigator:
14478
Wayne G Shrefﬂer, MD, PhD
Short Title: Tolerance Following Peanut Oral Immunotherapy
IND Sponsor:
Wayne G Shrefﬂer, MD, PhD
INSTRUCTIONS: The Principal Investigator will print, sign, and date at the indicated location below. A copy
should be kept in the investigator’s records and the original signature page sent to the NIAID. After signature,
please return the original of this form by surface mail to:
Ernestine Smartt, RN
NIAID, NIH
6610 Rockledge Drive, Room 6502A
Bethesda, MD 20892-6601
I conﬁrm that I have read the above protocol in the latest version. I understand it, and I will work according
to the principles of good clinical practice (GCP) as described in the US Code of Federal Regulations (CFR)
45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the International Conference on Harmonization
(ICH) document Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance dated April
1996. Further, I will conduct the study in keeping with local legal and regulatory requirements.
As the principal investigator, I agree to carry out the study by the criteria written in the protocol and
understand that no changes can be made to this protocol without written permission of the NIAID.
Wayne G Shrefﬂer, MD, PhD
Principal Investigator (Print)
Principal Investigator (Signature)
Date
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SYNOPSIS
Title
Clinical
Desensitization
and
Tolerance
Following
Peanut
Oral
Immunotherapy and Subsequent Allergen Avoidance
Short Title
Tolerance Following Peanut Oral Immunotherapy
Rationale
This protocol is designed to identify participants who have persistent
peanut allergy. By speciﬁcally targeting participants who are at the highest
risk for life-long peanut sensitivity, we anticipate that we might maximize
the beneﬁts of desensitization and/or clinical tolerance induction.
By
including in our protocol design a post-therapy challenge after a signiﬁcant
allergen avoidance period, we will better distinguish true tolerance from
desensitization and some of the immune changes associated with varying
clinical outcomes. A blinded placebo control group is included, to control
for possible changes in clinical sensitivity over time independent of therapy.
The selection of older adolescents and adults will also allow us to better
study immunological changes using assays that require blood volumes that
would not be feasible to obtain in a younger population.
The inclusion
of a post treatment avoidance period of 12 weeks is intended to address
whether lasting immunological changes have been induced.
This is
comparable to published trials and long enough to suggest long-lived
immunological memory without being so long so as to be impractical for
study recruitment and retention.
The primary goal of the study is to evaluate immunotherapy-induced
immune responses for their association to clinical outcomes to better
understand mechanisms of IT and identify potential biomarkers of
IT-induced tolerance.
Clinical Phase
I/II
Mechanistic Study
4 Yes
No
IND Sponsor
Wayne G Shrefﬂer, MD, PhD
Principal Investigator
Wayne G Shrefﬂer, MD, PhD
Participating Site(s)
Massachusetts General Hospital
Accrual Objective
40
Study Objective
To determine whether 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.
Study Design
Single-center, double blind, placebo controlled, randomized trial of peanut
OIT in adolescents and adults (7 to 55 years)
Study Duration
Approximately 74 weeks
Primary Endpoint
The difference in the proportion of induced Treg cells (CD45RA- CD25++
FoxP3++ of CD4+ T cells) from baseline to the end of maintenance therapy.
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SYNOPSIS CONTINUED
Secondary Endpoints (Clinical)
Tolerance:
• The change in median eliciting dose (ED) from DBPCFC1 to
DBPCFC3.
Desensitization:
• The change in median eliciting dose (ED) from DBPCFC1 to
DBPCFC2.
• The frequency of accidental ingestion reactions in active versus
control treatment.
Safety:
• 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.
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SYNOPSIS CONTINUED
Secondary Endpoints (Mechanistic)
• The change in the TCR clonal diversity of in vitro allergen-expanded
Treg cells and induced Treg cells measured by TCRβ 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.
• The change in ED of end-point dilution skin testing between actively
treated and placebo treated participants following maintenance
therapy.
• The change in ED of end-point dilution skin testing among actively
treated participants following maintenance therapy and avoidance
between clinical outcome groups.
• 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.
• The change in peanut allergen-speciﬁc IgG4 in actively treated
participants by the end of maintenance between clinical outcome
groups.
• The change in Ara h 2 speciﬁc surface and secreting B cells between
baseline (measured at 12 weeks of treatment) and the end of
maintenance.
• Statistically signiﬁcant gene expression changes by transcriptional
proﬁling of regulatory and effector T cell participants before and after
OIT between clinical outcome groups.
Inclusion Criteria
• Diagnosis of peanut allergy by medical history
• Evidence of peanut-speciﬁc IgE by either: positive skin prick test to
peanut (reaction wheal at least 5 mm larger than saline control) or
serum peanut-speciﬁc IgE ≥5 kU/L at screening visit.
• Ara h 2 speciﬁc IgE >0.35 kU/L at screening visit.
• Who are willing to sign informed consent or whose parent or legal
guardian is willing to sign the consent form (age appropriate)
• Who are willing to sign the assent form, if age appropriate
• Males and females of all ethnic/racial groups aged 7-55 years old who
are otherwise healthy.
• React to 443 mg of peanut protein during DBPCFC1
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SYNOPSIS CONTINUED
Exclusion Criteria
• History of severe anaphylaxis
• Severe or Moderate asthma
• Poorly controlled asthma
• Diagnosis
of
other
severe
or
complicating
medical
problems,
including autoimmune or chronic immune inﬂammatory conditions or
gastrointestinal inﬂammatory conditions
• 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
• Use within the past 6 months of other systemic immunomodulatory
treatments
• Hematocrit <0.36 for adult females or <0.38 for adult males
• Weight <23 kg
Investigational Product / Intervention
Active peanut ﬂour vs. placebo oat ﬂour
Study Procedures
OIT, DBPCFCs, physical examination, pregnancy testing, phlebotomy,
PFTs
Statistical Considerations
n=40, 3:1 active to placebo; Per protocol analysis of the Treg proportion
by clinical outcome for the anticipated 22 subjects completing DBPCFC3;
effect size of 1.5 for primary outcome [? ]; 27% (n=8) combined Partial
Tolerance / Tolerance versus Treatment Failure (n=14).
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Contents
1
BACKGROUND AND RATIONALE
12
1.1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
1.2
Rationale for Selection of Study Population
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
1.3
Investigational Product(s) / Intervention(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
1.4
Rationale for Selection of Investigational Product(s) / Intervention(s) and Regimen . . . . . . . . .
13
1.5
Preclinical and Clinical Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
1.5.1
Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
1.5.2
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
1.6
Risks
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
1.6.1
Risks of Investigational Product(s) / Intervention(s) . . . . . . . . . . . . . . . . . . . . . . .
14
1.6.2
Risk of Study Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
1.6.2.1
Double-blind placebo controlled food challenge (DBPCFC) . . . . . . . . . . . . .
14
1.6.2.2
Desensitization Procedure
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
1.6.2.3
Allergy Prick Skin Testing
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
1.6.2.4
Blood Draw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
1.6.3
Risk of Concomitant Medications, Prophylactic Medications and Rescue Medications
. . .
15
1.7
Beneﬁts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
1.7.1
Beneﬁts of Investigational Product(s) / Intervention(s)
. . . . . . . . . . . . . . . . . . . . .
16
1.7.2
Beneﬁts of Study Procedure(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
2
OBJECTIVES
16
2.1
Primary Objective(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
2.2
Secondary Objective(s)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
2.2.1
Clinical: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
2.2.2
Mechanistic:
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
2.2.3
Exploratory: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
3
STUDY DESIGN
17
3.1
Study Endpoints
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
3.1.1
Primary Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
3.1.2
Secondary Endpoint(s)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
3.2
Study Completion
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4
SELECTION AND WITHDRAWAL OF PARTICIPANTS
19
4.1
Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.2
Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.3
Participant Withdrawal Criteria
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
5
INVESTIGATIONAL PRODUCT(S) / INTERVENTION MATERIAL(S), OTHER STUDY PRODUCTS
21
5.1
Investigational Product(s) / Intervention(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5.2
Formulation, Packaging, Storage and Labeling
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5.3
Preparation, Administration, and Dosage
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5.4
Accountability of Investigational Product(s) / Intervention(s) . . . . . . . . . . . . . . . . . . . . . .
21
5.5
Assessment of Compliance with Investigational Product(s) / Intervention Material(s)
. . . . . . . .
22
5.6
Modiﬁcation or Discontinuation of Investigational Product(s) / Intervention Material(s) . . . . . . . .
22
5.6.1
Modiﬁcation of Investigational Product(s) / Intervention(s) . . . . . . . . . . . . . . . . . . .
22
5.6.2
Premature Discontinuation of Investigational Product(s) / Intervention(s) . . . . . . . . . . .
22
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6
OTHER MEDICATIONS
23
6.1
Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.2
Prophylactic Medications
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.3
Rescue Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.4
Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
7
STUDY VISITS AND PROCEDURES
23
7.1
Enrollment and Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
7.2
Screening Visit (Day −30 to −7)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
7.3
Baseline Visit (Day 0)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
7.4
Main Study Visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
7.4.1
Double-Blind Placebo-Controlled Food Challenge 1 (Day 28) . . . . . . . . . . . . . . . . .
25
7.4.2
Modiﬁed Rush Visit (Day 42)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
7.4.3
Build Up Visits (Days 43−350) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
7.4.4
Maintenance Visits (Days 350−434) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
7.4.5
Double-Blind Placebo-Controlled Food Challenge 2 (Day 434)
. . . . . . . . . . . . . . . .
26
7.4.6
Avoidance Visit (Day 434−518) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
7.4.7
Double-Blind Placebo-Controlled Food Challenge 3 (Day 518)
. . . . . . . . . . . . . . . .
26
7.5
Open Label Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
7.6
Visit Windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
7.7
Study Procedures
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
7.7.1
Double-Blind Placebo-Controlled Food Challenge
. . . . . . . . . . . . . . . . . . . . . . .
27
7.7.2
Immunotherapy Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
7.7.2.1
Modiﬁed Rush . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
7.7.2.2
Build Up
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
7.7.2.3
Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
7.7.3
Pulmonary Function Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
30
7.7.4
Titration Skin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
7.7.5
Symptom Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
7.7.6
Phlebotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
7.7.7
Stool Collection (Optional) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
7.7.8
Physical Examination
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.7.9
Urine Pregnancy Testing
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.8
Study Arm Assignment Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.8.1
Blinding and Randomization
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.8.2
Securing Blinding and Randomization Information
. . . . . . . . . . . . . . . . . . . . . . .
32
7.8.3
Requirements for Unblinding
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
7.8.4
Documenting an Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
8
SAFETY PROCEDURES
33
8.1
Stopping Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
8.1.1
Study Stopping Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
8.1.2
Individual Stopping Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
8.1.3
Early Discontinuation of Investigational Product(s) / Intervention(s) with continued study
participation / follow-up
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.1.3.1
Unscheduled Termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.1.4
Follow-up after early study termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.1.5
Participant Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
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8.2
Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.2.1
Deﬁnitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.2.1.1
Adverse Events
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34
8.2.1.2
Suspected Adverse Reaction and Adverse Reaction . . . . . . . . . . . . . . . . .
35
8.2.1.3
Adverse Events Associated with Study Procedures
. . . . . . . . . . . . . . . . .
35
8.2.1.4
Serious Adverse Event (SAE)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
8.2.1.5
Unexpected Adverse Event . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
8.2.1.6
Independent Safety Monitor
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
8.2.2
Collecting, Recording and Managing Adverse Events
. . . . . . . . . . . . . . . . . . . . .
36
8.2.2.1
Identifying Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
8.2.2.2
Recording AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
8.2.2.3
Recording SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
8.2.2.4
Managing Adverse Events
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
8.2.3
Grading and Attribution
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.2.3.1
Grading criteria
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
38
8.2.3.2
Deﬁnition of Attribution
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
8.2.4
SAE Reporting Criteria and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
8.2.4.1
Notifying the NIAID Medical Ofﬁcer
. . . . . . . . . . . . . . . . . . . . . . . . . .
40
8.2.4.2
Unexpected, Non-Serious Adverse Events
. . . . . . . . . . . . . . . . . . . . . .
41
8.2.4.3
Notifying the FDA
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
8.2.4.4
Notifying the Data and Independent Safety Monitor (ISM) . . . . . . . . . . . . . .
42
8.2.4.5
Notifying the Institutional Review Board . . . . . . . . . . . . . . . . . . . . . . . .
42
8.2.4.6
Notifying the Clinical Sites
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
8.2.4.7
Reporting Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
8.2.5
Non Serious Adverse Events (NSAES) Reporting
. . . . . . . . . . . . . . . . . . . . . . .
42
8.2.5.1
Notifying the Independent Safety Monitor . . . . . . . . . . . . . . . . . . . . . . .
42
8.2.5.2
Notifying the Institutional Review Board . . . . . . . . . . . . . . . . . . . . . . . .
42
8.3
Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
8.3.1
Protocol Deviation Deﬁnitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
8.3.1.1
Protocol Deviation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
8.3.1.2
Major Protocol Deviation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
8.3.1.3
Non-Major Protocol Deviation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
8.3.2
Reporting Protocol Deviations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
9
SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN
44
9.1
Sample Size and Power Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
9.2
Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
9.2.1
General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
9.2.2
Study Participant Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
9.2.3
Study Participant Baseline Characteristics and Demographics . . . . . . . . . . . . . . . . .
45
9.2.4
Study Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
9.2.4.1
Primary Endpoint
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
9.2.5
Study Completion
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
9.3
Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
9.4
Deviations from Statistical Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
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10 IDENTIFICATION AND ACCESS TO SOURCE DATA
46
10.1 Identifying Source Data
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
10.2 Updating Source Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
10.3 Permitting Access to Source Data
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
11 QUALITY CONTROL AND QUALITY ASSURANCE
47
12 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE
47
12.1 Statement of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
12.2 Informed Consent and Assent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
12.3 Privacy and Conﬁdentiality
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
13 PUBLICATIONS
48
14 REFERENCES
49
15
50
15.1 Study Schematic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
15.2 Modiﬁed Rush Dosing Schedule
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
15.3 Build Up Dosing Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
15.4 Treatment Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
15.5 Study Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
15.6 Power Calculation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
16 APPENDICES
56
16.1 Schedule of Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
16.2 Symptom Diary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
16.3 Serious Adverse Event Case Report Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
16.4 Protocol Deviation Report Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
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Glossary of Abbreviations / Deﬁnitions
AADCRC
Asthma and Allergic Diseases Cooperative Research Center
AE
Adverse Event
AR
Adverse Reaction
CFR
Code of Federal Regulations
CRA
Clinical Research Associate
CRC
Clinical Research Center
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DAIT
Division of Allergy, Immunology, and Transplantation
DBPCFC
Double-blind, placebo-controlled food challenge
DSMB
Data Safety Monitoring Board
ED
Eliciting dose
EoE
Eosinophilic esophagitis
Fc✏RI
High afﬁnity receptor for IgE
cGCP
Current Good Clinical Practice
HCG
Human Chorionic Gonadotropin
ICH
International Conference on Harmonization
ISM
Independent Safety Monitor
IT
Immunotherapy
IND
Investigational New Drug
IRB
Institutional Review Board
NCI
National Cancer Institute
NIAID
National Institute of Allergy and Infectious Diseases
OIT
Oral immunotherapy
PFT
Pulmonary Function Test
PI
Principal Investigator
PN
Peanut
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAR
Serious Adverse Reaction
SMC
Safety Monitoring Committee
SPT
Endpoint titration skin prick testing
SUSAR
Serious and Unexpected Suspected Adverse Reaction
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1
BACKGROUND AND RATIONALE
1.1
Background
Avoidance of allergenic foods and ready access to self-injectable epinephrine during an incident are the standard
of care for food allergy. Unfortunately, for a ubiquitous food such as peanut, the possibility of an inadvertent
ingestion is great. Symptoms occurring because of these accidental exposures can vary from mild local reactions
to life-threatening anaphylaxis.
Due to the persistence of allergic reactions and the lack of effective treatment, allergen-speciﬁc immunotherapy
(IT) is being actively investigated as a treatment option for people with peanut allergy. Effective peanut oral
immunotherapy (OIT) would beneﬁt participants by inducing a loss of clinical sensitivity to peanut, particularly if
such a change was long-lasting. An understanding of the immune mechanisms of peanut-speciﬁc OIT is vital to
ensure the eventual, successful treatment of all peanut-allergic participants.
In addition, several groups have recently reported on the use of oral or sublingual IT for other food allergies,
including primarily milk, peanut, and egg [? ? ? ? ? ? ]. The preliminary evidence of these studies supports
efﬁcacy with respect to clinical desensitization. There remains, however, a great deal to be learned from additional
trials. In particular, existing data do not adequately address the question of tolerance and few studies have applied
sophisticated laboratory techniques to investigate mechanisms.
1.2
Rationale for Selection of Study Population
This protocol is designed to identify participants who have persistent peanut allergy. By speciﬁcally targeting
participants who are at the highest risk for life-long peanut sensitivity, we anticipate that we might maximize the
beneﬁts of desensitization and/or clinical tolerance induction. By including in our protocol design a post-therapy
challenge after a signiﬁcant allergen avoidance period, we will better distinguish true tolerance from desensitization
and some of the immune changes associated with varying clinical outcomes. A blinded placebo control group is
included, to control for possible changes in clinical sensitivity over time independent of therapy. The selection of
older adolescents and adults will also allow us to better study immunological changes using assays that require
blood volumes that would not be feasible to obtain in a younger population.
1.3
Investigational Product(s) / Intervention(s)
The product that will be used in the proposed clinic trial is partially defatted peanut ﬂour. Peanut is currently
licensed as a food product in the United States. The peanut ﬂour proposed for use in this study will be purchased
in bulk from the Golden Peanut Company, located in Blakely, Georgia. The company states that the product is
manufactured under GMP for food products. No other allergens are processed at this facility. This peanut ﬂour is
not stored with any other allergens. The amount of peanut ingested orally will change as the study progresses
and the doses referred to throughout the protocol will be in terms of mg of protein content.
The placebo will be toasted oat ﬂour. The oat ﬂour proposed for use in this study will be purchased in bulk
from the Montana Gluten Free Processors, located in Belgrade, Montana. The company states that the drug is
manufactured under GMP for food products. No other allergens such as peanuts, tree nuts, wheat, corn, and soy
are processed at this facility. This oat ﬂour is not stored with any other allergens. The amount of oat ﬂour ingested
orally will change as the study progresses and will be matched to the equivalent dose of peanut ﬂour by weight.
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1.4
Rationale for Selection of Investigational Product(s) / Intervention(s) and Regimen
This product has been used in other trials and has been shown to contain the major peanut allergens. Toasted
oat ﬂour was selected for the placebo because it is the most similar to peanut ﬂour in appearance and texture
and is free from major allergens.
The inclusion of a post treatment avoidance period of 12 weeks is intended to address whether lasting immunological
changes have been induced.
This is comparable to published trials and long enough to suggest long-lived
immunological tolerance without being so long so as to be impractical for study recruitment and retention.
We will measure the following mechanistic outcomes for each of the three time points (baseline, on maintenance
therapy and following avoidance):
• The frequency of each of the CD4 T cell subsets deﬁned by cell surface markers (e.g., CD45RA, CD25,
etc).
• The frequency of each of four populations of CD4 T cells: resting T effector, activated T effector, native Treg
and induced Treg.
• The frequency of IL-13, IFN-γ and IL-10 expressing populations within the activated and resting Teff subsets.
• The frequency of antigen-expanded Treg as deﬁned by a methodology such as CFSE dilution and FoxP3
intracellular staining or equivalent and of cytokine expressing populations as demonstrated by intracellular
cytokine staining or equivalent methodology.
• Global (e.g., Illumina, Affymetrix, etc) or targeted (e.g., nanostring, qPCR, etc) transcriptional gene expression
patterns from activated and resting Treg and Teff subsets from participants divided evenly between the
following groups: successful tolerance, partial tolerance, failed tolerance, placebo arm;
• Global (e.g., Illumina, Affymetrix, etc) or targeted (e.g., nanostring, qPCR, etc) transcriptional gene expression
patterns from antigen-expanded or otherwise enriched T cells from 3 non-overlapping pools of subject
samples from each of the same four clinical groups: successful tolerance, partial tolerance, failed tolerance,
placebo arm;
• TCR parallel sequencing-based analysis of T cell repertoire of effector and regulatory subsets deﬁned by
expression of key phenotypic markers (e.g. CD45RA+CD25+FoxP3+; CD45RA-CD25+++FoxP3+; CD45RA-CD25+
CD45RA-CD25+/-IL-13+; CD45RA-CD25+/-IL-10+; CD45RA-CD25+/- IFN-?+ by ﬂow cytometry or other
methodology).
• T cell repertoire of in vitro expanded or enriched (e.g. by tetramer binding) T cell populations.
These studies will be carried out by ex vivo sorting of 100-300 million PBMC and in vitro expansion or enrichment
starting with 60-100 million PBMC. In large part, the cell number requirement is driven by the low frequency of
induced T reg and of antigen-speciﬁc CD4 T cells.
1.5
Preclinical and Clinical Experience
1.5.1
Preclinical Studies
The precise lineage of FoxP3-expressing regulatory (Treg) cells in humans is still being deﬁned and debated [?
]. In murine studies, numerous studies support the presence of both thymically-derived ‘natural’ Treg (nTreg) and
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inducible Treg (iTreg). A major source of iTreg appears to be under the inﬂuence of retinoid acid and TGF-β in
the gut-associated lymphoid tissue (GALT) [? ]. iTreg versus nTreg have a phenotype consistent with recent TCR
activation (CD45RA- CD62L- CD95+ CD31- CTLA4+). Miyara, et al. deﬁne two suppressive CD25++ FoxP3+
populations, which they term activated or resting and deﬁne using phenotypic markers that we plan to use in this
project, including CD45RO/RA, CD62L, Ki-67, and CD31.
1.5.2
Clinical Studies
Mucosal immunotherapy (oral or sublingual) has been studied for the treatment of allergic rhinitis and more
recently for food allergy [? ? ? ? ? ? ? ]. The majority of participants (85%) have been able to tolerate and
successfully complete OIT treatment regimens with mild side effects that can be controlled by the occasional use
of antihistamines.
There have been only two studies of carefully controlled peanut OIT with subjects characterized by double-blind
oral food challenge (total of 62 subjects involved) [? ? ? ? ]. Initial target maintenance doses were comparable
(300-500 mg protein) and drop out due to adverse reactions was low (10-18%). Those subjects who reached
maintenance achieved signiﬁcant increases in the threshold dose of peanut required to provoke symptoms.
Median threshold doses were >1000 mg protein after therapy (approximately 2 to 4 peanut kernels), well above
the average estimated amount of exposure during an accidental ingestion. Only the study by Blumchen, et al.
attempted to determine whether increased tolerance versus desensitization was achieved by holding all peanut
exposure for two weeks prior to reassessing the threshold dose by repeat oral food challenge [? ].
1.6
Risks
1.6.1
Risks of Investigational Product(s) / Intervention(s)
In previous studies of peanut oral immunotherapy, mild to moderate side effects of dose increases (done at study
visits) have included: lung symptoms (e.g., cough, increased use of albuterol for individuals with asthma), GI tract
symptoms (nausea, vomiting, diarrhea), skin symptoms (hives, itchiness) and nose symptoms (e.g. stufﬁness)
More rarely, similar side effects have also occurred during doses taken at home, especially when the child had
an intercurrent illness (e.g., a cold), exposure to another allergen (e.g., during pollen season for those who
have seasonal allergies), in association with exercise or when taken on an empty stomach [? ? ]. Menses
together with exercise has also been reported in one case as a potential co-factor for reactions to OIT [? ].
Additional rare risks of OIT and food challenges are those of anaphylaxis and include respiratory obstruction
(e.g., wheezing, coughing, and swelling of the voice box) and cardiovascular problems such as a drop in blood
pressure or cardiovascular collapse. Most OIT studies to date have targeted a younger patient population. A
2011 study [? ] of children aged 3 to 18 noted that peanut allergic patients over 10 years of age reacted at
lower eliciting doses than those in the youngest tertile (< 5.5 years). They did not attempt to report on reaction
severity. The median eliciting dose for the oldest age group was approximately 45 mg of peanut protein with an
interquartile range of 4.5 to 200 mg peanut protein. In a study of the efﬁcacy of anti-IgE for the treatment of
adolescents and adults (13−59 years) with peanut allergy, the mean pre-treatment eliciting dose was 330 mg of
peanut ﬂour (range 1 - 2000 mg) [? ].
1.6.2
Risk of Study Procedures
1.6.2.1
Double-blind placebo controlled food challenge (DBPCFC)
Possible adverse events during DBPCFCs
include: GI symptoms (vomiting, diarrhea or abdominal pain), respiratory symptoms (wheezing, coughing, laryngeal
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edema, or hoarseness) or skin symptoms (hives, angioedema or pruritus). A severe adverse event, systemic
anaphylaxis involving the above symptoms plus hypotension, circulatory collapse, upper airway (laryngeal) blockade
and lower airway blockade (asthma) is also a potential risk. Risk of reaction is minimized by administering doses
in a graded fashion, stopping at the ﬁrst sign of objective symptoms, and treating reactions promptly.
1.6.2.2
Desensitization Procedure
Possible reactions during the desensitization procedure may include adverse
events: GI symptoms (vomiting, diarrhea or abdominal pain), respiratory symptoms (wheezing, coughing, laryngeal
edema, or hoarseness) or skin symptoms (hives, angioedema or pruritus). Systemic anaphylaxis involving the
above symptoms plus hypotension, circulatory collapse, upper airway (laryngeal) blockade and lower airway
blockade (asthma) is also a potential risk. Reactions during desensitization following similar procedures in other
studies involving hundreds of subjects to date have been mild. At home doses have very rarely been associated
with serious adverse events (e.g., autoinjector epinephrine use) and no AEs have been reported to result in
hospitalization or long term impairment to date. Subjects may also develop new or worsening atopic dermatitis
(AD) or eosinophilic esophagitis (EoE) that is reversible with cessation of OIT.
1.6.2.3
Allergy Prick Skin Testing
Possible reactions during an allergy prick skin testing procedure may
include itchy skin rash or hives, mild fever, fever symptoms, asthma, and lower blood pressure. There is also a
very low risk of a severe adverse event, systemic anaphylaxis, involving the above symptoms plus hypotension,
circulatory collapse, upper airway (laryngeal) blockade and lower airway blockade (asthma). All of these are
treated with topical steroids, with inhaled albuterol, or, if necessary, with injections of epinephrine or other
anti-allergic drugs.
1.6.2.4
Blood Draw
May aggravate a pre-existing anemic condition but this risk is negligible since the volume
of blood to be drawn at each visit will be at most 3 ml/kg in pediatric participants and 1 unit of blood in adult
participants. Blood draws will occur four times spread out over the 90 week study (See Section 7 for speciﬁc
schedule). Other risks are those related to any needle puncture, including slight bruising, local infection, or the
possibility of the participant fainting. The discomfort involved is minimal.
1.6.3
Risk of Concomitant Medications, Prophylactic Medications and Rescue Medications
The following are the risks associated with concomitant and rescue medications:
• Albuterol: dysrhythmia, hypokalemia, and hypersensitivity reactions.
• Epinephrine: dysrhythmia, hypokalemia, and hypersensitivity reactions.
• Diphenhydramine: urinary retention, blurred vision, delirium, and hypersensitivity reactions.
• Hydroxyzine: urinary retention, blurred vision, delirium, and hypersensitivity reactions.
• Ranitidine: urinary retention, blurred vision, dysrhythmia, hepatitis, pancreatitis, and hypersensitivity reactions.
• Corticosteroid: hyperglycemia/glycosuria, ﬂuid retention, hypokalemia, hypernatremia, dysrhythmia, anxiety,
delirium or other mental status changes, and hypersensitivity reactions.
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1.7
Beneﬁts
1.7.1
Beneﬁts of Investigational Product(s) / Intervention(s)
The risks associated with participation in this study are minimal in relation to the potential beneﬁts derived by
both the subject and society. Subjects may derive two major beneﬁts from the study. First, subjects may be
desensitized to peanut and have a reduced risk of anaphylaxis from an accidental ingestion of peanut. Second,
subjects may become tolerant and no longer need to avoid peanut. However, there may be no direct beneﬁt to
subjects by participating in the study.
Potential beneﬁts to society include a better understanding of food hypersensitivity reactions, better methods to
treat food allergic individuals, and an improved understanding of food allergens involved in the human immune
response.
1.7.2
Beneﬁts of Study Procedure(s)
NA
2
OBJECTIVES
2.1
Primary Objective(s)
To determine whether 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.
We 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).
2.2
Secondary Objective(s)
2.2.1
Clinical:
• To evaluate whether PN OIT induces increased tolerance, deﬁned as a statistically signiﬁcant increase in
the median eliciting dose (ED) from DBPCFC1 to DBPCFC3.
• To evaluate whether PN OIT induces clinical desensitization, deﬁned as 1) a median 10-fold or greater
increase in ED from DBPCFC1 to DBPCFC2; 2) a statistically signiﬁcant higher median ED at DBPCFC2
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.
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2.2.2
Mechanistic:
• 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 maintenance.
• To determine whether either mast cell or basophil suppression at the end of maintenance therapy is
signiﬁcantly associated with clinical outcomes following avoidance.
2.2.3
Exploratory:
• 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.
• To determine whether microbial dysbiosis is associated with the development of desensitization, oral tolerance,
or persistent gastrointestinal adverse events while on oral immunotherapy.
3
STUDY DESIGN
This is a phase I/II double-blind placebo-controlled interventional study of peanut allergen oral immunotherapy
(OIT) for adolescents and adults (7 to 55 years of age) with IgE-mediated allergy to peanut (evidence of sensitization
and demonstrated clinical reactivity). The major objective of this study is to provide additional safety and mechanistic
data on OIT for people with IgE-mediated peanut allergy.
There will be 3:1 active to placebo randomization. The treatment substance is peanut ﬂour. The placebo is
roasted oat ﬂour. An schematic of the design is presented in Figure 15.1. See Appendix 16.1 for schedule of
study events.
Clinical assessments will be made by double-blind placebo-controlled food challenge at baseline (DBPCFC1),
after 12 weeks of maintenance therapy (DBPCFC2) and then after an additional 12 weeks off therapy while
strictly avoiding dietary peanut protein (DBPCFC3). Participants who do not react at ≥443 mg of peanut protein
(cumulative) during DBPCFC1 will be excluded from the study.
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3.1
Study Endpoints
3.1.1
Primary Endpoint(s)
The difference in the proportion of induced Treg cells (CD45RA- CD25++ FoxP3++ of CD4+ T cells) from baseline
to the end of maintenance therapy.
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 <1443 mg at DBPCFC2, or ED at DBPCFC3 <443 mg OR <10-fold more than at
DBPCFC1.
• Partial Tolerance: ED at DBPCFC3 <4430 mg but ≥430 mg AND >10-fold more than at DBPCFC1.
• Tolerance: Ingestion of 4430 mg of peanut protein at DBPCFC3 without symptoms.
3.1.2
Secondary Endpoint(s)
Secondary endpoints are:
Clinical:
• Tolerance:
– The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC3.
• Desensitization:
– The change in median eliciting dose (ED) from DBPCFC1 to DBPCFC2.
– The frequency of accidental ingestion reactions in active versus control treatment.
• Safety:
– 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:
• The change in the TCR clonal diversity of in vitro allergen-expanded Treg cells and induced Treg cells
measured by TCRβ 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.
• The change in ED of end-point dilution skin testing between actively treated and placebo treated participants
following maintenance therapy.
• The change in ED of end-point dilution skin testing among actively treated participants following maintenance
therapy and avoidance between clinical outcome groups.
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• 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.
• The change in peanut allergen-speciﬁc IgG4 in actively treated participants by the end of maintenance
between clinical outcome groups.
• The change in Ara h 2 speciﬁc surface and secreting B cells between baseline (measured after 12 weeks
of treatment) and the end of maintenance.
• Statistically signiﬁcant gene expression changes by transcriptional proﬁling of regulatory and effector T cell
participants before and after OIT between clinical outcome groups.
3.2
Study Completion
This study will be considered “completed” when the primary and secondary objectives have been met. This
includes the analysis of all the data required to meet the chosen objectives.
After the study is completed, the Principal Investigator or Data Center will compile a ﬁnal study report as per ICH
E6 and 21CFR312. The study report will be submitted to the local IRB, NIAID, ISM and the FDA.
4
SELECTION AND WITHDRAWAL OF PARTICIPANTS
4.1
Inclusion Criteria
Individuals who meet all of the following criteria are eligible for enrollment as study participants:
• Diagnosis of peanut allergy by medical history
• Evidence of peanut-speciﬁc IgE by either: positive skin prick test to peanut (reaction wheal at least 5 mm
larger than saline control) or serum peanut-speciﬁc IgE ≥5 kU/L at screening visit.
• Ara h 2 speciﬁc IgE >0.35 kU/L at screening visit.
• Who are willing to sign informed consent or whose parent or legal guardian is willing to sign the consent
form (age appropriate)
• Who are willing to sign the assent form, if age appropriate
• Males and females of all ethnic/racial groups aged 7-55 years old who are otherwise healthy.
• React to 443 mg of peanut protein during DBPCFC1
4.2
Exclusion Criteria
Individuals who meet any of these criteria are not eligible for enrollment as study participants:
• 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/).
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• 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
• Hematocrit <0.36 for adult females or <0.38 for adult males
• 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.
4.3
Participant Withdrawal Criteria
Participants may be terminated early from the study for the following reasons:
• The participant elects to withdraw consent from all future study activities, including follow-up.
• The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish
contact with the participant have failed).
• The participant dies.
• The participant develops a medical condition or is started on new medication(s) not previously mentioned
in the list of prohibited medications that, 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 of the data obtained from the study.
• The participant meets any of the individual stopping rules as delineated in section 8.
• Dose adjustment required more than twice due to missed at-home dosing.
• Rescheduling of two consecutive, or more than four total dose escalation visits.
Participants with early termination from this study will not be replaced.
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5
INVESTIGATIONAL PRODUCT(S) / INTERVENTION MATERIAL(S), OTHER
STUDY PRODUCTS (CONTROLS/PLACEBOS)
5.1
Investigational Product(s) / Intervention(s)
Placebo product: Toasted oat ﬂour (Montana Gluten Free, Belgrade, Montana)
Active product: Partially defatted peanut ﬂour (Golden Peanut Company, Alphretta, Georgia)
Refer to section 1.6, and applicable product labeling for known and potential risks to human participants associated
with the investigational product(s) intervention(s).
5.2
Formulation, Packaging, Storage and Labeling
The drug is organic nonfat dry peanut. The drug will be purchased from the Golden Peanut Company, located in
Alphretta, Georgia. The company states that the drug is manufactured under GMP for food products. No other
nuts are processed at this facility. The peanut ﬂour is not stored with material from other nuts. Analysis has been
completed to determine the protein content in the bulk peanut powder. Dr. Wayne Shrefﬂer will hold the IND.
The placebo will be toasted oat ﬂour. The oat ﬂour proposed for use in this study will be purchased in bulk
from the Montana Gluten Free Processors, located in Belgrade, Montana. The company states that the drug is
manufactured under GMP for food products. No other allergens such as peanuts, tree nuts, wheat, corn, and soy
are processed at this facility.
5.3
Preparation, Administration, and Dosage
Each dose for daily at home immunotherapy will be provided to the participant in a single-dose lidded portion
cup. The container will be a 2 oz Portion Cup PC-200 and XL250PC Portion Cup Lid (Fabri-Kal, Kalamazoo, MI),
supplied by the MGH CRC. No other product will be present in the daily dosage. The doses will be refrigerated.
Drug product will be prepared (weighed, aliquoted into the single dose lidded portion cups, and placed in a
transport bag) in the MGH CRC by trained Metabolic Kitchen Staff. Each visit the kitchen staff will calibrate the
balance and then weigh and record weight of bulk peanut (or oat) ﬂower in container. Next they will zero balance
an empty vial, measure dose into empty vial, record weight, label vial, and then re-weigh bulk peanut (or oat)
powder and container to ensure the correct amount of peanut (or oat) powder was removed. Participants will
ingest daily dose of immunotherapy mixed with vehicle food which they will provide. The starting dose will be
determined by the participant’s threshold sensitivity during the modiﬁed rush phase of the protocol. After the
initial dose has been determined the dose will follow the dosing schedule presented in Figure 15.3.
5.4
Accountability of Investigational Product(s) / Intervention(s)
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate
records of the disposition of the investigational product(s) / intervention material(s), including the date and quantity
of the drug received, to whom the drug was dispensed (participant-by-participant accounting), and a detailed
accounting of any investigational product(s) / intervention material(s) accidentally or deliberately destroyed.
Records for receipt, storage, use, and disposition will be maintained by the study site. A dispensing log will be
kept current for each participant. This log will contain the identiﬁcation of each participant and the date and
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quantity of investigational product(s) / intervention material(s) dispensed. Any drug that remains unused at the
end of study will be destroyed.
All records regarding the disposition of the investigational product(s) / intervention material(s) will be available for
inspection by the Clinical Research Associate (CRA) and NIAID.
5.5
Assessment of Compliance with Investigational Product(s) / Intervention Material(s)
Every study subject will be asked to record consumption of their home doses of peanut protein in a diary. In
order to assess each subject’s level of compliance with the investigational products, this diary will be reviewed
for compliance during all study visits between DBPCFC1 and DBPCFC2 by the study staff. The proper method
of recording and reporting accidental ingestions will also be reviewed with subjects following DBPCFC1. In order
to be prepared for accidental ingestions or any possible adverse reactions to peanut protein doses, the proper
method of carrying and using an epinephrine autoinjector will also be reviewed with the subjects throughout the
study.
5.6
Modiﬁcation or Discontinuation of Investigational Product(s) / Intervention Material(s)
5.6.1
Modiﬁcation of Investigational Product(s) / Intervention(s)
Participants receiving active treatment who react to <1443 mg peanut protein during DBPCFC2 will be considered
a treatment failure and be recommended to return to a strict peanut avoidance diet.
If the participant tolerates <4430 mg peanut protein during the DBPCFC3, he or she may elect to resume
daily peanut protein dosing either at the highest tolerated dose during the challenge or 4000 mg peanut protein
(whichever is less). If less than 4000 mg peanut protein, the daily dose will be increased by 25% every 2 weeks
(±4 days) as tolerated at the MGH CRC until they reach a dose of 4000 mg of peanut protein. They will continue
on a dose of 4000 mg peanut protein for 1 year. At that time, they may elect to repeat a challenge.
At study end, those participants who are neither treatment failures nor achieve full tolerance, as determined by
the DBPCFC3, may elect to have a nutrition consult to review a diet that would allow for the daily consumption
of peanut protein at a dose that is tolerated without symptoms. The subject may also elect to resume strict
avoidance. These subjects will continue to be followed at the MGH Food Allergy Center.
5.6.2
Premature Discontinuation of Investigational Product(s) / Intervention(s)
If the participant misses one or two days of the daily dose for any reason then he or she will continue on the
same dose. If the participant misses the dose for three days, the participant will be asked to return to the MGH
CRC for the next daily dose to ensure that there are no adverse effects from resuming dosing. If the participant
misses their dose for four or more days, he/she will have to return to the MGH CRC for a modiﬁed rush protocol
to escalate back to the highest previously tolerated dose beginning at 50%. Participants will be terminated from
the study (section 4.3) if dose adjustment is required more than twice for missed at-home dosing.
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6
OTHER MEDICATIONS
6.1
Concomitant Medications
Concomitant medications may be used as follows: Other medications may be used during study participation
unless noted in section 6.4.
6.2
Prophylactic Medications
NA
6.3
Rescue Medications
The following rescue medications may be used if a subject experiences an adverse event:
• Albuterol
• Epinephrine
• Diphenhydramine
• Hydroxyzine
• Ranitidine
• Corticosteroid
6.4
Prohibited Medications
Use within the past year of other systemic immunomodulatory treatment. including allergen immunotherapy, use
of biologics with an immune target, including Xolair is prohibited.
Prior to the food challenges, patients will be asked to restrict the use of antihistamines (short-acting, 72 hours:
long-acting, 7 days), beta-agonists (12 hours), theophylline (12 hours), and cromolyn (12 hours). For visits that
include skin prick testing, patients will be asked to restrict the use of antihistamines (short-acting, 72 hours:
long-acting, 7 days).
7
STUDY VISITS AND PROCEDURES
Appendix 16.1 summarizes the schedule of events for the study.
7.1
Enrollment and Randomization
Participants will be recruited from oral immunotherapy-interested individuals who have contacted us in response
to announcements and advertisements, referrals from Allergy/ Immunology Clinics, and by identiﬁcation using the
Partners Research Participant Data Registry. The referring physician may send potential participants and/or their
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parents a recruitment letter. The letter will include contact information for study staff so the participant and/or their
parents can opt-in to participate. This research study will be explained in lay terms to each potential research
participant. The potential participant or participant’s legal guardian will sign an informed consent form before
undergoing any baseline study procedures. Participants age 14-17 will co-sign the consent form with their legal
guardian. Participants age 7-13 will sign a child-speciﬁc assent form and their legal guardian will sign the consent
form.
Participants enrolled as minors will be provided an adult consent form for signature when they reach age 18
and will be re-consented before any study procedures take place. Any “new adult” who refuses consent will be
removed from the study. Participants who are deemed eligible for the study (see section 4) will be enrolled and
assigned a unique participant number.
Following DBPCFC1, participants will be randomly assigned by the study statistician to treatment or placebo
groups at a ratio of 3:1. Following DBPCFC2, assignment will be unblinded and placebo participants will be
offered open-label active treatment following the same desensitization procedures (Modiﬁed Rush, Build Up and
Maintenance).
7.2
Screening Visit (Day −30 to −7)
Informed consent will be obtained at this visit as described above. The screening visit will involve a medical
history, physical examination, standard skin prick testing (SPT), and a blood draw (10 ml). The physical examination
will include pulmonary function testing. Serum will be collected for total and peanut-speciﬁc IgE antibody measurements
and stored for speciﬁc IgG4 if subject is eligible. The blood draw will be performed if relevant testing has not been
performed within 2 months of the screening visit. If relevant testing has been performed with 2 months of the
screening visit, a copy of the results will be obtained. Urine will be collected for a Human Chorionic Gonadotropin
(HCG) test to determine pregnancy in female participants of childbearing potential. Women of childbearing age
will be advised on birth control options for the duration of this study. If a participant is found to be pregnant at
any time during this study, she will be immediately removed. The study physician will conﬁrm eligibility by history,
SPT and speciﬁc IgE following this visit.
7.3
Baseline Visit (Day 0)
The baseline visit will involve a medical history, physical examination, and a blood draw for mechanistic studies.
The physical examination will include pulmonary function testing and endpoint titration SPT. Urine will be collected
for a Human Chorionic Gonadotropin (HCG) test to check for pregnancy in female participants of childbearing
potential.
The participants and/or their parents will be instructed on recording adverse events and any known accidental
ingestion that occurs during the study. The participant and his or her parents will also have a nutritional consultation
with a registered dietitian to enhance adherence to a peanut-free diet. Participants will be asked about their
preferred and tolerated vehicle food to be used during the Build Up and Maintenance visits for the duration of the
study.
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7.4
Main Study Visits
7.4.1
Double-Blind Placebo-Controlled Food Challenge 1 (Day 28)
Participants will come to the MGH CRC four weeks (±4 days) after the baseline visit for a double-blind, placebo
-controlled food challenge (DBPCFC1) to peanut. In a DBPCFC, two challenges, one containing placebo material
(toasted oat ﬂour) and one containing peanut ﬂour will be performed on two days within a two week period. The
order of challenge will be determined by coin toss by the dietitian and will be unknown to the study nurse,
investigator, and study participant. The MGH CRC dietician will prepare the challenge materials. Details of the
DBPCFC procedure are below in section 7.7.1.
Prior to each challenge, the participant will have a physical exam with vital signs, spirometry, and an IV will be
placed. A negative urine pregnancy test will be documented for female participants of child-bearing potential; if
the test is positive, the visit will be cancelled and if pregnancy is conﬁrmed, the subject will be withdrawn from the
study. The participant will be required to have a baseline FVC and FEV1 >80% of their predicted values and an
FEV1/FVC of >0.7 or the DBPCFC will be rescheduled. A study nurse who is blinded to the testing material will
administer the challenge. The supervising physician will be present during the challenge and will also be blinded
to testing material.
A member of the study staff will follow up with participant with a telephone call the day after the DBPCFC for
active safety monitoring.
If the participant reacts at the 300 mg dose of peanut protein or less (443 mg cumulative), he/she will be
randomized to receive active or placebo OIT.
7.4.2
Modiﬁed Rush Visit (Day 42)
Two weeks following the completion of DBPCFC1, the participant will come to the MGH CRC for the modiﬁed
rush procedure as shown in Figure 15.2. The participant will undergo a medical history and physical exam
including vital signs, and spirometry. An IV will be placed. A negative urine pregnancy test will be documented
for female participants of child-bearing potential; if the test is positive, the visit will be cancelled and if pregnancy
is conﬁrmed, the subject will be withdrawn from the study. The participant will be required to have a baseline
FVC and FEV1 >80% of their predicted values and an FEV1/FVC of >0.7 or the visit will be rescheduled. A
study nurse who is blinded to the treatment material will administer the doses. The supervising physician will be
present during the procedure and will also be blinded to testing material. This visit will occur 2 weeks after the
completion of DCPCFC1.
7.4.3
Build Up Visits (Days 43−350)
Beginning with the day after the Modiﬁed Rush Visit and every two weeks following that, the participant will come
to the MGH CRC for a Build Up Visit during which an increased dose of study product is administered. Subjects
will advance sequentially through an up-dosing schedule as described in section 7.7.2.2. The dosing escalation
will be incremental based on previous OIT studies [? ]. When the participant reaches the 4000 mg peanut
protein dose they will enter the maintenance phase.The participant will undergo a medical history and physical
exam including vital signs, and spirometry. The symptom diary (Appendix 16.2) will be reviewed for evidence of
symptoms associated with the previous interval dose. A negative urine pregnancy test will be documented for
female participants of child-bearing potential; if the test is positive, the visit will be cancelled and if pregnancy is
conﬁrmed, the subject will be withdrawn from the study. The participant will be required to have a baseline FVC
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and FEV1 >80% of their predicted values and an FEV1/FVC of >0.7 or the visit will be rescheduled. A study
nurse who is blinded to the treatment material will administer the doses.
7.4.4
Maintenance Visits (Days 350−434)
Maintenance visits will occur on the MGH CRC monthly during the 12 weeks of maintenance therapy. Each visit
will involve a medical history and physical examination. The medical history will consist of a structured interval
clinical history and review of systems concerning any types of allergic symptoms related to their food allergy,
atopic dermatitis or asthma. The participants and/or their parents will record any known accidental ingestion that
occurs during the study. The physical exam will include vital signs, and spirometry. A negative urine pregnancy
test will be documented for female participants of child-bearing potential; if the test is positive, the visit will be
cancelled and if pregnancy is conﬁrmed, the subject will be withdrawn from the study.
Blood will be collected and skin prick testing will be performed at three follow-up visits for research laboratory
studies at baseline, on maintenance therapy (after 12 weeks at 4000 mg of peanut protein or maximum tolerated)
prior to DBPCFC2, and prior to DBPCFC3 (12 weeks post avoidance). An additional blood draw will occur during
build up (12 weeks after beginning treatment). Blood will be drawn by trained study staff or Clinical Research
nurses.
Urine will be collected from female participants for a Human Chorionic Gonadotropin (HCG)-based
pregnancy test at all follow up visits throughout the study.
7.4.5
Double-Blind Placebo-Controlled Food Challenge 2 (Day 434)
After taking maintenance dose for 12 weeks, participants will come to MGH CRC for their second double-blind,
placebo-controlled food challenge (DBPCFC2).
7.4.6
Avoidance Visit (Day 434−518)
An avoidance study visit will occur on the MGH CRC four weeks (+/- 4 days) before the Double-Blind Placebo-Controlled
Food Challenge 3. This visit will involve a medical history and physical examination. The medical history will
consist of a structured interval clinical history and review of systems concerning any types of allergic symptoms
related to their food allergy, atopic dermatitis or asthma. The participants and/or their parents will record any
known accidental ingestion that occurs during the study. The physical exam will include vital signs, and spirometry.
A negative urine pregnancy test will be documented for female participants of child-bearing potential; if the test
is positive, the visit will be cancelled and if pregnancy is conﬁrmed, the subject will be withdrawn from the study.
This visit will include a blood collection for mechanistic studies.
7.4.7
Double-Blind Placebo-Controlled Food Challenge 3 (Day 518)
After 12 weeks of complete peanut avoidance after the DBPCFC2, participants will come to MGH CRC for their
third double-blind, placebo-controlled food challenge (DBPCFC3). The DBPCFC3 will be similar to DBPCFC2,
differing only in the dosing schedule. See Section 7.7.1 for details.
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7.5
Open Label Treatment
Participants receiving placebo treatment will be offered open-label active treatment after DBPCFC2. The open-label
oral immunotherapy schedule will follow a seperate protocol for participants initially receiving placebo treatment.
Participants receiving active treatment who fail the post-avoidance challenge will be offered the option to repeat
the desensitization up to the level reached during initial up dosing. Participants will then be referred to the MGH
Food Allergy Center or other qualiﬁed allergist to be advised on diet choices and appropriate peanut protein
exposure.
Following active therapy, participants will be referred to the MGH Food Allergy Center or other qualiﬁed allergist.
7.6
Visit Windows
Study visits should take place within the time limits below:
• Subjects will have a ±14 day window to complete study visits.
7.7
Study Procedures
7.7.1
Double-Blind Placebo-Controlled Food Challenge
In a DBPCFC, two challenges, one containing placebo oat ﬂour and one containing peanut ﬂour, will be performed.
The dietitian will perform the preparation of the challenge materials. Prior to the food challenge, participants will
be asked to restrict the use of antihistamines (short-acting, 72 hours: long-acting, 7 days), beta-agonists (12
hours), theophylline (12 hours), and cromolyn (12 hours). For DBPCFC1, one challenge will consist of 5 doses
of peanut powder given every 20 minutes in increasing amounts up to a cumulative total of 443 mg of peanut
protein masked by inclusion in vehicle food. Available vehicle foods will include rice milk, soymilk, mint chocolate
mousse, or applesauce. The other challenge will consist of oat ﬂour given also in 5 doses in an identical volume
of vehicle food. For the active challenge, the ﬁrst ingested dose will be 3 mg, then increasing to 10 mg, 30 mg,
100 mg, and 300 mg of peanut protein[? ]. The placebo challenge doses will be the equivalent amount of oat
ﬂour by weight.
The protocol of the DBPCFC2 will be identical to DBPCFC1, but with additional doses of 1000 mg and 3000 mg
for a cumulative dose of 4443 mg peanut protein. DBPCFC3 will follow a slightly different schedule of doses: 30
mg, 100 mg, 300 mg, 1000 mg, and 3000 mg for a cumulative dose of 4430 mg peanut protein.
If the participant has a subjective reaction to one of the doses, the study nurse may repeat that dose or consult
with the supervising physician. If symptoms do not recur, the study nurse will continue the DBPCFC protocol after
conﬁrming with the supervising physician. If the study nurse is unsure about how to proceed, the supervising
physician will be consulted to determine the appropriate action. Food challenges will be immediately stopped and
the participant promptly treated for objective signs and symptoms as indicated in Figure 15.4, consistent with the
2010 NIAID-sponsored expert guidelines for the diagnosis and management of food allergies [? ].
After the ﬁnal dose of each challenge or the resolution of any suspected reaction symptoms, the participant will
be observed for a minimum of 2 additional hours.
All food challenges will be performed under direct physician supervision. The supervising physician may stop a
challenge if he/she feels it is in the best interest of the participant. Incomplete or indeterminate challenges will be
rescheduled.
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7.7.2
Immunotherapy Administration
Drug product will be prepared in the MGH CRC as described in Section 5.3. Participants will ingest daily dose
of immunotherapy mixed with one of a few vehicle foods they may choose and which they will provide. The oral
immunotherapy procedure consists of three phases: Modiﬁed Rush, Build Up, and Maintenance.
7.7.2.1
Modiﬁed Rush
The modiﬁed rush procedure begins with 0.1 mg peanut protein-containing peanut
powder or equivalent placebo, stirred in a vehicle food, approximately doubling the dose every 30 minutes until a
maximum of 6 mg is tolerated (cumulative dose of 12 mg; Figure 15.2). Available vehicle foods will include rice
milk, soymilk, mint chocolate mousse, or applesauce, depending on the participant’s other allergies and p s. The
MGH CRC will prepare all doses. This visit will occur within 2 weeks after the completion of DCPCFC1.
Participants will not have active wheezing or a current ﬂare in atopic dermatitis. If symptoms occur preventing
escalation to 6 mg, the highest tolerated dose (at least 1.5 mg) will be accepted as the dose for further escalation.
Participants must tolerate at least 1.5 mg as a ﬁnal dose to remain in the study.
Participants may develop symptoms during the initial escalation. For isolated oral or pharyngeal pruritus, the
action should be to continue the normal dosing in 30 minutes. If symptoms are not limited to isolated oral or
pharyngeal pruritus, the investigator’s judgment will be required to determine the best course of action with
possible actions being the following:
1. Extend time interval between dosing (up to an additional 30 minutes) and advance forward
2. Return to previously tolerated dose (i.e., repeat of last tolerated dose) then advance forward
3. Discontinue protocol and deﬁne the starting Build Up dose as the previously given dose
The Modiﬁed Rush procedure will be immediately stopped and the participant promptly treated for objective signs
and symptoms as indicated in Figure 15.4, consistent with the 2010 NIAID-sponsored expert guidelines for the
diagnosis and management of food allergies [? ].
For a completed initial escalation protocol with no symptoms or only mild symptoms, subjects should have a
2-hour post-protocol observation period.
For moderate to severe symptoms, the observation period will be
extended based on the participants symptoms and the treatment regimen required to stabilize the participant.
7.7.2.2
Build Up
Participants will then begin the starting dose for the Build Up phase of peanut ﬂour or oat
ﬂour in an acceptable and tolerated food into which the powder can be stirred. The initial daily dose will be
the highest dose tolerated during the modiﬁed rush phase on Day 1 (maximum 6 mg). To ensure there are no
ill effects of the once daily dosing, the ﬁrst daily dose of peanut or placebo will be given in the MGH CRC on
Day 43 (one day after completion of the Modiﬁed Rush). Thereafter, the daily dose will be given at home from
pre-aliquoted single dose portion cups, prepared by the MGH CRC dietitian. The participants will then be seen in
the MGH CRC every two weeks (±4 days) to follow the dosage escalation schedule according to Figure 15.3 to
a target daily dose of 4000 mg of peanut protein.
Participants will be free from active wheezing or a ﬂare of atopic dermatitis prior to any Build Up dose. Participants
will be maintained on their current dose of study product until their ﬂare of asthma or atopic dermatitis resolve.
Participants may develop symptoms during the ﬁrst administration of the new Build Up dose. The investigator’s
judgment will be required to determine the best course of action with possible actions being the following:
1. Continue with daily home dosing at the new Build Up dose
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2. Continue with daily home dosing at the previously tolerated daily dose for the next (additional) 2-week
interval
3. Return the following day for repeat trial at the new Build Up dose in the MGH CRC
4. Return the following day for dosing of previously tolerated dose (without escalation) in the MGH CRC
5. Discontinue dosing
If a participant has a Build Up dose in the MGH CRC without symptoms, the action should be to continue with
daily home dosing of the new dose until the next Build Up visit at the MGH CRC two weeks later.
If the participant has a Build Up dose in the MGH CRC and experiences isolated oral/pharyngeal pruritus or very
mild and self-limited symptoms, deﬁned as:
• Skin: limited or localized hives/swelling, skin ﬂushing or pruritus
• Respiratory: rhinorrhea/ sneezing, nasal congestion, occasional cough, throat discomfort
• GI: mild abdominal discomfort/ minor episode of vomiting
then the same dose can be repeated the next day at home and continued for the next two week interval unless
other symptoms begin to develop at home (see below).
If the participant has a Build Up dose in the MGH CRC and experiences symptoms that require treatment in
accordance with Figure 15.4, the patient will continue on the previously tolerated dose for the next two week
interval.
Participants may also develop symptoms during the subsequent at home administrations of the Build Up doses.
The participants will be instructed to contact study staff for any symptoms. The study physician’s judgment will
be required to determine the best course of action with possible actions being the following:
1. Continue with daily home dosing at the current Build Up dose
2. Continue with daily home dosing at the previously tolerated daily dose for the next (additional) 2-week
interval
3. Return the following day to the MGH CRC for repeat trial at the current Build Up dose
4. Return the following day to the MGH CRC for dosing at a previously tolerated dose
5. Discontinue dosing
For reactions for which epinephrine was given (1-2 doses) or was indicated (as outlined in Figure 15.4), treatment
will be withheld until it can be resumed (as below) in the MGH CRC. As per individual stopping rules (see
section 8.1.2) participants who receive more than two doses of epinephrine for a single reaction will be withdrawn.
For minor reactions (appropriately treated without epinephrine as outlined in Figure 15.4), treatment will be
resumed at home unless the study physician determines that resumption should take place in the CRC.
Resumption of treatment will proceed as follows: 50% of the previously tolerated amount for 4-5 days, 75% for
4-5 days and then 100%. The previously scheduled Build Up visit will be postponed to take place 2 weeks (12
days minimum) after resumption of the 100% dose.
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If a participant fails to tolerate 3 consecutive Build Up attempts prior to reaching 600 mg or if the participant fails
to reach 600 mg by week 50, then the participant will be considered a treatment failure.
If the participant misses one or two days of the daily dose for any reason then he or she will continue on the
same dose. If the participant misses the dose for three days, the participant will be asked to return to the MGH
CRC for the next daily dose to ensure that there are no adverse effects from resuming dosing. If the participant
misses their dose for four or more days, he/she will have to return to the MGH CRC for a modiﬁed rush protocol
to escalate back to the highest previously tolerated dose beginning at 50%. For the duration of the study, the
participant will be asked to continue to follow a peanut elimination diet.
7.7.2.3
Maintenance
At the end of the Build Up phase, the participants will continue on the achieved daily
dose for 12 weeks in the maintenance phase. Participants in a reported study have tolerated a very similar
dosing schedule with minimal symptoms [? ]. Participants will enter the Maintenance phase at the highest dose
tolerated by week 50 (at least 600 mg).
Participants may develop symptoms during the at home administrations of the Maintenance doses. The participants
will be instructed to contact study staff for any symptoms. The study physician’s judgment will be required to
determine the best course of action with possible actions being the following:
1. Continue with daily home dosing at the current Maintenance dose
2. Continue with daily home dosing at 50% of the Maintenance dose
3. Return the following day to the MGH CRC for observed trial at the current Maintenance dose
4. Return the following day to the MGH CRC for observed trial of a reduced dose (e.g. 50%, 75%)
5. Discontinue dosing
For reactions for which epinephrine was given (1-2 doses) or was indicated (as outlined in Figure 15.4), treatment
will be withheld until it can be resumed (as below) in the MGH CRC. As per individual stopping rules (see
section 8.1.2) participants who receive more than two doses of epinephrine for a single reaction will be withdrawn.
For minor reactions (appropriately treated without epinephrine as outlined in Figure 15.4), treatment will be
resumed at home unless the study physician determines that resumption should take place in the CRC.
Resumption of treatment will proceed as follows: 50% of the previously tolerated amount for 4-5 days, 75% for
4-5 days and then 100%. The previously scheduled Build Up visit will be postponed to take place 2 weeks (12
days minimum) after resumption of the 100% dose.
If the participant misses one or two days of the daily dose for any reason then he or she will continue on the
same dose. If the participant misses the dose for three days, the participant will be asked to return to the MGH
CRC for the next daily dose to ensure that there are no adverse effects from resuming dosing. If the participant
misses their dose for four or more days, he/she will have to return to the MGH CRC for a modiﬁed rush protocol
to escalate back to the highest previously tolerated dose beginning at 50%. For the duration of the study, the
participant will be asked to continue to follow a peanut elimination diet.
7.7.3
Pulmonary Function Testing
Spirometry is a standard technique performed in our pulmonary function laboratory. In the procedure the participant
is asked to take a deep breath to full lung capacity, exhale forcibly and fully, and then inhale fully while breathing
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into a tube connected to a spirometry device. The participant is asked to do this 3 times over a 10 minute period.
The participant wears a nose clip during the procedure. Spirometry will be performed before and 15 minutes
following administration of 2 puffs of albuterol MDI
7.7.4
Titration Skin test
End point titration SPT will be conducted by a study nurse using commercial peanut test extract (Greer) at full
strength and four 10-fold serial dilutions in saline prepared by the study nurse or pharmacy on the day of use
and stored at 4◦C. Histamine and saline controls will be administered at the same time and the mean orthogonal
diameters of the wheal will be measured for each test by the study nurse after 15 minutes.
7.7.5
Symptom Assessment
Symptoms will be recorded by participants using a 2 week diary and reviewed at each visit by the research
coordinator and study physician (see Appendix 16.2).
7.7.6
Phlebotomy
At visits 0, 27 and 30, 3ml/kg (for participants <18 years and/or participants weighing <50 kg) or 1 unit (550 ml)
of blood will be obtained by standard venipuncture at the MGH blood bank. One (1) ml of blood will be used to
measure peanut speciﬁc IgE, IgG, and IgG4. Five (5) ml of blood will be used to measure basophil activation.
The remaining blood will be used for mechanistic T cell and B cell studies. Prior to each scheduled large blood
draw, a rapid test of hemoglobin level will be performed.
The following criteria will be used to determine for adult participants whether the proposed 550 ml can be drawn:
• AGE must be at least 18 years old
• WEIGHT must be greater than 110 lbs (50 kg);
• PULSE must be between 50 and 100 beats/minute with no cardiac irregularity;
• TEMPERATURE must not exceed 37.55◦C or 99.5◦F;
• Hematocrit <0.36 for adult females or <0.38 for adult males;
An additional blood collection of 200 ml (adults) and 3ml/kg (children) will occur after 12 weeks of treatment
to be used for mechanistic B cell studies. For B cell studies, 100-200 million PBMCs will be used for afﬁnity
single-cell sorting of Arah2-speciﬁc B cells by ﬂowcytometry (see Patil et al. 2015 JACI) as well as bulk sorting of
CD19+ CD27+ IgM- cells. These will be used for cloning of functional mAbs and next generation sequencing of
BCR, respectively.
7.7.7
Stool Collection (Optional)
At visits 1, 8, 14, 20, 27, 38 and 50 a stool samples will be collected from the participants up to every three months
during the ﬁrst year, and every 6-12 months once they have reached a maintenance dose. These samples will
be banked in an -80F freezer. The stool samples will be used for 16S rRNA sequencing for gut microbiome.
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7.7.8
Physical Examination
This will include measurement of heart rate, blood pressure and examination of the skin, ears, nose and throat,
lungs and heart.
7.7.9
Urine Pregnancy Testing
For participants of childbearing potential a urine beta-HCG determination will be preformed immediately before
each study visit.
7.8
Study Arm Assignment Procedures
7.8.1
Blinding and Randomization
Participants will be randomly assigned to treatment or placebo groups for the ﬁrst weeks at a ratio of 3:1, after
which time, placebo participants will be offered open-label active treatment. Randomization will be performed by
the study statistician who will provide that information directly to the CRC dietitian in sealed disclosure envelopes.
7.8.2
Securing Blinding and Randomization Information
Randomization lists will be maintained in a secured area by the individual(s) responsible for maintaining the blind.
During site visits, the Clinical Research Associate will check the occluded labels (or disclosure envelopes) to
ensure that they are intact and in a secure, yet accessible, location for study personnel. If any of the occluded
labels or disclosure envelopes is opened, the Clinical Research Associate will verify that the Principal Investigator,
the Independent Safety Monitor of the study and the NIAID Medical Ofﬁcer have been notiﬁed and that a written
account has been completed and forwarded to the above individuals.
7.8.3
Requirements for Unblinding
This study may be unblinded only for safety reasons or only if the study information is needed for an interim or
ﬁnal analysis as described below.
If a clinically signiﬁcant event occurs and knowledge of treatment assignment is required, the blind may be broken.
Unblinding must be approved by the Independent Safety Monitor unless an immediate life threatening condition
has developed and the Independent Safety Monitor is not accessible. In all cases of unblinding, the NIAID Medical
Ofﬁcer will be notiﬁed immediately.
Unblinding the study because of an approved interim analysis, ﬁnal analysis, or study termination (as described
in section 8.1) will require written approval from NIAID.
7.8.4
Documenting an Unblinding
Any unblinding (opening of a label or disclosure envelope) will require a full written account of the event(s) that
necessitated the unblinding of the treatment assignment for an individual participant(s). This account will be
made in the participant(s) study ﬁle and in the ﬁnal study report and will include the reason(s) for the unblinding,
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the name of the Independent Safety Monitor who was notiﬁed and approved the unblinding, the names of the
individuals unblinded, and the date and time the unblinding occurred.
8
SAFETY PROCEDURES
8.1
Stopping Rules
8.1.1
Study Stopping Rules
Study enrollment and study procedures will be suspended pending expedited review of all pertinent data by the
Partners institutional review board (IRB), the ISM, the DAIT DSMB, and the NIAID Medical Ofﬁcer, if a participant
at any time or in any group develops a severe or life threatening adverse event such that he or she requires an
emergency room visit, hospitalization, or an unexpected (non-allergy-related) hospitalization or death.
Study enrollment will be suspended pending expedited review of all pertinent data by the DSMB if any of the
following occur:
• Any death related to peanut OIT dosing
• More than one event of severe systemic anaphylaxis, deﬁned by any of the following: hypoxia (cyanosis or
SpO2 <92% during reaction), documented hypotension (>30% fall from baseline systolic BP), neurological
compromise (confusion, loss of consciousness), or incontinence after ingestion of peanut at any stage of
the protocol
• More than 3 participants requiring more than 2 injections of epinephrine during dosing of the peanut product.
All above events will be reported immediately to the Partners IRB and to the FDA, the DSMB, and the NIAID
Medical Ofﬁcer. The study will not resume until approval is given by the FDA and IRB, the DSMB, and NIAID.
8.1.2
Individual Stopping Rules
Safety of the participant will remain of primary importance.
Any participant who develops severe systemic
anaphylaxis, deﬁned by any of the following: hypoxia (cyanosis or SpO2 <92% during reaction), documented
hypotension (systolic BP>30% fall from baseline systolic BP), neurological compromise (confusion, loss of
consciousness), or incontinence after ingestion of peanut, signiﬁcant hypotension during any stage of the protocol,
and/or requires more than 2 injections of epinephrine during any administration of the peanut product will be
withdrawn from the study.
Participants who are ingesting daily maintenance dose of peanut will be dropped from the study if they are having
NCI-CTCAE grade 2 or higher gastrointestinal, respiratory, or dermatologic symptoms at home within 2 hours
of taking the daily dose of peanut for 5 or more consecutive days. The determination of symptoms and their
relativity to the daily dose rather than a concurrent illness must be evaluated by the PI and thought to be related
to the peanut before being dropped from the study. Recurrent symptoms for 5 or more consecutive days that are
occurring more than 2 hours after the daily IT dose may prompt an individual being dropped, if the investigator
believes that they are related to IT dosing.
Mild or moderate adverse events such as nausea, vomiting, increased asthma symptoms, allergic dermal reactions,
or fever will cause the procedure on the individual patient to be discontinued, will be reported in the required timely
manner to the Partners IRB, but will not automatically cause the study to be halted. Each participant will be treated
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for worsening asthma, atopic dermatitis, or suspected EoE symptoms and removed from the study when deemed
necessary by the PI.
8.1.3
Early Discontinuation of Investigational Product(s) / Intervention(s) with continued study participation
/ follow-up
8.1.3.1
Unscheduled Termination
In accordance with the Declaration of Helsinki, patients have the right to
withdraw from the study at any time for any reason. Participants may withdraw with or without medical advice.
The investigator also has the right to withdraw participants from the study. Participants will be removed from the
study for the following reasons: adverse experience, intercurrent illness or medication that in the judgment of
the investigator may place the participant at risk, request of the investigator or participant for administrative or
other reasons, protocol violation, determination that the participant is non-compliant or has unreliable behavior.
Withdrawal from this study will have no impact on the future care of the participant at the Massachusetts General
Hospital or any of its afﬁliated hospitals or health clinics.
8.1.4
Follow-up after early study termination
Participants who are prematurely terminated from the study will be followed to monitor safety for a minimum of 30
days or until resolution of the disqualifying event whichever is longer or until the Independent Safety Monitor, the
NIAID Medical Ofﬁcer and the Principal Investigator determine that the follow-up is complete.
8.1.5
Participant Replacement
Participants who are permanently discontinued from the study during or after the Modiﬁed Rush will not be
replaced.
8.2
Adverse Events
This section deﬁnes the types of adverse events and outlines the procedures for appropriately collecting, grading,
recording, and reporting them.
Information in this section complies with ICH Guideline E2A: Clinical Safety
Data Management: Deﬁnitions and Standards for Expedited Reporting and ICH E6: Guideline for Good Clinical
Practice, and applies the standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria
for Adverse Events version 4.0. These criteria have been reviewed by the study investigators and have been
determined appropriate for this study population.
8.2.1
Deﬁnitions
8.2.1.1
Adverse Events
An adverse event (AE) is any occurrence or worsening of an undesirable or unintended
sign, symptom, laboratory ﬁnding, or disease that is experienced during participation in the trial. An AE can
therefore be any unfavorable and unintended sign (including an abnormal laboratory ﬁnding), symptom, or
disease temporarily associated with the use of a medicinal (investigational) Study Agent(s) whether or not related
to the medicinal (investigational) Study Agent(s).
Any medical condition that is present at the time that the
participant is screened will be considered as baseline and not recorded as an AE. However, if the condition
deteriorates or changes in severity at any time during the study it will be recorded and reported as an AE.
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8.2.1.2
Suspected Adverse Reaction and Adverse Reaction
Suspected adverse reaction (SAR) means
any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the
purposes of safety reporting, “reasonable possibility” means there is evidence to suggest a causal relationship
between the drug and the adverse event. An adverse reaction (AR) means any adverse event caused by a drug.
Adverse reactions are a subset of all suspected adverse reactions for which there is reason to conclude that the
drug caused the event. A suspected adverse reaction implies a lesser degree of certainty about causality than
adverse reaction, which means any adverse event caused by a drug.
8.2.1.3
Adverse Events Associated with Study Procedures
The following clinical situations, when associated
with study procedures are deﬁned as adverse events and will be recorded on the AE CRF. These situations do
not limit the principal investigator from recording and reporting any other events as AEs, associated or not with
these procedures.
8.2.1.3.1
Double Blind Placebo Controlled Food Challenge
• Anaphylaxis as deﬁned in section 6.2.1 of Guidelines for the Diagnosis and Management of Food Allergy in
the United States: Report of the NIAID-Sponsored Expert Panel [? ]. Modiﬁed Rush, Build Up visits, and
Maintenance
• Anaphylaxis as deﬁned in section 6.2.1 of Guidelines for the Diagnosis and Management of Food Allergy in
the United States: Report of the NIAID-Sponsored Expert Panel [? ].
• Worsening asthma symptoms
• Worsening atopic dermatitis symptoms
• Onset of EoE symptoms
8.2.1.3.2
Blood Draws
• Fainting /Vasovagal events
• Bruising at puncture site larger than 2 cm diameter
• Bleeding from puncture site lasting more than 30 minutes
• Swelling at puncture site larger than 2 cm
8.2.1.3.3
Allergen Skin Testing
• Prolonged (>24 hours) itching at test site
• Swelling (> 10 cm ) at site of test lasting more than 24 hours
• Nasal allergic symptoms within 30 minutes from the procedure
• Fainting /Vasovagal event within 30 minutes from the procedure
• Anaphylaxis
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8.2.1.4
Serious Adverse Event (SAE)
An AE or SAR (including AR) is considered serious if, in the view of
either the investigator or DAIT/NIAID it results in any of the following outcomes (21 CFR 312.32):
• Death. A death that occurs during the study or that comes to the attention of the investigator during the
protocol-deﬁned follow-up.
• A life-threatening event. A life-threatening event is any adverse experience that, in the view of the investigator
or sponsor, places the study participant at immediate risk of death from the reaction as it occurred. It does
not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form,
might have caused death.
• An inpatient hospitalization or prolongation of existing hospitalization.
• Persistent or signiﬁcant disability/incapacity or substantial disruption of the ability to conduct normal life
functions.
• An important medical event that may not result in death, be life threatening, or require hospitalization may
be considered an SAE when, based on appropriate medical judgment, it may jeopardize the participant and
may require medical or surgical intervention to prevent one of the outcomes listed above.
• Congenital anomaly or birth defect.
Regardless of the relationship of the adverse event to the study, the event will be reported per Section 8.2.2.3 as
an SAE if it meets any of the above deﬁnitions.
8.2.1.5
Unexpected Adverse Event
An AE or SAR (including AR) is considered “unexpected” if it is not
consistent with the risk information described in the study protocol.
8.2.1.6
Independent Safety Monitor
The Independent Safety Monitor (ISM) is a physician who is independent
from the study team and will review all SAEs to assess for possible changes to the overall risk of the study. This
person will be expected to communicate with the PI and the NIAID Medical Ofﬁcer regarding any safety issues
and may be requested to review study safety documentation. Our ISM will be Aleena Banerji, MD.
8.2.2
Collecting, Recording and Managing Adverse Events
8.2.2.1
Identifying Adverse Events
Any adverse event that occurs from the moment the participant has
signed the consent form will be recorded and is reportable. Adverse events will be reported until the participant
has completed the long-term follow-up phase.
Adverse events may be discovered through any of these methods:
• Observing the participant.
• Questioning the participant, with standardized questions/procedures.
• Receiving an unsolicited complaint from the participant.
• An abnormal value or result from a clinical or laboratory evaluation (e.g., a radiograph, an ultrasound, or an
electrocardiogram) can also indicate an adverse event.
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Adverse events will be captured as follows: (1) every occurrence as per the NCI-CTCAE criteria, (2) for protocol-speciﬁc
adverse events (Section 8.2.1.3) or (3) when determined to be clinically signiﬁcant by the Principal Investigator.
All adverse events occurring during or within 24 hours of the study procedures will be reported as an adverse
event.
8.2.2.2
Recording AEs
Throughout the study all identiﬁed adverse events (serious and non-serious) will be
recorded on all appropriate source document and adverse event case report forms regardless of their severity or
relation to the study.
A complete description of all adverse events will include event description, time of onset, investigator assessment
of severity, relationship to study agent(s) or procedures/intervention(s), time of resolution/stabilization of the event,
expectedness, determination of whether the AE qualiﬁes as a SAE, and action taken. A change in the severity
of the AE will also be documented. The PI will document assessment of severity and relationship on the source
documents or the on the CRF.
8.2.2.3
Recording SAEs
Serious adverse events will be recorded on the serious adverse event case report
form (Appendix 16.3) and will include a narrative of the event signed and dated by the Principal Investigator and
the Independent Safety Monitor.
8.2.2.4
Managing Adverse Events
The site investigator must apply his or her clinical judgment as to whether
an AE is of sufﬁcient severity to require that the participant immediately be removed from further treatment under
the protocol. The investigator must institute any necessary medical therapy to protect a participant from any
immediate risk.
At home reactions are anticipated and from previous reports, co-factors of intercurrent illness and exercise have
been identiﬁed. All participants will have epinephrine auto-injectors and diphenhydramine and will be instructed
to have them available at all times and trained in their use (i.e. an emergency action plan) as indicated in Section
15.5 and as is clinically indicated generally for all individuals with a diagnosis of immediate-type food allergies. If
reactions occur in association with at home doses, they will be instructed to treat according to the action plan and
contact study staff.
Any reaction for which epinephrine was given or was indicated by signs/symptoms deﬁned in Figure 15.4 will be
immediately reported to the study nurse or physician. Reactions for which epinephrine was given (1-2 doses) or
was indicated (as outlined in Figure 15.4), treatment will be withheld until it can be resumed (as below) in the
MGH CRC. As per individual stopping rules (see section 8.1.2) participants who receive more than two doses of
epinephrine for a single reaction will be withdrawn. For minor reactions (appropriately treated without epinephrine
as outlined in Figure 15.4), treatment will be resumed (as described in Section 7.7.2.2) at home unless the study
physician determines that resumption should take place in the CRC.
Resumption of treatment will proceed as follows: 50% of the previously tolerated amount for 4-5 days, 75% for
4-5 days and then 100%. The previously scheduled Build Up visit will be postponed to take place 2 weeks (12
days minimum) after resumption of the 100% dose.
The same protocol will be recommended when signs/symptoms of acute respiratory or gastrointestinal infection
occur. An adverse event will be followed until any of the following takes place: a) it is resolved, b) participant is
stable, c) a minimum of 30 days after participant is terminated from the study and the Independent Safety Monitor
and the Principal Investigator determine that follow-up is complete. An abnormal value or result from a clinical or
laboratory evaluation (e.g., a radiograph, an ultrasound, or an electrocardiogram) can also indicate an adverse
event. If this is the case, then the evaluation that produced the value or result should be repeated until the value
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or result returns to normal or can be explained and the participant’s safety is not at risk. If an abnormal value or
result is determined by the investigator to be clinically signiﬁcant, it must be recorded as an adverse event on the
appropriate laboratory evaluation form(s).
8.2.3
Grading and Attribution
8.2.3.1
Grading criteria
In addition to determining whether an adverse event fulﬁlls criteria for a serious
adverse event or not, the severity of adverse events experienced by study participants will be graded according to
the criteria set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version
4.0. This document (referred to herein as the NCI-CTCAE manual) provides a common language to describe
levels of severity, to analyze and interpret data, and to articulate the clinical signiﬁcance of all adverse events.
The grading criteria listed below will supersede any in the NCI-CTCAE manual.
All adverse events whether or not listed in the NCI-CTCAE will be graded on a scale from 1 to 5 according to the
following standards in the NCI-CTCAE manual (A semi-colon indicates “or” within the description of the grade.):
• Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
indicated.
• Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental
ADL (preparing meals, shopping for groceries or clothes, using the telephone, money, etc).
• Grade 3 = Severe or medically signiﬁcant but not immediately life-threatening; hospitalization or prolongation
of hospitalization indicated; disabling; limiting self care ADL (bathing, dressing and undressing, feeding self,
using he toilet, taking medications, and not bedridden).
• Grade 4 = Life-threatening consequences; or urgent intervention indicated.
• Grade 5 = Death related to AE.
Adverse events not included in the NCI-CTCAE listing or which have relative speciﬁcity for this protocol will be
recorded and graded 1 to 5 according to the grade deﬁnition provided below:
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ADVERSE EVENT: ANAPHYLAXIS
Deﬁnition: A disorder characterized by an acute inﬂammatory reaction resulting from the release of histamine and histamine-like substances from
mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difﬁculty, dizziness, hypotension, cyanosis and loss of
consciousness and may lead to death.
Grade 1 = Transient or mild discomforts (< 48 hours), no or minimal medical intervention/therapy required. These symptoms may include pruritus,
swelling or rash, abdominal discomfort or other transient symptoms.
Grade 2 = Symptoms that produce mild to moderate limitation in activity some assistance may be needed; no or minimal intervention/therapy is required.
Hospitalization is possible. These symptoms may include persistent hives, wheezing without dyspnea, abdominal discomfort/ increased vomiting or
other symptoms
Grade 3 = Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalization is possible. Symptoms
may include bronchospasm with dyspnea, severe abdominal pain, throat tightness with hoarseness, transient hypotension among others. Parenteral
medication(s) are usually indicated.
Grade 4 = Extreme limitation in activity, signiﬁcant assistance required; Signiﬁcant medical/therapy. Intervention is required; hospitalization is probable.
Symptoms may include persistent hypotension and/or hypoxia with resultant decreased level of consciousness associated with collapse and/or
incontinence or other life threatening symptoms.
Grade 5 = Death
ADVERSE EVENT: CARDIAC ARRHYTHMIA (CONDUCTION DISORDER)
Deﬁnition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Grade 1 = Mild symptoms; intervention not indicated
Grade 2 = Moderate symptoms
Grade 3 = Severe symptoms; intervention indicated
Grade 4 = Life-threatening consequences; urgent intervention indicated
Grade 5 = Death
ADVERSE EVENT: BRONCHOSPASM
Deﬁnition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Grade 1 = Mild symptoms; intervention not indicated
Grade 2 = Symptomatic; medical intervention indicated; limiting instrumental ADL
Grade 3 = Limiting self care ADL; oxygen saturation decreased
Grade 4 = Life-threatening respiratory or hemodynamic compromise; intubation or urgent intervention indicated
Grade 5 = Death
ADVERSE EVENT: COUGH
Deﬁnition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the
lungs and usually accompanied by a distinctive sound.
Grade 1 = Mild symptoms; nonprescription intervention indicated
Grade 2 = Moderate symptoms, medical intervention indicated; limiting instrumental ADL
Grade 3 = Severe symptoms; limiting self care ADL
Grade 4 = N/A
Grade 5 = N/A
ADVERSE EVENT: FEVER
Deﬁnition: A disorder characterized by elevation of the body’s temperature above the upper limit of normal.
Grade 1= 38.0 - 39.0 degrees C (100.4- 102.2 degrees F) despite use of acetaminophen
Grade 2= >39.0 - 40.0 degrees C (102.3- 104.0 degrees F) despite use of acetaminophen
Grade 3= >40.0 degrees C (>104.0degrees F) for <24 hrs despite use of acetaminophen
Grade 4= >40.0 degrees C (>104.0degrees F) for >24 hrs despite use of acetaminophen
Grade 5= Death
ADVERSE EVENT: NAUSEA
Deﬁnition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Grade 1 = Loss of appetite without alteration in eating habits
Grade 2 = Oral intake decreased without signiﬁcant weight loss, dehydration or malnutrition
Grade 3 = Inadequate oral caloric or ﬂuid intake, likely associated with losses due to vomiting; hospitalization may be warranted
Grade 4 = N/A
Grade 5 = N/A
ADVERSE EVENT: ABDOMINAL PAIN
Deﬁnition: A disorder characterized by pain or discomfort localized to the abdominal cavity.
Grade 1 = Mild: possibly associated with loss of appetite without alteration in eating habits, or normal activity
Grade 2 = Moderate: Oral intake and normal activity decreased without signiﬁcant weight loss, dehydration or malnutrition
Grade 3 = Severe: Inadequate oral caloric or ﬂuid intake; debilitating pain causing signiﬁcant curtailment of normal activity
Grade 4 = N/A
Grade 5 = N/A
8.2.3.2
Deﬁnition of Attribution
The attribution, of an adverse event to the study will initially be determined
by the Principal Investigator or designated physician co/sub-investigator. The Principal Investigator or designee
will record the determination of attribution on the appropriate adverse event or serious adverse event form. The
attribution of an adverse event to the investigational drug(s) or other study drug (s) will be determined using the
descriptors in the following table.
For the purpose of this study, in addition to all study medications, the following interventions/procedures will be
considered when determining attribution:
8.2.3.2.1
Products
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• Peanut ﬂour
• Placebo (oat) ﬂour
8.2.3.2.2
Interventions
• Titration Skin Testing
• Double Blind Placebo Controlled Food Challenge
• Desensitization
Code
Descriptor
Deﬁnition (guidelines)
UNRELATED CATEGORIES
1
Unrelated
The adverse event is clearly not related to study. The event is completely related to an etiology
other than the study product or study intervention (the alternative etiology must be documented
in the study participant’s medical record).
2
Unlikely
The adverse event is doubtfully related to study and likely to be related to factors other than
study product or study intervention.
RELATED CATEGORIES
3
Possible
The adverse event may be related to study. There is an association between the event and the
administration of study product and there is a plausible mechanism for the event to be related
to the study product; there may be also an alternative etiology, such as characteristics of the
participant’s clinical status and/or underlying disease.
4
Probable
The adverse event is likely related to study. There is (1) an association between the event and
the administration of study product or study intervention, (2) a plausible mechanism for the
event to be related to the study product, and (3) the event could not be reasonably explained
by known characteristics of the participant’s clinical status and or an alternative etiology is not
apparent.
5
Deﬁnite
The adverse event is clearly related to study. There is (1) an association between the event
and the administration of the study product or study intervention, (2) a plausible mechanism
for the event to be related to the related to the study product, and (3) causes other than the
study product have been ruled out and/or the event re-appeared on re-exposure to the study
product.
(For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE website:
http://ctep.cancer.gov/reporting/ctc.html) will be consulted.
In a clinical trial, the study product/intervention will always be suspect when attributing an AE and the “unrelated”
attribution will be used only when there is an indisputable or likely alternative explanation for the AE.
8.2.4
SAE Reporting Criteria and Procedures
The Principal Investigator will be notiﬁed by the study staff as soon as a staff member becomes aware of the
SAE. In the absence of the Principal Investigator, a physician sub-investigator will be notiﬁed.
8.2.4.1
Notifying the NIAID Medical Ofﬁcer
The NIAID Medical Ofﬁcer and the Independent Safety will be
notiﬁed by the Principal Investigator no later than 24 hours after the investigative site becomes aware of the SAE,
regardless of the presumed relationship to the study product. Reporting to the NIAID Medical Ofﬁcer will utilize
an initial SAE case report form in draft format. Contact information for the NIAID Medical Ofﬁcer is listed below:
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Lisa Wheatley, MD NIAID, NIH
6610 Rockledge Drive, Room 6613
Bethesda, MD 20892-6601
Tel 301-451-3181 or 301-641-1301
lisa.wheatley@nih.gov
Within another 24 hours, the NIAID Medical Ofﬁcer, Independent Safety Monitor, and the Principal Investigator
will discuss the impact of the SAE on the participant and on the study and the NIAID Medical Ofﬁcer will decide
whether standard or expedited reporting will be applied. A ﬁnalized, initial SAE case report form (Appendix 16.3)
and a MedWatch 3500A form will be generated by the Principal Investigator and must be approved by the NIAID
Medical Ofﬁcer. The ﬁnalized, NIAID-approved case report form will be placed in the participant study chart.
Both forms will be sent to the NIAID Medical Ofﬁcer. As additional clinical information is obtained by the Principal
Investigator regarding the SAE, the SAE case report form and the MedWatch 3500A will be revised and submitted
to the NIAID Medical Ofﬁcer and the Independent Safety Monitor.
8.2.4.2
Unexpected, Non-Serious Adverse Events
An unexpected, non-serious adverse event that is of
Grade 2 severity or higher and study related will be recorded and reported to the Independent Safety Monitor and
the NIAID Medical Ofﬁcer under the serious adverse event reporting procedure outlined in the SAE Reporting
and Criteria Section (Section 8) of the protocol (i.e. within 24 hours).
8.2.4.3
Notifying the FDA
The IND Sponsor is responsible for FDA safety submissions as follows:
The following process for reporting a serious adverse event ensures compliance with the ICH guidelines, 21 CFR
46 and 21CFR Section 312.32.
8.2.4.3.1
Expedited reporting to the FDA applies if the adverse event is considered as:
• Serious and unexpected suspected adverse reaction (SUSAR) (Sections 8.2.1.4, 8.2.1.5 and 8.2.3.2) OR
• Aggregate analysis of serious adverse events that suggest a causal relationship to the study medications
OR
• Any ﬁndings from clinical, epidemiological, pooled analysis of data pooled across multiple studies, published
or unpublished scientiﬁc papers or any ﬁndings from animal or in vitro testing that would result in a safety-related
change in the protocol, informed consent, investigator brochure or other aspects of the overall conduct of
the trial will be reported.
Expedited events will be reported by the IND Sponsor within 15 calendar days after the IND sponsor becomes
aware of the SAE; fatal or life-threatening events will be reported within 7 calendar days. Each 7-day report must
be followed up by a 15-day report.
The Sponsor will monitor the safety database and comply with 21CFR 312.32
SAEs that do not strictly ﬁt the above criteria may be reported to the FDA in an expedited manner if the IND
Sponsor or the NIAID Medical Ofﬁcer chooses to do so.
8.2.4.3.2
Standard reporting (non-expedited)
All SAEs not meeting the criteria for expedited reporting will
be reported to the FDA in the IND Annual Report. As such, they are classiﬁed as one of the following:
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• Serious, expected, suspected adverse reactions
• Serious and not a suspected adverse reaction
For standard reporting, the IND Sponsor will ﬁle the IND Annual Report.
The Principal Investigator will be
responsible for compiling the IND Annual Report.
8.2.4.4
Notifying the Data and Independent Safety Monitor (ISM)
The Principal Investigator is responsible
for submitting all expedited SAEs on an ongoing basis to the Independent Safety Monitor. Individual or clusters
of SAEs may be reported expeditiously to the ISM either when speciﬁed by the ISM, or upon determination of the
NIAID Medical Ofﬁcer.
8.2.4.5
Notifying the Institutional Review Board
The Principal Investigator will ensure the timely dissemination
of SAE information, including expedited reports, to the IRB in accordance with IRB regulations and guidelines.
8.2.4.6
Notifying the Clinical Sites
NA
8.2.4.7
Reporting Pregnancy
The investigator will be informed immediately of any pregnancy and will report
all pregnancies within 24 hours to the NIAID Medical Ofﬁcer (as described in Section 8.2.4.1) utilizing the SAE
report form. This report is for tracking purposes only. All pregnancies that are identiﬁed during the study will be
followed to conclusion and the outcome of each will be reported. The investigator will discuss with the participant
and/or the treating physician the known possible risks of the investigational product(s) on the fetus. Monitoring of
the participant will continue until the conclusion of the pregnancy, and a follow-up SAE report form detailing the
outcome of the pregnancy will be submitted to the NIAID Medical Ofﬁcer and Project Manager. If a participant is
found to be pregnant they will be terminated from the study.
8.2.5
Non Serious Adverse Events (NSAES) Reporting
8.2.5.1
Notifying the Independent Safety Monitor
The Principal Investigator will provide the Independent
Safety Monitor with a listing of all AEs in a NIAID-provided standard format and timeline for review during planned
protocol reviews. Individual or clusters of AEs may be reported expeditiously to the ISM either when speciﬁed by
the ISM, or upon determination of the NIAID Medical Ofﬁcer.
8.2.5.2
Notifying the Institutional Review Board
The Principal Investigator will ensure the timely dissemination
of AE information to the IRB in accordance with applicable regulations and guidelines.
8.3
Protocol Deviations
The practices below are consistent with Good Clinical Practice (GCP ICH E6) Sections:
• Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3
• Quality Assurance and Quality Control, section 5.1.1
• Noncompliance sections 5.20.1, and 5.20.2
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8.3.1
Protocol Deviation Deﬁnitions
8.3.1.1
Protocol Deviation
- Any change, divergence, or departure from the study design or procedures of a
research protocol that affects the participant’s rights, safety, or well being and/or the completeness, accuracy and
reliability of the study data constitutes a protocol violation. Changes or alterations in the conduct of the trial which
do not have a major impact on the participant’s rights, safety or well-being, or the completeness, accuracy and
reliability of the study data are considered minor protocol deviations. The Principal Investigator is responsible for
reporting protocol deviations to the IRB using the standard reporting form. As a result of deviations, corrective
actions are to be developed by the site and implemented promptly.
8.3.1.2
Major Protocol Deviation
– A protocol violation is a deviation from the IRB approved protocol that
may affect the participant’s rights, safety, or well being and/or the completeness, accuracy and reliability of the
study data.
If the deviation meets any of the following criteria, it is considered a major protocol deviation (protocol violation).
Example list is not exhaustive.
1. The deviation has harmed or posed a signiﬁcant or substantive risk of harm to the research participant.
Examples:
• A research participant received the wrong treatment or incorrect dose.
• A research participant met withdrawal criteria during the study but was not withdrawn.
2. The deviation compromises the scientiﬁc integrity of the data collected for the study. Examples:
• A research participant was enrolled but does not meet the protocol’s eligibility criteria.
• Failure to treat research participants per protocol procedures that speciﬁcally relate to primary efﬁcacy
outcomes. (if it involves patient safety it meets the ﬁrst category above)
• Changing the protocol without prior IRB approval.
• Inadvertent loss of samples or data.
3. The deviation is a willful or knowing breach of human participant protection regulations, policies, or procedures
on the part of the investigator(s). Examples:
• Failure to obtain informed consent prior to initiation of study-related Procedures
• Use of outdated or incorrect consent forms
• Falsifying research or medical records
• Performing tests or procedures beyond the individual’s professional scope or privilege status (credentialing)
4. The deviation involves a serious or continuing noncompliance with federal, state, local or institutional human
participant protection regulations, policies, or procedures. Examples:
• Working under an expired professional license or certiﬁcation
• Failure to follow federal and/or local regulations, and intramural research
• Repeated minor deviations.
5. The deviation is inconsistent with the NIH Human Research Protection Program’s research, medical, and
ethical principles. Examples:
• A breach of conﬁdentiality.
• Inadequate or improper informed consent procedure.
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8.3.1.3
Non-Major Protocol Deviation
A non-major protocol deviation is any change, divergence, or departure
from the study design or procedures of a research protocol that has not been approved by the IRB and which
DOES NOT have a major impact on the participant’s rights, safety or well-being, or the completeness, accuracy
and reliability of the study data.
8.3.2
Reporting Protocol Deviations
Upon determination that a protocol deviation has occurred, the study staff will a) notify the Principal Investigator,
b) notify the NIAID Project Manager(refer to investigator’s signature page for contact information) and c) will
complete the Protocol Deviation form (Appendix 4). NIAID may request discussion with the Principal Investigator
and the Independent Safety Monitor to determine the effect of the protocol deviation on the study participant and
his/her further study participation, the effect of the protocol deviation on the overall study and corrective actions.
The Principal Investigator will complete and sign the Protocol Deviation form and submit it to the NIAID Medical
Ofﬁcer and Project Manager, to the Independent Safety Monitor and to the site IRB, per IRB regulations. Major
protocol deviations will be reported to the ISM by the NIAID Medical Ofﬁcer. The IND sponsor will be responsible
for notifying the FDA.
All study staff be educated about the adverse event reporting policy, and will be instructed to notify an investigator
if an event occurs.
9
SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN
9.1
Sample Size and Power Calculations
As the hypothesis regarding Treg induction and clonal tolerance can only be deﬁned among those individuals
who achieve desensitization and go on to DBPCFC3, the analysis will be per protocol for those participants who
complete both post treatment challenges. The difference in the proportion of Treg will be compared between
the groups using Students t test for comparison of means. Because we are expecting the primary outcome
variable (difference in the proportion of Treg) to be log-normally distributed, we plan to carry out the t test on the
log transformed variable. We will be powered at the expected effect on Treg if as few as six individuals (20%
clinical effect and 10% dropout) who complete the protocol achieve our deﬁned measure of at least partial clinical
tolerance. Table 15.6 shows power calculations around these assumptions using a two sided t test at an alpha
level of 0.05.
The sample size selected is 30 active treatment and 10 placebo treatment.
We are applying the following
assumptions for our power analysis (see Figure 15.5 for schema of assumptions).
• Approximately 27% of the Active Treatment group (8/30) will achieve Partial Tolerance (ED at DBPCFC3
<4430 mg but ≥430 mg AND >10-fold more than at DBPCFC1) or Full Tolerance (no reaction at DBPCFC3).
• The comparison of interest is between the combined Tolerance/Partial Tolerance and Active Treatment
Failure groups who complete DBPCFC3.
• Those who fail to become desensitized after active treatment and those who receive placebo treatment are
not fully informative for the primary endpoint and are therefore excluded for the per protocol analysis.
• The difference from baseline to the end of maintenance therapy in the mean proportion of induced Treg
(CD45RA- CD25++ FoxP3++ of CD4+ T cells) between the Tolerance/Partial Tolerance and Treatment
Failure groups will be 1.5 times the standard deviation.
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The placebo group will be used primarily to assess whether and to what extent there are more AEs associated
with treatment. However, we will be able to also perform an intention to treat analysis of the primary outcome
(difference in Treg proportion at the second blood draw from baseline) including the Placebo group. There is
no expected effect on Treg in the placebo group and as above the comparison of interest is of outcomes within
the actively treated participants who complete DBPCFC3. Estimating that 27% of active arm treatment achieve
signiﬁcant tolerance (n=8; see Figure 15.5) and that all Placebo group participants are deﬁned as Treatment
Failures after DBPCFC2 (n=10) and that the remaining Active Treatment participants will lose tolerance during
avoidance (n=14), then we will have 100% power at an ↵level of 0.05 to detect the expected 1.5 X SD difference.
9.2
Data Analysis
9.2.1
General Considerations
Data will be collected and curated in a REDCap database [? ] with support from the Human Subjects Core and
exported into a suitable analysis format (e.g. STATA, SPSS, R analysis) for analysis. For continuous variables
that are normally distributed we will summarize them using mean with standard derivations and for those that are
non-normally distributed, we will summarize with medians and inter-quartile ranges. For dichotomous data we
will provide proportions. In addition to the baseline and outcome data, we will also summarize the recruitment
numbers, those participants lost to follow-up, protocol violations and other relevant data.
9.2.2
Study Participant Populations
As described above, the per protocol sample will consist of all active treatment participants completing DBPCFC3.
9.2.3
Study Participant Baseline Characteristics and Demographics
Summary of descriptive statistics for baseline and demographic characteristics will be provided for all enrolled
participants. Demographic data will include age, race, sex, body weight, and height; these data will be presented
in the following manner: summary tables.
9.2.4
Study Endpoints
9.2.4.1
Primary Endpoint
The difference in the proportion of induced Treg cells (CD45RA- CD25++ FoxP3++
of CD4+ T cells) from baseline to the end of maintenance therapy.
9.2.4.1.1
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 <1443 mg at DBPCFC2, or ED at DBPCFC3 <430 mg OR <10-fold more than at
DBPCFC1.
• Partial Tolerance: ED at DBPCFC3 <4430 mg but ≥430 mg AND >10-fold more than at DBPCFC1.
• Tolerance: Ingestion of 4430 mg of peanut protein at DBPCFC3 without symptoms.
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9.2.5
Study Completion
The percent of participants who complete the study, losses to follow-up, time to lost to follow-up, and reasons
for discontinuation (e.g., adverse events) will be tracked and presented in tabular form. For the primary outcome
(Tolerance as deﬁned above), the analysis will be performed as per protocol for all participants who complete the
modiﬁed rush visit. For immune / mechanistic outcomes, missing or spurious data will be excluded from analyses.
9.3
Interim Analyses
An interim safety analysis will be performed after the ﬁrst ﬁve patients have undergone desensitization and dosage
escalation. Aleena Banerji, MD has agreed to serve as an independent medical monitor during this analysis
and also thereafter. The interim analyses will asses if the rate of adverse advents occurring during the study
procedures are similar to previous studies and to determine if any protocol amendments are needed to address
the clarity of study procedures and/or participant education. We will also have an interim review after one year of
recruitment at the request of the NIAID DSMB.
9.4
Deviations from Statistical Plan
The principal features of the study design and of the plan for statistical analysis of the data are outlined in this
protocol. Any changes in these principal features will require a protocol amendment and will be described in the
ﬁnal report. Any such changes will be subject to review by the IRB, ISM, NIAID, and the FDA.
10
IDENTIFICATION AND ACCESS TO SOURCE DATA
10.1
Identifying Source Data
The investigator will keep accurate records to ensure that the conduct of the study is fully documented. Data
derived from source documents will be transferred to protocol-speciﬁc CRFs. The results of all clinical and clinical
laboratory evaluations will be maintained in the participant’s medical records or hospital database and the data
will be transferred to clinical CRFs, as applicable.
10.2
Updating Source Documentation
Documents describing the safety proﬁle of an investigational product(s) / Intervention material(s), such as the
investigator’s brochure and the package insert, will be amended as needed by the investigational product(s) /
Intervention material(s) manufacturer to ensure that the description of safety information adequately reﬂects any
new clinical ﬁndings.
(The Principal Investigator will provide the Independent Safety Monitor, the NIAID Medical Ofﬁcer, and the IRB
with the most up-to-date versions of the above documents as soon as the Principal Investigator becomes aware
of any changes. For purchased investigational product(s) / Intervention material(s), the Principal Investigator will
conﬁrm that there are no changes to the package insert every 3 months. In case of package insert changes, the
Principal Investigator will notify the Independent Safety Monitor the NIAID Medical Ofﬁcer, and the IRB.
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10.3
Permitting Access to Source Data
The investigational site participating in this study will maintain the highest degree of conﬁdentiality for the clinical
and research information obtained from the participants in this clinical trial.
Medical and research records
will be maintained at each site in the strictest conﬁdence. However, as a part of the quality assurance and
legal responsibilities of an investigation, the investigational site will permit authorized representatives of the IND
sponsor, NIAID and health authorities to examine (and when required by applicable law, to copy) clinical records
for the purpose of quality assurance reviews, audits, and evaluations of the study safety and progress. Unless
required by the laws that permit copying of records, only the coded identity associated with documents or with
other participant data may be copied (and all personally identifying information will be removed). Authorized
representatives as noted above are bound to maintain the strict conﬁdentiality of medical and research information
that is linked to identify individuals.
11
QUALITY CONTROL AND QUALITY ASSURANCE
The Principal Investigator will keep accurate records to ensure that the conduct of the study is fully documented.
The investigator will ensure that all CRFs and participant study ﬁles are legible and complete for every participant.
The Principal Investigator, through the use of a Clinical Research Associate (CRA) will be responsible for the
regular review of the conduct of the trial, for verifying adherence to the protocol, and for conﬁrming the completeness,
consistency, and accuracy of all documented data and accuracy of source documentation veriﬁcation. The reports
of the CRA will be submitted to the Principal Investigator and the NIAID Project Manager. NIAID will independently
review these reports.
When the CRFs are complete, they will be reviewed and signed by the Principal Investigator. All discrepancies
identiﬁed by the CRA or NIAID will be reviewed, and any resulting queries will be resolved with the Principal
Investigator and the CRFs will be amended as needed.
12
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL
PRACTICE
12.1
Statement of Compliance
This study was designed to ensure the protection of participants according to the ethical principles of the Declaration
of Helsinki and amendments concerning medical research in human participants.
This clinical study will be
conducted using current good clinical practice (cGCP), as delineated in Guidance for Industry: E6 Good Clinical
Practice Consolidated Guidance 1 , and according to the criteria speciﬁed in this study protocol. Before study
initiation, the protocol and the informed consent documents will be reviewed and approved by NIAID, ISM, IRB,
as well as any other appropriate health authorities. Any amendments to the protocol or to the consent materials
will also be approved by the appropriate bodies listed above prior to implementation.
12.2
Informed Consent and Assent
The informed consent form will provide information about the study to a prospective participant or participant’s
legal representative to allow for an informed decision about participation in the study.An age-appropriate assent
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form will be provided for children under 14 years of age. Prospective participant or participant’s legal representative
must be given ample opportunity to review the informed consent and inquire about the results of the study. All
participants (or their legally acceptable representative) must read, sign, and date a consent form prior to study
participation. Subjects under 14 years old must read, sign, and date an assent form. Consent materials for
participants who do not speak or read English will be translated into the participants’ appropriate language.
The informed consent form will be revised and receive IRB approval whenever important new safety information
is available, whenever the protocol is amended, and/or whenever any new information becomes available that
may affect participation in the trial.
A copy of the appropriate informed consent or assent form will be given to a prospective participant for review.
The Principal Investigator or an approved designee, will discuss the consent with the prospective participant and
answer questions. The prospective participant will be told that being in the trial is voluntary and that he or she
may withdraw from the study at any time, for any reason.
12.3
Privacy and Conﬁdentiality
A participant’s privacy and conﬁdentiality will be respected throughout the study. Each participant will be assigned
a sequential identiﬁcation number and these numbers rather than names will be used during collection, storage,
and reporting of participant information.
13
PUBLICATIONS
Publication of any data form this study must be carried out in accordance with the clinical or mechanistic study
agreement.
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14
REFERENCES
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15
15.1
Study Schematic
Baseline evaluation 
•Informed consent
•Medical History
•Physical Exam
•Baseline Blood Draw
•Endpoint dilution skin testing
•Nutrition Consult
Active n~30
Placebo n~10
Day 28
DBPCFC 1
Randomization 3:1 (N=40)
Modiﬁed Rush
Day 42
Build Up
Days 43-350
Maintenance Therapy (4000 mg) 12 weeks
Days 350-434
DBPCFC 2
Day 434
6000 mg w/o Sxs
Desensitization
Resume Avoidance
>10X DBPCFC 1 w/o Sxs
Partial Desensitization
<10X DBPCFC 1 w/o Sxs
Treatment Failure
Failure to reach at least 
600 mg by week 50
Treatment Failure 
Post Rx 
Avoidance(Active)
Days 434-518
DBPCFC 3
6000 mg w/o Sxs
Tolerance
>10X DBPCFC 1 w/o Sxs
Partial Tolerance
<10X DBPCFC 1 w/o Sxs
Treatment Failure
Day 518
ED >444 mg
Withdrawn from study 
and will be replaced
Visit 29 Blood Draw
Visit 27 Blood Draw
Visit 1 Blood Draw
Assessment of Outcomes
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15.2
Modiﬁed Rush Dosing Schedule
Dose no.
Peanut Dose (mg protein)
Cumulative Peanut Dose (mg protein)
1
0.1
0.1
2
0.2
0.3
3
0.4
0.7
4
0.8
1.5
5
1.5
3.0
6
*3.0
6.0
7
6.0
12
⇤Minimum dose necessary to continue
15.3
Build Up Dosing Schedule
Note: Build Up dosing may begin at dose 7 if maximum tolerated at Modiﬁed Rush was 3 mg
Dose no.
Dose (mg protein)
Interval (weeks)
% Increase
8
12
2
1.0
9
25
2
1.08
10
50
2
1.00
11
75
2
0.50
12
100
2
0.33
13
125
2
0.25
14
160
2
0.28
15
200
2
0.25
16
245
2
0.23
17
300
2
0.22
18
385
2
0.28
19
480
2
0.25
20
600
2
0.25
21
750
2
0.25
22
940
2
0.25
23
1200
2
0.28
24
1465
2
0.22
25
1830
2
0.25
26
2285
2
0.25
27
2860
2
0.25
28
3575
2
0.25
29
4000
2
0.12
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15.4
Treatment Table
Signs / Symptoms
Treatments
LUNG: wheeze, cough
1. Epinephrine, IM; auto-injector or 1:1,000 solution IM (anterior-lateral thigh)
• 0.3 mg epinephrine autoinjector, IM (anterior-lateral thigh) OR
• Epinephrine (1:1,000 solution) (IM), 0.01 mg/kg per dose; maximum
dose, 0.5 mg per dose (anterior-lateral thigh)
2. H1 antihistamine: diphenhydramine
• 1 to 2 mg/kg per dose
• Maximum dose, 50 mg IV or oral (oral liquid is more readily absorbed
than tablets)
3. Bronchodilator (b2-agonist): albuterol
• MDI (child: 4-8 puffs; adult: 8 puffs) or
• Nebulized solution (child: 1.5 ml; adult: 3 ml) every 20 minutes or
continuously as needed
4. Supplemental oxygen therapy
5. Corticosteroids
• Prednisone at 1 mg/kg with a maximum dose of 60 to 80 mg oral or
• Methylprednisolone at 1 mg/kg with a maximum dose of 60 to 80 mg
IV
HEART:
hypotension,
cardiovascular collapse
1. Epinephrine, IM; auto-injector or 1:1,000 solution
• Same as above
2. H1 antihistamine: diphenhydramine
• Same as above
3. Corticosteroids
• Same as above
4. H2 antihistamine: ranitidine
• 1 to 2 mg/kg per dose
• Maximum dose, 75 to 150 mg oral or IV
5. Vasopressors (other than epinephrine) for refectory hypotension, titrate to
effect
6. Glucagon for refractory hypotension, titrate to effect
• Child: 20-30 mg/kg
• Adult: 1-5 mg
• Dose may be repeated or followed by infusion of 5-15 mg/min
7. Atropine for bradycardia, titrate to effect
8. IV ﬂuids in large volumes if patient presents with orthostasis, hypotension,
or incomplete response to IM epinephrine
9. Place the patient in recumbent position if tolerated, with the lower extremities
elevated
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Signs / Symptoms
Treatments
THROAT: hoarse, swelling
1. Epinephrine, IM; auto-injector or 1:1,000 solution
• Same as above
2. H1 antihistamine: diphenhydramine
• Same as above
3. Corticosteroids
• Same as above
4. Consider H2 antihistamine: ranitidine
• Same as above
SKIN: hives, swelling, pruritus
1. H1 antihistamine: diphenhydramine
• Same as above
2. Consider Epinephrine, IM; auto-injector or 1:1,000 solution
• Same as above
3. Consider H2 antihistamine: ranitidine
• Same as above
GUT:
vomiting,
nausea,
diarrhea, pain or discomfort
1. H1 antihistamine: diphenhydramine
• Same as above
2. Consider Epinephrine, IM; auto-injector or 1:1,000 solution
• Same as above
3. Consider H2 antihistamine: ranitidine
• Same as above
MOUTH: hives, swelling, oral
pruritus
1. H1 antihistamine: diphenhydramine
• Same as above
2. Consider Epinephrine, IM; auto-injector or 1:1,000 solution
• Same as above
3. Consider H2 antihistamine: ranitidine
• Same as above
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15.5
Study Assumptions
8  
Desensitization 
Failures 
40 Subjects Total 
10 Placebo 
30 Active Treatment 
22 
 Desensitized 
Without Drop out 
Tolerant 
Failure 
Clinical 
Effect 
Size 
10 
12 
33% 
8 
14 
27% 
7 
15 
22% 
10 
Desensitization 
Failures 
0  
Desensitized 
Randomization 
Build-Up 
DBPCFC2 
DBPCFC1 
DBPCFC3 
DBPCFC2 
Post-Avoidance 
With 10% Drop out 
No Drop 
Out 
With 10% 
Drop Out 
Clinical 
Effect 
Size 
9 
10 
33% 
7 
12 
27% 
6 
13 
22% 
Participant outcomes predicted from varying clinical effect and retention.
We estimate that 75% of subjects
will achieve Desensitization at DBPCFC2. Tolerance is deﬁned at DBPCFC3. There are 3 possible outcomes following
DBPCFC3 illustrated here, with what we have called the clinical effect size (the percent of active treatment subjects who
become tolerant or partially tolerant): 33%, 27% and 22% clinical effect size. We will be powered at the expected effect size
if as few as six individuals (22% clinical effect and 10% dropout) who complete the protocol achieve our deﬁned measure
of at least partial clinical tolerance. Table 15.6 shows power calculations for several permutations of effect size and sample
size around these assumptions using a two sided analysis with an alpha level of 0.05.
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15.6
Power Analysis for Comparison of Tolerance and Treatment Failure groups
Clinical Effect
Tol
Fail
power
Tol
Fail
power
33%
10
12
0.97
9
10
0.95
27%
8
14
0.96
7
12
0.93
23%
7
15
0.95
6
13
0.92
Treg difference = 1.75σ
Clinical Effect
Tol
Fail
power
Tol
Fail
power
33%
10
12
0.91
9
10
0.87
27%
8
14
0.90
7
12
0.84
23%
7
15
0.88
6
13
0.82
Treg difference = 1.5σ
Clinical Effect
Tol
Fail
power
Tol
Fail
power
33%
10
12
0.79
9
10
0.73
27%
8
14
0.77
7
12
0.70
23%
7
15
0.74
6
13
0.67
Treg difference = 1.25σ
Power calculations for varying clinical effect and Treg effect sizes using a two sided t test (↵=0.05).
The
difference in induced Treg proportion between combined Partial Tolerance and Tolerance groups (Tol) versus the Active
Treatment Failure group (Fail) is the primary endpoint. We are hypothesizing a difference in Treg proportion (mean of
log-transformed data) of 1.5σ (based on Jones, et al. [? ]). Left side of table without drop out; right side with drop out (10%
of the estimated 22 avoiding between DBPCFC2 and DBPCFC3).
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16
APPENDICES
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16.1
Schedule of Events
Time Points (day)
-7
0
28
42
43–350
350–434
434
434–518
518
Visit
0
1
2
3
4 to 25
26 to 28
28
29 to 31
31
(Screening)
(Baseline)
(DBPCFC1)
(Modiﬁed Rush)
(Build Up)
(Maintenance)
(DBPCFC2)
(Avoidance)
(DBPCFC3)
GENERAL ASSESSMENTS
Informed consent
X
Medical history
X
X
X
X
X
X
X
X
X
Verify eligibility
X
Randomization
X
Physical exam
X
X
X
X
X
X
X
X
X
Pulmonary Function Testing
X
X
X
X
X
X
X
X
X
OIT Dosing
X
X
X
DBPCFC
X
X
X
AE assessment
X
X
X
X
X
X
X
X
Nutrition Consult
X
X
Skin prick test
X
Titration skin test
X
X (Visit 27)
X
LAB ASSESSMENTS
Urine pregnancy test
X
X
X
X
X
X
X
X
X
Mechanistic T cell
X
X (Visit 27)
X
Basophil Activation
X
X (Visit 27)
X
Mechanistic B cell
X
X (Visit 10)
X
sIgE, IgG4
X
X (Day 448)
X
Stool Collection (optional)
X
X (Every 3 months)
X (Every 6-12 months)
X (Every 6-12 months)
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16.2
Symptom Diary
Subject ID:
Subject Initials:
Date:
Symptom and Medication Use Diary
Week beginning on:
/
/
(MM/DD/YY)
Symptom: Please record symptoms every evening using the 5-point scale shown below:
Severity
Deﬁnition
0
Not bothered
1
Bothered a little (causing minimal awareness and easy to tolerate)
2
Bothered more than a little but not a lot (bothersome, but tolerable)
3
Bothered a lot (hard to tolerate; interferes with activities of daily living and/or sleeping)
4
Extremely bothered (very hard to tolerate; may require medications to relieve)
Symptom
Sunday
Monday
Tuesday
Wednesday Thursday
Friday
Saturday
LUNGS: wheeze, cough,
tightness
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
MOUTH/THROAT: itching,
swelling, obstruction,
hoarseness
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
SKIN: hives, itching,
swelling, redness
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
GUT: vomiting, nausea,
diarrhea, pain or
discomfort
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
HEART: passing out,
feeling faint, drowsiness
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
OTHER: please record
any other allergy-related
symptoms here
q 0
q 0
q 0
q 0
q 0
q 0
q 0
q 1
q 1
q 1
q 1
q 1
q 1
q 1
q 2
q 2
q 2
q 2
q 2
q 2
q 2
q 3
q 3
q 3
q 3
q 3
q 3
q 3
q 4
q 4
q 4
q 4
q 4
q 4
q 4
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Medications – list daily study doses, all prescription, PRN (as needed), OTC (over-the-counter) therapy
Medication Use
Sunday
Monday
Tuesday
Wednesday Thursday
Friday
Saturday
(Dose and Units)
study product
Subject Signature:
Date:
/
/
(MM/DD/YY)
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16.3
Serious Adverse Event Case Report Form
Participant ID:
Date of Report:
/
/
(MM/DD/YY)
SERIOUS
ADVERSE
EVENT
(SAE)
REPORTING FORM
(one form per SAE):
Initial Report
q
Follow-up Report
q
(if follow-up) Initial Report Date:
/
/
(MM/DD/YY)
Reason for SAE designation (select one):
q Death
q Life-threatening event
q Persistent or signiﬁcant disability / incapacity
q Congenital anomaly / birth defect
q Hospitalization
q Prolongation of hospitalization
q Other important medical event
q
Required
signiﬁcant
disability/
incapacity
or
substantial
disruption of the ability to conduct normal life functions
q Other reason
(Pregnancy should be
recorded here)
1.
Date of SAE:
/
/
(MM/DD/YY)
2.
Date site became aware of the SAE:
/
/
(MM/DD/YY)
3.
SAE description:
(attach continuation form, if needed)
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
4.
Relation to the Study:
q Unrelated
q Unlikely related
q Possibly related
q Probably related
q Deﬁnitely related
5.
Relation to the investigational product, other product or to a study procedure:
(attach continuation form, if needed)
6.
Life Threatening:
YES
q
NO
q
7.
EXPECTED
q
UNEXPECTED
q
8.
Other relevant history including preexisting medical conditions and concomitant medications:
(attach continuation form, if needed)
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
9.
Relevant tests and laboratory data (include dates):
(attach continuation form, if needed)
10.
Action taken:
(attach continuation form, if needed)
11. If the participant was hospitalized:
q
not applicable
Date of admission:
/
/
(MM/DD/YY)
Date of discharge:
/
/
(MM/DD/YY)
12.
Outcome of Event:
q Resolved, no residual effects; date:
/
/
(MM/DD/YY)
q Resolved with sequelae;
date:
/
/
(MM/DD/YY)
q Persistent condition
q Death; date:
/
/
(MM/DD/YY)
13. List any sequelae:
not applicable
q
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
Name and Signature of Independent Safety Monitor
Date Completed
Name and Signature of Principal Investigator
Date Completed
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
SERIOUS ADVERSE EVENT REPORTING FORM CONTINUATION PAGE
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16.4
Protocol Deviation Report Form
Participant ID:
Date of Report:
/
/
(MM/DD/YY)
PROTOCOL DEVIATION REPORTING FORM
(one form per deviation)
1.
Date Deviation occurred:
/
/
(MM/DD/YY)
2.
Date site staff became aware of Deviation:
/
/
(MM/DD/YY)
3.
Description of Deviation:
(attach continuation form, if needed)
4.
Circumstances explaining / contributing to the deviation:
(attach continuation form, if needed)
5.
Effect of Deviation on subject’s safety or risk from study participation:
q
No effect
q
Safety concern or increased risk
(A. AE or SAE form required B. Qualiﬁes as “major deviation”)
Explain why the deviation has (or has not) an effect on subject’s safety or risk from study participation. In case that
deviation has an effect please provide extent of potential safety impact:
(attach continuation form, if needed)
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
6.
Effect of Deviation on the quality of study data:
q
No effect
q
Potential effect on data quality
(Qualiﬁes as ”major deviation”)
Explain why deviation has (or has not) an effect on the quality of study data. In case that deviation has an effect
please provide extent of potential effect on data quality:
(attach continuation form, if needed)
7.
Major Deviation (as determined by the NIAID
Project Manager)
YES
q
NO
q
8.
Corrective action(s) to resolve this Deviation:
(attach continuation form, if needed)
9.
Corrective action(s) to prevent similar occurrences in the future:
(attach continuation form, if needed)
10.
Participant will continue as a study subject?
YES
q
NO
q
Justiﬁcation:
(attach continuation form, if needed)
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
11. Notiﬁcations
Date Notiﬁed
NIAID Project Manager
Independent Safety Monitor
IRB
Name and Signature of Independent Safety Monitor
(if required)
Date Completed
Name and Signature of Principal Investigator
Date Completed
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Participant ID:
Date of Report:
/
/
(MM/DD/YY)
PROTOCOL DEVIATION REPORTING FORM CONTINUATION PAGE
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