Phase 2 Randomised Study of Oral Immunotherapy Using Boiled Peanut to Induce Desensitisation in Children With Challenge-proven, IgE-mediated Peanut Allergy
Phase: NA
Conditions: IgE Mediated Peanut Allergy
Sponsor: Imperial College London

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Boiled!Oral!Peanut!Immunotherapy!
!for!the!treatment!of!Peanut!Allergy!
!(The!BOPI!Study)!
!
Version!2.6!dated!5!June!2018!
!
SPONSOR:!
!
Imperial!College!London!
FUNDING:!!
!
Imperial/NIHR!Biomedical!Research!Centre!!
STUDY!CENTRE:!! !
Imperial!College!London!
!
NRES!reference:!!!15/LO/0287!
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Protocol'authorised'by:'
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Name'&'Role'
Date'
Signature'
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PROTOCOL'SYNOPSIS'
!
!
Title!
Boiled!Oral!Peanut!Immunotherapy!for!the!treatment!of!Peanut!Allergy!
Abbreviated!title!
BOPI!study'
Clinical!Trials.gov!number!
NCT02149719!
NREC!Number!
London!Central!15/LO/0287!!
Sponsor!R&D!Number!
15SM2492!
IRAS!Number!
158693!
Primary!objectives!
To!evaluate!the!effectiveness!of!Oral!Immunotherapy!(OIT)!using!boiled!
peanut!to!induce!desensitization!to!roasted!peanut!in!children!with!IgE^
mediated!peanut!allergy!
Intervention!
Randomised!open!trial!of!12!months!of!oral!immunotherapy!using!a!
combination!of!boiled!followed!by!roasted!peanut.!Control!group!receive!
standard!clinical!care,!with!option!to!undergo!OIT!after!12!months.!!
Clinical!reactivity!to!roasted!peanut!will!be!determined!pre^!and!post^OIT!
using!double^blind,!placebo^controlled!food!challenge.!
Participants!will!be!invited!to!return!after!3!years!for!a!set!of!assessments!
to!determine!longer^lasting!tolerance!to!peanut.!
Safety!
Food!challenges!and!updosing!will!take!place!in!a!dedicated!hospital!
paediatric!research!unit,!by!personnel!qualified!in!the!recognition!and!
treatment!of!anaphylaxis,!and!observed!for!at!least!60!minutes!following!a!
dose.!!
All!families!will!be!provided!with!an!Allergy!Management!Plan,!rescue!
medication!including!adrenaline!autoinjector!devices,!and!appropriate!
training!in!the!recognition!and!management!of!allergic!reactions.!
Patient!group!
Children!and!young!people!with!a!diagnosis!of!IgE^mediated!peanut!allergy!
between!8!^16!years!old.!Target!recruitment!of!46!subjects!
Sponsor!
Imperial!College!London!
Funding!
NIHR!Biomedical!Research!Centre!at!the!Imperial!Academic!Health!Sciences!
Centre!(AHSC),!a!partnership!between!Imperial!College!Healthcare!NHS!
Trust!and!Imperial!College!London.!

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Study'Management'!
Chief!Investigator:!!
Dr!Paul!Turner,!Imperial!College!London!
!
Co^investigators:!!!
Dr!Marta!Vazquez^Ortiz,!Imperial!College!London!!
!
!
!
Dr!Mohamed!Shamji,!Imperial!College!London!
!
!
!
Dr!Audrey!Dunn^Galvin,!University!College!Cork!
!
!
!
Prof!Dianne!Campbell,!University!of!Sydney,!Australia!
!
!
!
Dr!Sam!Mehr,!Children’s!Hospital!at!Sydney,!Australia!
!
!
!
Dr!Bernhard!Gibbs,!Medway!School!of!Pharmacy,!!
!
Study!Management:!!
Ms!Sarah!Lindsley,!Imperial!College!London!
'
Independent'Data'Monitoring'Committee'
Chair:!
!
!!
Dr!Mich!Erlewyn^Lajeunesse,!University!of!Southampton!
Members:!
!!
Dr!Jonathan!Cohen,!University!College!London!Hospitals!
!
!
!
Mrs!Karen!Brunas,!Parent!of!peanut^allergic!child!
!
Sponsor'
Imperial!College!London!is!the!research!Sponsor!for!this!study.!!For!further!information!regarding!the!sponsorship!
conditions,!please!contact!the!Head!of!Regulatory!Compliance!at:!
!
!
!
Joint!Research!Compliance!Office!
Imperial!College!London!and!Imperial!College!Healthcare!NHS!Trust!
Room!5L10B,!5th!Floor!Lab!Block!
Charing!Cross!Hospital!
Fulham!Palace!Road!
London!W6!8RF!
Tel:!0203!311!0212!
Fax:!0203!311!0203!
'
Funding'
Funding!has!been!obtained!from!the!NIHR!Biomedical!Research!Centre!at!the!Imperial!Academic!Health!Sciences!Centre!
(AHSC),!a!partnership!between!Imperial!College!Healthcare!NHS!Trust!and!Imperial!College!London.!Mechanistic!
investigations!are!co^funded!through!a!Clinician!Scientist!award!from!the!Medical!Research!Council!to!Dr!Paul!Turner!
(Imperial!College!London).!
!
!
Clinical'Queries!
Clinical!queries!should!be!directed!to!Dr!Paul!Turner!(Imperial!College!London)!who!will!direct!the!query!to!the!
appropriate!person!
!
!
!
This!protocol!describes!the!BOPI!study!and!provides!information!about!procedures!for!entering!participants.!!Every!care!
was!taken!in!its!drafting,!but!corrections!or!amendments!may!be!necessary.!These!will!be!circulated!to!investigators!in!
the!study.!!Problems!relating!to!this!study!should!be!referred,!in!the!first!instance,!to!the!Chief!Investigator.!!
!
This!study!will!adhere!to!the!principles!outlined!in!the!NHS!Research!Governance!Framework!for!Health!and!Social!Care!
(2nd! edition).! It! will! be! conducted! in! compliance! with! the! protocol,! the! Data! Protection! Act! and! other! regulatory!
requirements!as!appropriate.!!
!
!

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AMENDMENT'HISTORY'
!
Amendment'
No.'
Protocol'
Version'
No.'
Date'issued'
Author(s)'
of'changes'
Details(of(Changes(made(
1"
2.1"
26(Oct(2015(
approved(
19.11.15(
Paul"
Turner"
1)!Change!inclusion!criteria![section!4.1]!to:!
i.!
Allow!for!the!assessment!of!potential!participants!
who!have!never!had!an!allergic!reaction!to!peanut,!
but!are!highly!likely!to!have!peanut!allergy!given!
diagnostic!testing.!
ii.!
Tolerance!to!¼!boiled!peanut!at!visit!3!(from!1!
peanut)!
2)!Follow^up!of!participants!excluded!from!the!study!due!to!
failure!to!tolerate!boiled!peanut!or!significant!reactions!
during!updosing![section!5.7.2]!
3)!Changing!some!of!the!in^hospital!updosing!stages!into!a!
split^dose!procedure!where!there!had!been!a!change!in!
boiling!time!e.g.!rather!than!give!4!peanuts!as!a!single!dose,!
to!split!this!into!1!peanut!followed!by!3!peanuts!30!minutes!
later![section!5.3.4.1]!
2"
2.2"
9(Dec(2015(
approved(
15.12.15(
Paul"
Turner"
1.! Assess!a!mobile!'app'!as!an!alternative!to!the!patient!
diaries!currently!being!used![sections!5.3.3!and!5.3.4]!
2.! Extended!laboratory!work![section!5.7.3]!
3.! Recruit!via!PIC!sites![section!5.1]!
3"
2.3"
28(Jan(2016(
Approved(
16(Feb(2016(
Paul"
Turner"
1.! Extension!of!observation!times!following!challenges!to!
minimum!2!hours!![sections!5.3/5.4]!
2.! Clarification!of!SPT!at!6!month!visit!revised!(non^
substantial!amendment)![section!5.7.1]!
4"
2.4"
8(April(2016(
Approved(
24(Apr(2016(
Paul"
Turner"
1.! Inclusion!of!cardiac!echocardiography!as!a!non^invasive!
assessment![section!5.2.3]!
2.! Extend!laboratory!work!on!patient!samples!section!
5.7.3]!
5"
2.5"
8(Feb(2017(
Approved(
19(Apr(2017(
Paul"
Turner"
1.! Inclusion!of!DNA!collection!(opt^in)![section!5.2.3]!
2.! Increase!in!blood!sample!volume!to!max!75ml!per!visit!
(no!change!in!per!kg!body!weight!volume)!
3.! Clarifications:!
i.! Blood!analyses!at!challenge!(5.2.3)!
ii.! Addition!of!blood!sample!at!13!months!(5.7.3)!
iii.! Correction!of!typo!in!12mth!challenge!(5.4.1)!
iv.! Updated!co^investigators!
v.! 24hr!follow^up!after!challenges!(5.2.2)!
vi.! Use!of!peanut!M&Ms!instead!of!peanut!(5.3.4.4)!
6"
(minor)"
2.5"
22(Mar(2018(
Approved(
19(Apr(2018(
Paul"
Turner"
Extension!to!study!end!date!(minor,!no!changes!to!protocol)!
7"
2.6"
5(June(2018(
(
Approved(
21(Jun(2018(
Paul"
Turner"
1.! Addition!of!year!3!assessments!with!associated!
extension!to!study!end!date!(section!5.7).!
2.! Change!in!maintenance!dose!beyond!1st!year!to!thrice!
weekly!dosing!(section!5.4.2)!

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GLOSSARY'OF'ABBREVIATIONS'
!
ABBREVIATION'
TERM'
AE!
Adverse!Event!
BSACI!
British!Society!for!Allergy!&!Clinical!Immunology!
DBPCFC!
Double!blind,!placebo^controlled!food!challenge!
FAQL^Q!
Food!Allergy!Quality!of!Life!^!Questionnaire!
IDMC!
Independent!Data!Monitoring!Committee!
LOAEL!
Lowest!observed!adverse!event!level!
NOAEL!
No!observed!adverse!event!level!
OIT!
Oral!Immunotherapy!
PN!
Peanut!
PSS!
Perceived!Stress!Scale!
QoL!
Quality!of!Life!
SAE!
Serious!adverse!event!
SAR!
Serious!adverse!reaction!
SCORAD!
SCORing!Atopic!Dermatitis!tool!
SPT!
Skin!Prick!test!
!
'

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TABLE'OF'CONTENTS'
PROTOCOL!SYNOPSIS!......................................................................................................................................................................................!2!
AMENDMENT!HISTORY...................................................................................................................................................................................!4!
GLOSSARY!OF!ABBREVIATIONS!.....................................................................................................................................................................!5!
1.!INTRODUCTION!............................................................................................................................................................................................!8!
1.1!BACKGROUND!.......................................................................................................................................................................................!8!
1.2!STUDY!RATIONALE!&!JUSTIFICATION!..............................................................................................................................................!8!
Study!hypothesis:.................................................................................................................................................!8!
2.!!STUDY!OBJECTIVES!.....................................................................................................................................................................................!9!
2.1!Primary!objective!.................................................................................................................................................................................!9!
2.2!Secondary!objectives!..........................................................................................................................................................................!9!
3.!!STUDY!DESIGN!..........................................................................................................................................................................................!10!
3.1!Study!outcomes!measures..............................................................................................................................................................!11!
3.1.1!Primary!study!outcome..........................................................................................................................!11!
3.1.2.!Secondary!study!outcomes!..................................................................................................................!11!
3.2!Study!design!rationale!.....................................................................................................................................................................!12!
4.!STUDY!POPULATION!................................................................................................................................................................................!13!
4.1.!Inclusion!criteria!...............................................................................................................................................................................!13!
4.2.!Exclusion!criteria!..............................................................................................................................................................................!13!
4.3.!Withdrawal!criteria!.........................................................................................................................................................................!13!
5!Study!procedures!.......................................................................................................................................................................................!14!
5.1!Recruitment!and!Screening!visits!..................................................................................................................................................!15!
5.2!Double^blind,!placebo^controlled!food!challenge!(DBPCFC)!to!roasted!peanut!...............................................................!15!
5.2.1!Clinical!assessment!and!checks!prior!to!DBPCFC!............................................................................!15!
5.2.2!DBPCFC!.......................................................................................................................................................!16!
5.2.3!Assessments!during!food!challenges!..................................................................................................!18!
5.2.4!Management!of!symptoms!during!peanut!exposure!.....................................................................!19!
5.3!Tolerance!check,!Randomisation!and!WP1:!Oral!immunotherapy!......................................................................................!21!
5.3.1!Tolerance!challenge!to!boiled!peanut!................................................................................................!21!
5.3.2!Randomisation!.........................................................................................................................................!21!
5.3.3!Control!group!...........................................................................................................................................!21!
5.3.4!Active!group:!oral!immunotherapy.....................................................................................................!22!
5.4!1!year!assessment!.............................................................................................................................................................................!25!
5.4.1!12!month!DBPCFC!...................................................................................................................................!26!
5.4.2!Tolerance!challenge!at!13!months!......................................................................................................!26!
5.5!WP2:!Year!2!of!study!........................................................................................................................................................................!27!
5.6!2!year!assessment!.............................................................................................................................................................................!27!

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5.7!!YEAR!3/4!ASSESSMENTS!.................................................................................................................................................................!27!
5.8!OTHER!ASSESSMENTS!......................................................................................................................................................................!28!
5.8.1!Allergy!Skin!Prick!Testing!.......................................................................................................................!28!
5.8.2!Quality!of!Life!Assessments!..................................................................................................................!29!
5.8.3!Laboratory!Assessments!........................................................................................................................!29!
5.9!Study!Completion..............................................................................................................................................................................!30!
5.9.1!Early!study!termination!.........................................................................................................................!30!
6.!ADVERSE!EVENT!REPORTING!.................................................................................................................................................................!31!
6.1!Definitions!...........................................................................................................................................................................................!31!
6.2!Documentation!of!Adverse!Events!...............................................................................................................................................!31!
6.3!Grading!and!attribution!of!adverse!events!................................................................................................................................!32!
7.!STATISTICS!AND!DATA!ANALYSIS!..........................................................................................................................................................!34!
7.1!Sample!Size!Estimation!....................................................................................................................................................................!34!
7.2!Statistical!Analysis!Plan....................................................................................................................................................................!34!
7.2.1!Analysis!of!primary!endpoint!...............................................................................................................!34!
7.2.2!Analysis!of!secondary!endpoints!.........................................................................................................!35!
7.2.3!Interim!Analysis!.......................................................................................................................................!35!
8.!ADMINISTRATIVE!AND!REGULATORY!ISSUES!....................................................................................................................................!36!
8.1!Ethics!approval!..................................................................................................................................................................................!36!
8.2!Informed!consent!and!participant!assent!...................................................................................................................................!36!
8.3!MHRA!Exemption!..............................................................................................................................................................................!36!
8.4!Confidentiality....................................................................................................................................................................................!36!
8.5!INDEMNITY!.........................................................................................................................................................................................!36!
8.6!SPONSOR!.............................................................................................................................................................................................!36!
8.7!FUNDING!.............................................................................................................................................................................................!37!
8.8!AUDITS!.................................................................................................................................................................................................!37!
9!STUDY!MANAGEMENT!.............................................................................................................................................................................!37!
10!PUBLICATION!POLICY!.............................................................................................................................................................................!37!
Appendix!1:!Management!of!anaphylaxis!..............................................................................................................................................!38!
Appendix!2!MHRA!Exemption!....................................................................................................................................................................!40!
Appendix!3!STRUCTURED!TELEPHONE!INTERVIEW!for!study!participants!who!fail!the!OIT!protocol!.....................................!42!
!
!
'

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1.'INTRODUCTION'
'
1.1!BACKGROUND!
!
Peanut!allergy!is!the!most!common!cause!of!severe!allergic!reactions!to!food.1!Onset!is!common!in!childhood,!but!in!
contrast!to!other!food!allergies!such!as!cow’s!milk!and!egg,!peanut!allergy!tends!to!persist!into!adulthood.2!It!is!
associated!with!a!significant!impact!on!quality!of!life,!both!for!the!affected!individual!and!their!family.!
There!is!no!current!cure!for!peanut!allergy.!Oral!peanut!immunotherapy!(OIT)!using!roasted!allergen!has!been!
demonstrated!to!offer!potential!in!this!regard,!but!is!associated!with!significant!and!frequent!reactions!and!can!cause!
life^threatening!allergic!symptoms.3!Furthermore,!although!study!regimes!have!been!relatively!successful!in!inducing!
transient!desensitisation,!most!have!not!assessed!for!the!induction!of!sustained!unresponsiveness;!where!this!has!been!
investigated,!OIT!(typically!under!6!months!duration)!has!been!largely!unsuccessful!in!demonstrating!when!daily!
allergen!is!ceased.4!A!recent!study!involving!peanut!OIT!for!12^18!months!appears!to!be!more!successful!in!inducing!
sustained!unresponsiveness,5!which!is!consistent!with!the!clinical!data!for!immunotherapy!to!aeroallergens.!Current!
protocols!generally!mandate!increases!in!dose!during!induction!to!take!place!under!medical!supervision,!due!to!the!
frequency!and!unpredictable!nature!of!reactions!experienced.!This!places!a!significant!burden!on!families!of!children!
undergoing!OIT,!due!to!the!need!for!frequent!hospital!visits!along!with!observation!after!dosing!at!home.!!
We!have!previously!demonstrated!that!the!processing!of!peanuts!through!boiling!results!in!a!relatively!hypoallergenic!
product!due!to!the!loss!of!key!allergenic!components!from!peanut!into!the!water.6!Our!pilot!has!demonstrated!that!a!
desensitization!protocol,!using!boiled!peanut,!can!successfully!result!in!desensitization!to!raw!peanut;!ongoing!follow^
up!suggests!these!children!also!demonstrate!desensitization!to!roasted!peanut,!but!this!has!not!been!formally!studied.!
The!use!of!boiled!peanut!was!well^tolerated!with!minimal!symptoms!at!updosing,!suggesting!that!this!approach!may!
well!be!appropriate!as!a!safer,!better!tolerated!approach!to!achieving!successful!OIT,!with!the!possibility!of!improved!
sustained!tolerance.!
!
1.2!STUDY!RATIONALE!&!JUSTIFICATION!
We!wish!to!formally!assess,!in!a!randomized!controlled!study,!whether!a!modified!approach!using!boiled!peanut!for!
peanut!OIT!can!result!in!desensitisation!and!sustained!unresponsiveness!(i.e.!tolerance)!to!roasted!peanut.!We!will!
assess!the!safety!of!this!approach,!and!study!the!immunological!mechanisms!involved,!our!secondary!aim!being!to!
develop!clinically^useful!predictors!for!identifying!individuals!likely!to!undergo!successful!desensitization.!!
STUDY!HYPOTHESIS:!
A!pragmatic!protocol!utilizing!increasing!doses!of!boiled!peanut!can!induce!desensitisation!to!roasted!peanut,!in!
peanut^allergic!individuals,!with!an!acceptable!safety!profile.!
!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
1Turner!PJ,!Gowland!MH,!Sharma!V,!et!al.!Increase!in!anaphylaxisNrelated!hospitalizations!but!no!increase!in!fatalities:!An!analysis!of!United!
Kingdom!national!anaphylaxis!data,!1992N2012.!JACI!2014;!doi:!10.1016/j.jaci.2014.10.021.!!
2Bégin!P,!Paradis!L,!Paradis!J,!Picard!M,!Des!Roches!A.!Natural!resolution!of!peanut!allergy:!a!12Nyear!longitudinal!followNup!study.!JACI!In!
Practice!2013;1:528N30.e1N4.!
3Wood!RA,!Sampson!HA.!Oral!immunotherapy!for!the!treatment!of!peanut!allergy:!is!it!ready!for!prime!time?!!
JACI!In!Practice!2014;2:97N8.!
4Vickery!BP,!Scurlock!AM,!Kulis!M,!et!al.!Sustained!unresponsiveness!to!peanut!in!subjects!who!have!completed!peanut!oral!immunotherapy.!
JACI!2014;133:468N75.!
5Tang!ML,!Ponsonby!AL,!Orsini!F,!et!al.!Administration!of!a!probiotic!with!peanut!oral!immunotherapy:!A!randomized!trial.!!
J!Allergy!Clin!Immunol.!2015.!doi:!10.1016/j.jaci.2014.11.034.!!
6Turner!PJ,!Mehr!S,!Sayers!R,!et!al.!Loss!of!allergenic!proteins!during!boiling!explains!tolerance!to!boiled!peanut!in!peanut!allergy.!JACI!
2014;134:751N3.!

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2.''STUDY'OBJECTIVES'
2.1!PRIMARY!OBJECTIVE!
•!
To!evaluate!the!effectiveness!of!OIT!using!boiled!peanut!to!induce!desensitization!to!roasted!peanut!in!
children!with!IgE^mediated!peanut!allergy.!!
2.2!SECONDARY!OBJECTIVES!
•!
To!evaluate!the!safety!of!peanut!OIT!in!children!with!IgE^mediated!peanut!allergy.!!
•!
To!assess!the!rate!of!sustained!unresponsiveness!following!peanut!OIT!
•!
To!identify!predictors!which!can!identify!individuals!likely!to!undergo!successful!desensitization!and!sustained!
unresponsiveness!using!boiled!peanut!
•!
To!assess!the!impact!of!peanut!OIT!on!quality!of!life!(QoL)!measures,!both!from!the!child/young!person’s!
perspective!as!well!as!their!parents’.!
•!
To!assess!how!duration!of!OIT!impacts!on!sustained!unresponsiveness!
!
!

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3.''STUDY'DESIGN'
The!study!consists!of!2!related!work!packages!(see!Figure!1):!
WP1:!
A!52!week,!phase!2!single!centre!open!label!interventional!randomized!controlled!trial!to!assess!the!efficacy!of!
OIT!using!boiled!peanut!to!induce!desensitization!in!children!with!IgE^mediated!peanut!allergy.!Participants!will!
be!randomized!2:1!to!active!intervention!or!control!(current!best!standard!care,!i.e.!strict!peanut!avoidance!
plus!provision!of!rescue!medication!and!training)!for!12!months.!
WP2:!
Subjects!in!the!active!group!will!undergo!a!4!week!period!OFF!peanut!intake,!followed!by!an!unblinded!peanut!
challenge!to!assess!for!sustained!unresponsiveness.!Those!who!pass!the!challenge!will!continue!weekly!
maintenance!with!roasted!peanut,!those!who!fail!will!resume!daily!peanut!for!a!further!year.!
Subjects!in!the!control!group!will!be!offered!the!option!of!receiving!the!active!intervention!following!the!12!
month!control!phase!(boiled!peanut!immunotherapy).!This!will!allow!confirmation!that!the!two!groups!are!
similar!in!response!to!OIT!using!boiled!peanut,!increasing!the!precision!of!the!results.!!!
!
Figure'1:!CONSORT!diagram!for!the!BOPI!study.!
![PN:!Peanut;!SU:!Sustained!unresponsiveness]!
'
!
Assessed for eligibility 
Excluded 
♦!!Not meeting inclusion criteria 
♦!!!Declined/unable to participate 
DBPCFC (to roasted PN) after 12 months to determine threshold to roasted PN 
Allocation)
Follow,Up)
Initial DBPCFC to roasted peanut 
Enrollment)
Work)Package)1:)
Months)0,12)
Randomized (2:1) 
CONTROL INTERVENTION: 
Best current practice (12mths) 
Work)Package)2:)
Months)12,24)
ACTIVE INTERVENTION: 
Boiled PN OIT (12mths) 
Boiled Peanut OIT 
(12 months) 
Integration into routine clinical allergy service for ongoing management 
Continue maintenance PN:  
- 
weekly PN in those with SU 
- 
daily PN in remainder 
Stop daily PN intake for 4 
weeks and repeat OFC to 
assess for sustained 
unresponsiveness (SU) 
DBPCFC to roasted PN 
after 12 months to determine 
threshold to roasted PN 

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Summary'of'Study'components:'
1.! Recruitment'and'eligibility'screen:!Peanut^allergic!subjects!will!be!recruited!from!both!our!local!patient!population!
and!through!our!local!paediatric!allergy!network!in!North!West!London.!
2.! Initial'doubleTblind,'placeboTcontrolled'food'challenge!(DBPCFC)!to!roasted!peanut.!This!will!demonstrate!true!
clinical!reactivity!to!roasted!peanut!rather!than!sensitization!alone,!as!it!is!unethical!to!undertake!peanut!OIT!in!
children!who!are!not!clinically!allergic!to!roasted!peanut.!!
3.! Randomisation'and'WP1:!Peanut^allergic!children!will!be!randomized!2:1!to!either!active!treatment!(OIT!using!
boiled!PN)!or!control!(current!best!practice,!i.e.!strict!peanut!avoidance!plus!provision!of!rescue!medication!and!
training)!during!months!0^12.!
4.! 1'year'assessment:!At!12!months,!all!subjects!will!undergo!a!DBPCFC!to!roasted!PN,!to!assess!for!ongoing!clinical!
allergy!(and!determine!threshold!of!reactivity)!to!roasted!PN.!Subjects!in!the!active!group!will!stop!all!peanut!for!4!
weeks!and!then!undergo!a!further!open!challenge!to!assess!for!sustained!unresponsiveness!(ie.!tolerance!without!
the!need!for!ongoing!peanut!exposure).!
5.! WP2:!Those!subjects!in!the!control!group!will!be!offered!OIT!using!boiled!PN!during!months!12^24.!Subjects!in!the!
active!intervention!groups!will!be!offered!ongoing!maintenance!therapy!within!the!study!protocol.!
6.! 2'year'assessment!and!option!to!determine!longer^term!tolerance!to!peanut.!
Subjects!will!be!invited!to!remain!in!the!study!for!a!3rd!year!to!allow!longer^term!evaluations!to!be!performed.!
The!efficacy!and!impact!of!OIT!on!quality!of!life!will!be!assessed!at!6,!12,!24!and!36!months!in!all!subjects!(and!their!
parents),!using!a!validated!questionnaire.!!
!
3.1!STUDY!OUTCOMES!MEASURES!
3.1.1!PRIMARY!STUDY!OUTCOME!!
!
•!
The!proportion!of!participants!who!tolerate!1.4g!(or!more)!roasted!peanut!protein!(equivalent!to!≥!6!roasted!
peanuts)!after!12!months!of!OIT!as!assessed!by!DBPCFC,!in!the!active!vs!control!group.!
3.1.2.!SECONDARY!STUDY!OUTCOMES!!
!
•!
Relative!change!in!clinical!threshold!(No!observed!adverse!event!level,!NOAEL;!Lowest!observed!adverse!event!
level,!LOAEL)!to!roasted!peanut!at!6!and!12!months.!
•!
Rate!of!sustained!unresponsiveness!after!4!week!cessation!of!maintenance!OIT!at!1!year!and!3!years.!
•!
Change!in!quality!of!life!(QoL)!assessments!at!6!and!12!months!after!OIT,!as!assessed!by!FAQL^Questionnaire!in!
children,!teenagers!and!their!parents!–!in!the!active!vs!control!group.!
•!
Safety!of!OIT!using!boiled!peanut!as!defined!by!frequency!and!nature!of!allergic!symptoms!experienced.!
•!
Compliance!with!study!protocol!
•!
Immunological!outcome!measures!pre^,!during!and!post^OIT!
!
!

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!
3.2!STUDY!DESIGN!RATIONALE!
The!is!a!randomized'controlled'study,!utilizing!a!control!group!with!a!delayed!start!to!control!for!the!incidence!of!
natural!resolution!of!peanut!allergy!over!12!months.!Natural!resolution!of!peanut!allergy!occurs!in!10%^20%!of!peanut!
allergic!children!over!a!longer!time!period.!Inclusion!of!a!control!group!also!facilitates!the!assessment!of!the!safety!of!
OIT!and!QoL!measures!(by!comparing!active!to!control!patients!who!may!experience!accidental!allergic!reactions!
despite!best!management).7!!
Controls!will!be!offered!a!deferred!start!to!OIT!(using!boiled!peanut)!after!12!months!on!current!standard!care!
(avoidance!advice!and!provision!of!a!rescue!plan!and!medications!in!the!event!of!an!accidental!allergic!reaction).!We!
consider!it!unethical!not!to!offer!control!participants!the!opportunity!to!undergo!active!treatment!having!undertaken!
peanut!challenges!during!the!12!months!of!non^intervention.!We!also!expect!that!this!design!will!encourage!
compliance!with!the!study!protocol.!!
To!avoid!selection!bias,!participants!will!be!randomized!to!active!or!control!groups.!A!level!of!stratification!will!be!
included!to!distinguish!between!those!who!are!predominantly!sensitized!to!a!specific!peanut!protein!epitope!(Ara!h!2).!
This!is!because!pilot!data!indicates!that!the!boiling!process!affects!leaching!of!Ara!h!2!from!peanut!more!than!other!
proteins.!Patients!who!are!predominantly!sensitized!to!Ara!h!2!may!be!more!likely!to!have!a!successful!outcome!than!
those!allergic!to!other!peanut!proteins.!The!stratification!will!reduce!the!risk!of!skewing!the!results!through!
randomization.!
As!with!most!OIT!studies,!this!study!will!be!open'label,!as!we!wish!to!assess!a!pragmatic!approach!to!dosing!which!
would!not!be!possible!with!blinding.!Families!will!be!provided!with!a!specific!peanut!cultivar!(Holt!Runner,!Peanut!
Company!of!Australia!Ltd);!families!will!be!given!specific!instructions!on!preparing!the!peanut!for!OIT!(through!boiling)!
at!home.!The!supply!of!raw!peanuts!direct!from!the!wholesaler!also!reduces!potential!nut^contamination.!We!have!
chosen!a!specific!cultivar!with!higher!oleic!oil!content,!resulting!in!a!longer!shelf^life!(at!least!18!months!when!vacuum!
packed!and!stored!at!4°C).!To!perform!OIT!safely,!supervision!and!frequent!appointments!to!the!research!unit!are!
required.!A!blinded!study!would!increase!the!burden!on!families.!Finally,!the!use!of!blinding!might!lead!participants!
(and!their!families)!to!believe!they!are!indeed!tolerant!to!peanut!and!therefore!result!in!less!stringent!allergen!
avoidance,!putting!them!at!increased!risk!of!accidental!reactions.!!
We!have!chosen!a!daily!maintenance!dose!of!800mg!roasted!peanut!protein,!on!the!basis!of!previous!reports!that!this!
amount!is!generally!well^tolerated!by!subjects!undergoing!OIT!on!an!daily!basis,!and!is!also!associated!with!a!suggestion!
of!efficacy.7!Our!primary!endpoint!(able!to!tolerate!1.4mg!roasted!peanut!protein,!equivalent!to!≥!6!roasted!peanuts)!
has!been!chosen!on!the!basis!of!efficacy!and!ability!to!protect!against!accidental!exposure!to!peanut!in!the!community.!
This!will!be!assessed!using!a!blinded!food!challenge,!an!established!research!tool!in!food!allergy.8!
The!inclusion!of!an!assessment!to!determine!tolerance!(sustained!unresponsiveness)!to!peanut!in!the!absence!of!
ongoing!daily!peanut!exposure!is!essential.!The!realities!of!day^to^day!life!mean!that!outside!the!safety!of!a!clinical!trial,!
maintenance!peanut!doses!are!often!omitted.!It!is!therefore!important!to!demonstrate!ongoing!tolerance!to!peanut!in!
the!absence!of!daily!maintenance.!Furthermore,!the!reassurance!through!the!demonstrated!tolerance!in!children!with!
previous!peanut!allergy!may!well!improve!quality!of!life!further.!This!outcome!needs!to!be!corrected!for!the!possibility!
of!natural!resolution,!thus!a!comparison!to!controls!who!have!not!undergone!OIT!is!required.!
The!study!has!been!designed!as!a!single'centre!study:!the!procedures!involved!are!complex!and!require!intensive!
clinical!assessment!only!available!at!a!specialist!allergy!centre.!The!use!of!a!single!centre!allows!a!more!efficient!use!of!
resources!and!promotes!consistency!in!clinical!management.!Our!location!(in!central!London)!allows!for!the!
recruitment!of!patients!from!a!diverse!geographical!area!and!ethnic!background.!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
7Anagnostou!K,!Islam!S,!King!Y,!et!al.!Assessing!the!efficacy!of!oral!immunotherapy!for!the!desensitisation!of!peanut!allergy!in!children!(STOP!
II):!a!phase!2!randomised!controlled!trial.!Lancet.!2014;383(9925):1297N304.!
8Plaut!M,!Sawyer!RT,!Fenton!MJ.!Summary!of!the!2008!National!Institute!of!Allergy!and!Infectious!Diseases–US!Food!and!Drug!Administration!
Workshop!on!Food!Allergy!Clinical!Trial!Design.!J!Allergy!Clin!Immunol!2009;124:671N8.e1.!

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!
4.'STUDY'POPULATION'
4.1.!INCLUSION!CRITERIA!
1.! Age!8^16!years.!
2.! Past!history!of!peanut!allergy,!with:!
•!
Previous!clinical!reaction!with!ongoing!sensitisation!to!peanut,!OR!positive!allergy!test!to!peanut!(either!
skin!prick!test!≥8mm!or!serum!specific!IgE!>!15kUA/l)!to!peanut!consistent!with!>95%!likelihood!of!clinical!
allergy9,!AND!
•!
further!confirmation!of!clinical!reactivity!to!roasted!peanut!at!double^blind!placebo^controlled!food!
challenge!at!screening!!
3.! Tolerates!at!least!¼!boiled!peanut!(boiled!for!4!hours)!at!open!food!challenge!at!screening.!
4.! Full!informed!consent!of!parent/legal!guardian!and!patient!assent.!
4.2.!EXCLUSION!CRITERIA!
1.! Required!previous!admission!to!an!intensive!care!unit!for!management!of!an!allergic!reaction!to!peanut.!
2.! Clinically!significant!chronic!illness!(other!than!asthma,!rhinitis!or!eczema).!
3.! Undergoing!subcutaneous!or!sublingual!immunotherapy!and!within!the!first!year!of!therapy,!for!respiratory!
allergy.!
4.! Subjects!receiving!anti^IgE!therapy,!oral!immunosupressants,!beta^blocker!or!ACE!inhibitor.!
5.! Clinical!allergy!to!either!soya!or!sunflower!seed!
6.! Tolerance!to!≥1.4!g!peanut!protein!(approx.!6!peanuts)!at!initial!DBPCFC!during!screening.!
7.! Subjects!allergic!to!¼!boiled!peanut!(boiled!for!4!hours)!at!screening.!
8.! Poorly!controlled!asthma!within!the!previous!3!months!(as!defined!by!clinician!judgement!with!reference!to!
the!ICON!consensus10),!or!asthma!requiring!oral!corticosteroid!therapy!within!the!previous!3!months.!
9.! Pregnancy!
10.! Unwilling!or!unable!to!fulfil!study!requirements!
4.3.!WITHDRAWAL!CRITERIA!!
Subjects!will!be!free!to!withdraw!from!the!study!at!any!time!without!affecting!their!future!medical!care.!Subjects!who!
are!withdrawn!from!active!treatment!will!remain!in!the!study!for!assessment!of!outcome!relating!to!QoL!measures.!
The!safety!of!the!child!is!paramount!in!this!study.!Thus,!children!who!experience!anaphylaxis!to!an!OIT!dose!at!home,!
but!who!do!not!receive!IM!adrenaline!as!per!the!management!plan,!will!have!further!updosing!suspended!until!the!
family!undergo!retraining!on!the!recognition!and!management!of!allergic!symptoms.!
A!participant!will!be!withdrawn!from!the!study!under!the!following!circumstances:!
•!
If,!in!the!opinion!of!the!study!team,!compliance!with!study!procedures!is!suboptimal!such!that!it!compromises!
the!patient’s!safety.!
•!
If,!in!the!opinion!of!the!study!team,!further!participation!would!adversely!affect!the!participant’s!health.!
•!
A!child!develops!an!exclusion!criteria!during!the!updosing!phase!of!the!study!e.g.!a!new!medication!(which!
would!normally!be!a!contra^indication)!is!commenced.!
•!
If!consent!is!withdrawn!or!the!subject!fails!to!return!for!a!study!visit.!!
•!
In!the!event!of!a!serious!adverse!reaction!to!OIT!and/or!if!presenting!with!anaphylaxis!requiring!more!than!
one!IM!adrenaline!dose!within!2!hours!after!an!OIT!dose.'
!
Any!subject!excluded!from!further!participation!will!not!be!replaced.!!
'
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
9!Sporik!R,!Hill!DJ,!Hosking!CS.!Specificity!of!allergen!skin!testing!in!predicting!positive!open!food!challenges!to!milk,!egg!and!peanut!in!
children.!Clin!Exp!Allergy!2000;!30:1540–6.;!AND!Sampson!HA.!Utility!of!foodNspecific!IgE!concentrations!in!predicting!symptomatic!food!
allergy.!J!Allergy!Clin!Immunol!2001;107:!891–6.!
10Papadopoulos!NG,!Arakawa!H,!Carlsen!KH,!et!al.!International!consensus!on!(ICON)!pediatric!asthma.!Allergy.!2012;67:976N97.!

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5'STUDY'PROCEDURES'
The!main!study!procedures!are!shown!in!Figure!2,!and!consist!of!the!following!stages:!
!
1.! Recruitment'and'initial'screening!
2.! Initial'doubleTblind,'placeboTcontrolled'food'challenge!(DBPCFC)!to!roasted!peanut.!!
3.! Randomisation'and'WP1:!Following!demonstration!of!tolerance!to!one!boiled!peanut,!peanut^allergic!children!will!
be!randomized!2:1!to!either!active!treatment!(OIT!using!boiled!PN)!or!control!(current!best!practice)!during!months!
0^12.!
4.! 1'year'assessment:!All!subjects!will!undergo!a!DBPCFC!to!roasted!PN,!to!assess!for!ongoing!clinical!reactivity!(and!
determine!threshold!of!reactivity)!to!roasted!PN.!Subjects!in!the!active!group!(Group!A)!will!stop!all!peanut!for!4!
weeks!and!then!undergo!a!further!open!challenge!to!assess!for!tolerance!(i.e.!sustained!unresponsiveness!without!
the!ongoing!peanut!exposure).!
5.! WP2:!Children!in!the!control!group!(Group!B)!will!be!offered!OIT!using!boiled!PN!during!months!12^24.!Subjects!in!
the!active!intervention!groups!will!be!offered!ongoing!maintenance!therapy!within!the!study!protocol.!
6.! 2'year'assessment!and!option!to!determine!longer^term!tolerance!to!peanut.!
!
!
Figure'2:!Study!flowchart!and!interventions!
!
!
Ques%onnaire
+++++++
+
+++++Skin+prick+test
+
+Blood+test+
+
Peanut+challenge+(1+visit)+
+++++(2+visits)++++++++++++ +
+(3+visits)+
3+
CONTROL+GROUP+
ACTIVE+GROUP+
0
+
+3
+
+6
+
+
+
+12+++++13
+15
+
+18
+
+
+
+24+months+
1+
1+
2+
1+
3+
2+
2+
1+
2+
1+
ORAL+IMMUNOTHERAPY+
ORAL+IMMUNOTHERAPY+
MAINTENANCE+PEANUT+DOSES+
3+

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5.1!RECRUITMENT!AND!SCREENING!VISITS!!
Peanut^allergic!children!will!be!recruited!through!our!clinical!service!at!St!Mary’s!Hospital!(Imperial!College!Healthcare!
NHS!Trust),!one!of!the!largest!tertiary!services!in!Europe!providing!specialist!paediatric!allergy!services!to!the!North!
Thames!Region.!We!will!also!recruit!through!our!local!paediatric!allergy!network!in!North!West!London,!including!the!
use!of!PIC!sites!at!the!larger!allergy!centres.!This!study!requires!frequent!visits!(once!every!2^4!weeks)!to!the!Research!
Unit,!thus!it!is!important!that!participants!live!relatively!local!to!the!unit!to!minimize!travel!time!and!impact!on!other!
daily!activities.!
Potential!participants!will!receive!the!Study!Information!either!in!person,!by!post!or!via!email,!following!which!the!
participants!will!be!screened!by!telephone!conversation!with!their!parents,!to!determine!likelihood!of!true!peanut!
allergy!and!thus!suitability!for!this!study.!Suitable!participants!will!then!have!an!appointment!made!for!a!screening!visit.!
The!following!will!take!place!at!the!first!screening!visit:!
•!
Informed!consent!
•!
Clinical!history!and!physical!examination!
•!
Skin!prick!test!(SPT)!to!commercial!crude!peanut!extract!and!boiled!peanut!slurry!according!to!national!
guidelines!
•!
For!children!with!asthma,!current!asthma!status!will!be!assessed!by!the!clinician,!with!the!help!of!lung!function!
testing!and!completion!of!a!validated!asthma!control!test!!
•!
For!children!with!eczema,!eczema!will!be!assessed!using!the!SCORAD!system11!(which!provides!an!objective!
measure!of!eczema!severity)!as!well!as!completion!of!a!POEM!questionnaire,!a!validated!patient^based!
symptom!measure!questionnaire!
The!first!screening!visit!may!take!place!on!the!same!day!as!the!first!baseline!food!challenge,!if!requested!by!the!family.!
5.2!DOUBLE^BLIND,!PLACEBO^CONTROLLED!FOOD!CHALLENGE!(DBPCFC)!TO!ROASTED!PEANUT!
All!participants!who!fulfil!eligibility!criteria!for!the!study!will!undergo!a!baseline!DBPCFC!to!roasted!peanut!at!
enrolment.!The!DBPCFC!is!established!as!the!gold^standard!test!of!diagnosis!of!food!allergy!by!international!consensus.!
The!objectives!are:!
i.!
to!confirm!the!diagnosis!of!IgE^mediated!peanut!allergy,!
ii.!
to!determine!the!threshold!of!clinical!reactivity!to!peanut!prior!to!OIT!
The!DBPCFC!involves!2!half^day!visits,!at!least!one!week!apart.!Participants!are!given!incremental!doses!of!peanut!or!
placebo!30!minutes!apart,!and!monitored!for!signs/symptoms!of!allergic!reaction!throughout.!The!challenge!is!halted!
once!pre^determined!stopping!criteria!have!been!reached.!DBPCFC!will!be!performed!according!to!the!international!
PRACTALL!consensus!for!best!practice.12!
5.2.1!CLINICAL!ASSESSMENT!AND!CHECKS!PRIOR!TO!DBPCFC!
All!subjects!will!be!assessed!prior!DBPCFC!to!determine!suitability!for!a!challenge,!as!follows:!
•!
No!intercurrent!illness!(viral!or!otherwise)!
•!
No!exacerbation!in!allergic!symptoms!(eczema,!asthma,!food!allergy)!in!the!preceding!week.!
•!
No!short^acting!β2!agonists!used!in!the!past!12!hours!
•!
No!short^acting!antihistamine!taken!(e.g.!cetirizine,!loratadine)!in!the!past!48!hours!(72!hours!for!
fexofenadine)!
•!
No!long^acting!antihistamine!(e.g.!chlorphenamine,!desloratadine)!in!the!previous!5!days.!
•!
No!oral!steroids!have!been!taken!in!the!past!2!weeks!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
11Kunz,!B.,!Oranje,!A.P.,!Labreze,!L.,!Stalder,!J.F.,!Ring,!J.,!and!Taieb,!A.!Clinical!validation!and!guidelines!for!the!SCORAD!index:!consensus!report!
of!the!European!Task!Force!on!Atopic!Dermatitis.!Dermatology.!1997;!195:!10–19!
12Sampson!HA,!Gerth!van!Wijk!R,!BindslevNJensen!C,!et!al.!Standardizing!doubleNblind,!placeboNcontrolled!oral!food!challenges:!AAAAINEAACI!
PRACTALL!consensus!report.!J!Allergy!Clin!Immunol.!2012;130:1260N74.!

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•!
Baseline!observations!(temperature,!blood!pressure,!heart!and!respiratory!rate,!oxygen!saturation)!within!
normal!range.!!!
•!
Baseline!physical!examination!must!not!reveal!any!significant!acute!findings.!
Challenges!will!occur!on!a!Paediatric!Allergy!Research!Unit!(PRU)!where!food!challenges!are!performed!on!a!regular!
basis,!and!staff!are!familiar!with!the!management!of!allergic!reactions!including!anaphylaxis!through!clinical!experience!
and!regular!training.!Emergency!equipment!(including!oxygen!and!suction)!and!medication!will!be!checked!beforehand,!
as!per!local!protocol!and!international!criteria!for!performance!of!DBPCFC.!
5.2.2!DBPCFC!
The!challenge!will!consist!of!seven!consecutive!increasing!doses!of!roasted!peanut!(or!placebo)!at!30!minutes!intervals!
with!an!observation!period!of!2!hours!after!the!final!dose:!
!
Protocol'1:'
DBPCFC'to'peanut'
Roasted'peanut'OFC'(using'defatted'flour)'
TIME!POINT!(mins)!
Peanut!flour!(mg)!
Peanut!protein!(mg)!
0!
6!
3!
30!
20!
10!
60!
60!
30!
90!
200!
100!
120!
600!
300!
150!
2000!
1000!
180!
6000!
3000!
Cumulative'dose'
'
4443mg'
2!hours!observation!period!following!last!dose!to!monitor!for!signs!of!reaction!
The!food!challenge!doses!will!be!prepared!prior!to!challenge,!in!a!matrix!containing!soya!(soya^allergic!children!will!be!
given!a!matrix!based!on!sunflower!seed!instead).!Tolerance!to!at!least!one!of!these!will!be!established!at!enrolment.!All!
doses!(irrespective!of!active!or!placebo)!will!be!double^checked!prior!to!administration.!The!order!of!challenge!days!
(active!or!placebo!control)!will!be!randomized!by!an!independent!research!associate,!according!to!a!computer^
generated!randomization!list!(www.sealedenvelope.com).!The!randomization!key!will!be!recorded!in!a!separate!file!and!
logged!once!both!pair!of!challenges!have!taken!place.!
In!brief,!symptoms!will!be!monitored!during!the!challenge,!with!detailed!assessment!prior!to!each!challenge!dose,!
according!to!Figure!3.!
•!
Green!symptoms:!Not!generally!sufficient!to!consider!a!challenge!positive!unless!symptoms!persist!for!at!least!
120!minutes.!
•!
Orange!symptoms:!Symptoms!that!recur!on!3!doses,!or!persist!(e.g.!40!minutes)!are!more!likely!indicative!of!a!
reaction!than!when!such!symptoms!are!transient!and!not!reproducible.!^!3!or!more!scoring!areas!in!orange!
more!likely!represent!a!true!response,!and!if!present!the!challenge!should!be!halted.!
•!
Red!symptoms:!A!single!red!symptom!is!likely!to!indicate!a!true!response,!and!if!present!the!challenge!should!
be!halted.!
The!outcome!of!the!challenge!(positive!or!negative)!and!the!apparent!eliciting!threshold!dose!will!be!recorded!in!the!
participant!record.!
!
!
!

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Challenge!outcome!will!be!determined!as!per!the!PRACTALL!Consensus!criteria,9!as!shown!in!Figure!3:!
I.!SKIN!
A.!Pruritus!
0!=!Absent!
1!=!Occasional!scratching!
2!=!Scratching!continuously!for!>2!minutes!at!a!time!
3!=!Hard!continuous!scratching!causing!excoriations!
B.!Urticaria/Angioedema!
0!=!Absent!
1!=!<!3!hives,!or!mild!lip!oedema!
2!=!<!10!hives!but!>3,!or!significant!lip,!tongue!or!facial!oedema!
3!=!Generalized!involvement!
C.!Rash!
0!=!Absent!
1!=!Few!areas!of!faint!erythema!
2!=!Areas!of!erythema!
3!=!Generalized!marked!erythema!(>50%)!
II.!UPPER!RESPIRATORY!
A.!Sneezing/Itching!
0!=!Absent!
1!=!Rare!bursts,!occasional!sniffing!
2!=!Bursts!<10,!intermittent!rubbing!of!nose/eyes!or!frequent!sniffing!
3!=!Continuous!nasal/eye!itch,!periocular!swelling!and/or!long!bursts!of!!
!!!!!!!sneezing,!persistent!rhinorrhoea!
III.!LOWER!RESPIRATORY!
A.!Wheezing!
0=!Absent!
1!=!Expiratory!wheeze!on!auscultation!
2!=!Biphasic!wheeze!
3!=!Use!of!accessory!muscles,!audible!wheezing!
B.!Laryngeal!
0=!Absent!
1!=!>3!discrete!episodes!of!throat!clearing/cough,!or!persistent!throat!
!!!
!
!!!!!!tightness/pain!
2!=!Vocal!hoarseness,!frequent!cough!
3!=!Stridor!
IV.!GASTROINTESTINAL!
A.!Subjective!Complaints!
0!=!Absent!
1!=!Complaints!of!nausea!or!abdominal!pain,!itchy!mouth/throat!
2!=!Frequent!c/o!nausea!or!pain!with!normal!activity!
3!=!Notably!distressed!due!to!GI!symptoms!with!decreased!activity!
B.!Objective!Complaints!
0!=!Absent!
1!=!1!episode!of!emesis!
2!=!2^3!episodes!of!emesis!or!diarrhoea!or!1!of!each!
3!=!>3!episodes!of!emesis!or!diarrhoea!or!2!of!each!
V.!CARDIOVASCULAR/NEUROLOGIC!
0!=!normal!heart!rate!or!BP!for!age/baseline!
1!=!Subjective!symptoms!(weak,!dizzy),!or!tachycardia!
2!=!Drop!in!mBP!of!>20%!from!baseline,!or!significant!change!in!mental!status.!
3!=!Cardiovascular!collapse,!signs!of!impaired!circulation!(unconscious)!
Figure'3:!PRACTALL!consensus!stopping!criteria!for!food!challenges.9!

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For!safety!reasons,!families!will!be!asked!to!provide!their!child!with!a!snack!one!hour!after!the!challenge!has!ceased!i.e.!
prior!to!leaving!the!research!unit.!This!is!to!avoid!the!possibility!of!further!symptoms!on!feeding!outside!the!medical!
unit,!something!which!can!occur!if!no!food!is!eaten!prior!to!discharge.!
All!families!will!be!contacted!by!email!or!telephone!the!day!following!challenge!to!collect!any!data!relating!to!the!
occurrence!of!delayed!(late!phase)!symptoms.!
5.2.3!ASSESSMENTS!DURING!FOOD!CHALLENGES!
The!baseline!food!challenges!are!termed!‘high^risk’!on!the!basis!that!we!expect!the!challenges!to!be!positive.!To!
minimize!risk!to!the!patient,!all!challenges!will!take!place!on!a!Paediatric!Allergy!Research!Unit!(PRU)!where!food!
challenges!are!performed!on!a!regular!basis,!and!staff!are!familiar!with!the!management!of!allergic!reactions!including!
anaphylaxis!through!clinical!experience!and!regular!training.!Since!many!of!the!study!participants!will!be!new!to!the!
research!team,!we!propose!additional!safety!precautions!at!the!initial!baseline!challenge:!
!
i.!
Intravenous'access:!Cannulation!will!be!performed!in!order!to!secure!intravenous!access.!This!will!allow!
treatment!to!be!easily!and!rapidly!administered!in!the!event!of!a!significant!allergic!reaction.!In!order!to!
minimize!discomfort!to!the!child,!we!will!offer!local!anaesthetic!cream!to!be!applied!at!least!30!minutes!prior!
to!cannulation,!according!to!local!practice.!!
!
Blood!will!be!collected!prior!to,!during!and!after!challenge!via!the!cannula,!in!order!to!confirm!a!clinical!
reaction!using!objective!laboratory!assessments.!This!procedure!will!not!cause!discomfort!to!the!child,!as!the!
cannula!will!already!be!in!situ.!Where!the!cannula!does!not!bleed!back,!no!further!venepuncture!will!be!
attempted.!If!cannulation!is!not!possible!(for!whatever!reason),!the!challenge!may!proceed!if!authorised!by!
the!Chief!Investigator,!on!the!basis!that!emergency!medicines!can!also!be!given!by!the!intramuscular!route.!
!
At!the!challenge!visit,!a!maximum!total!volume!of!2.5ml/kg!(max!75ml)!blood!(up!to!40ml!prior!to!starting!
the!challenge)!will!be!collected!for!baseline!laboratory!assessments!of!immunological!function!relating!to!
peanut!allergy!and!assessment!of!tolerance!(see!section!5.7.2).!These!tests!will!include!IgE!antibodies!to!
peanut!(including!peanut!components);!inflammatory!mediators;!inflammatory!cell!activation!(by!flow!
cytometry);!and!storage!of!RNA!(using!the!PAXgene!system)!and!DNA!for!latter!analysis!of!protein!signal!
transcription.!We!have!elected!to!perform!this!test!at!this!initial!challenge,!rather!than!at!the!screening!visit,!
in!order!to!reduce!the!number!of!blood!tests!required.!
!
ii.!
NonTinvasive'monitoring:!Children!will!be!monitored!during!food!challenges,!using!non^invasive!monitoring.!
In!addition!to!standard!measurements!of!heart!rate,!blood!pressure!and!oxygen!saturations,!we!propose!
additional!non^invasive!measurements!in!order!to!gain!as!much!information!as!possible!about!allergic!
reactions!under!controlled!conditions,!as!follows:!
!
a.! Central'blood'pressure:!In!addition!to!peripheral!(brachial)!BP,!central!BP!will!be!measured!using!the!
Pulsecor!BPplus!non^invasive!CardioScope!II!monitor!(CE^marked)!(Figure!4).!Use!is!similar!to!a!
conventional!BP!cuff/monitor!with!measurements!obtained!within!60!seconds,!and!is!very!well!
tolerated!by!children.!
Rationale:!The!difference!between!central!and!peripheral!systolic!BP!may!be!more!representative!of!
the!effect!of!vasodilatation!during!a!food!allergic!reaction.!Furthermore,!central!diastolic!BP!correlates!
better!with!coronary!perfusion!than!peripheral!diastolic!BP.!There!may!be!a!difference!between!the!
ability!of!individuals!to!maintain!central!BP!during!a!systemic!allergic!reaction,!which!could!relate!to!
the!clinical!symptoms!observed.!

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Figure'4:!Pulsecor!II!Central!Blood!Pressure!monitor.!
!
b.! NonTinvasive'hemodynamic'monitoring:!In!older!children!(above!12!years),!continuous!data!will!be!
obtained!using!non^invasive!hemodynamic!monitoring!(Cheetah!NICOM!monitor);!this!type!of!
monitoring!is!not!validated!in!younger!children,!nor!is!practical!due!to!the!need!to!be!inactive!during!
measurements.!!The!NICOM!monitor!has!been!extensively!validated,!has!FDA!approval!and!is!CE!
marked.!Data!is!collected!through!4!ECG^type!sensors!(size!108!x!20!mm)!placed!on!the!front!or!back!
of!the!thorax,!as!shown!in!Figure!5.!Measurements!are!not!prone!to!movement!artefact.!The!monitor!
allows!for!continuous!cardiovascular!monitoring!(including!cardiac!output!and!peripheral!resistance)!
during!challenges.!
Rationale:!It!is!unknown!as!to!how!cardiac!output!varies!during!an!allergic!reaction.!Some!individuals!
may!be!able!to!compensate!for!capillary!bed!vasodilatation!during!a!systemic!allergic!reaction!by!
modulating!cardiac!output.!The!assessment!of!cardiac!output!will!also!facilitate!the!estimation!of!
peripheral!vasodilatation!through!measurement!of!total!peripheral!resistance.!
!
Figure'5:!NICOM!Sensor!placement!
To!provide!further!validation!of!the!measurements!taken!by!the!NICOM!monitor,!during!some!challenges!participants!
will!also!be!invited!to!undergo!intermittent!cardiac!echocardiography!(performed!by!a!trained!healthcare!professional!
according!to!standard!protocols!in!use!at!our!hospital).!
5.2.4!MANAGEMENT!OF!SYMPTOMS!DURING!PEANUT!EXPOSURE!
Any!allergic!reaction!happening!during!the!observation!period!following!dose!administration!will!be!managed!according!
to!the!British!Society!for!Allergy!and!Clinical!Immunology!(BSACI)!Allergy!Action!Plans!for!children!(Figure!6).!!
Mild^moderate!(non^anaphylactic)!symptoms!(as!defined!in!Figure!6)!will!be!treated!with!cetirizine!as!per!local!policy.!
Symptoms!of!anaphylaxis!will!be!treated!initially!with!IM!adrenaline.!Where!feasible,!the!child!or!parent!will!use!their!
adrenaline!auto^injector!device!to!administer!the!(first)!dose!of!adrenaline!in!this!event,!as!this!can!increase!compliance!
with!the!Plan’s!recommendations!outside!the!home!environment!and!reduce!anxiety!relating!to!the!use!of!auto^
injector!devices.!
!
Front
Back

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Figure'6:!BSACI!Allergy!Management!Plan!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy Action Plan 
 
Name:  
 
DOB:  
 
 
 
 
 
 
 
 
 
 
 
Parent / Carer details: 
 
1) 
      
 
2) 
      
 
 
 
THIS CHILD HAS THE FOLLOWING ALLERGIES: 
 
 
AIRWAY:  
Persistent cough, hoarse voice,  
difficulty swallowing, swollen tongue 
BREATHING:  
Difficult or noisy breathing, 
 
wheeze or persistent cough 
CONSCIOUSNESS:  Persistent dizziness / Pale or floppy 
 
Suddenly sleepy, collapse, unconscious 
 
If ANY ONE of these signs are present: 
 
1. Lie child flat. If breathing is difficult, allow to sit 
2. Give EpiPen® or EpiPen® Junior 
3. Dial 999 for an ambulance* and say 
ANAPHYLAXIS (“ANA-FIL-AX-IS”) 
If in doubt, give EpiPen® 
After giving Epipen: 
1. Stay with child, contact parent/carer 
2. Commence CPR if there are no signs of life 
3. If no improvement after 5 minutes, give a further EpiPen® 
or alternative adrenaline autoinjector device, if available 
 
 
 
 
 
Photo 
Keep your EpiPen device(s) at room temperature,  
do not refrigerate.  
For more information and to register for a free 
reminder alert service, go to www.epipen.co.uk 
 
Patient support groups: 
http://www.allergyuk.org or www.anaphylaxis.org.uk  
 
The British Society for Allergy & Clinical Immunology 
www.bsaci.org  
*You can dial 999 from any phone, even if there is no credit left on a mobile. 
Medical observation in hospital is recommended after anaphylaxis. 
Watch for signs of ANAPHYLAXIS 
(life-threatening allergic reaction): 
Child’s 
Weight:                   Kg 
Mild-moderate allergic reaction: 
 Swollen lips, face or eyes 
 Itchy / tingling mouth 
 Hives or itchy skin rash 
 
ACTION: 
 Stay with the child, call for help if necessary 
 Give antihistamine:  
 Contact parent/carer 
 Abdominal pain or vomiting 
 Sudden change in behaviour 
(if vomited, can repeat dose) 
This is a medical document that can only be completed by the patient's treating health professional and cannot be 
altered without their permission.  
This plan has been prepared by: 
Hospital/Clinic: 
                
 
 
 
 
  Date: 
British Society for Allergy and 
Clinical Immunology 
Additional instructions: 
 
 
 
Clinic details 

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5.3!TOLERANCE!CHECK,!RANDOMISATION!AND!WP1:!ORAL!IMMUNOTHERAPY!
Eligible!participants!(who!have!a!positive!DBPCFC,!confirming!IgE^mediated!peanut!allergy)!will!then!undergo!a!one^
shot!food!challenge!to!confirm!tolerance!to!at!least!¼!boiled!peanut!to!confirm!eligibility.!Children!able!to!tolerate!
boiled!peanut!will!then!be!randomized!to!either!active!treatment!(OIT)!or!control,!on!a!2:1!basis.!!
!
Randomisation!needs!to!occur!after!tolerance!to!¼!boiled!peanut!has!been!demonstrated,!and!updosing!commenced!
immediately!on!safety!grounds.!Were!randomisation!(and!thus!further!daily!dosing)!to!be!delayed,!there!would!be!
potential!for!priming!which!might!result!in!subsequent!reactivity!to!a!previously!tolerated!dose!of!boiled!peanut.!
Immediate!randomisation!and!updosing!thus!ensures!safety.!
5.3.1!TOLERANCE!CHALLENGE!TO!BOILED!PEANUT!
All!children!will!undergo!a!single^dose!OPEN!(unblinded)!food!challenge!to!determine!the!starting!dose!of!boiled!
peanut.!Tolerance!to!at!least!¼!boiled!peanut!is!an!eligibility!criterion,!and!must!be!demonstrated!prior!to!
randomisation!in!all!children.!The!open,!single!dose!challenge!will!involve!the!consumption!of!¼!boiled!peanut!(boiled!
for!4!hours)!followed!by!a!2!hour!observation!period.!The!criteria!listed!in!Section!5.2.2!will!be!used!to!determine!
outcome!of!this!food!challenge.!!
Children!who!are!unable!to!tolerate!¼!boiled!peanut!will!not!be!eligible!for!the!study,!and!will!be!transferred!back!to!
routine!clinical!care.!
5.3.2!RANDOMISATION!
Once!tolerance!to!¼!boiled!peanut!has!been!demonstrated,!the!participant!will!be!randomised!using!an!online!
randomization!tool!(www.sealedenvelelope.com).!Randomisation!will!be!blocked!(using!random!permuted!blocks)!to!
ensure!that!the!groups!are!balanced,!and!include!a!level!of!stratification!according!to!whether!the!child!is!
predominantly!sensitized!to!a!specific!peanut!protein!components!(Ara!h!2).!Pilot!data!indicates!that!the!boiling!process!
affects!Ara!h!2!content!more!than!other!peanut!proteins.!Thus,!patients!who!are!predominantly!sensitized!to!Ara!h!2!
may!be!more!likely!to!have!a!successful!outcome!than!those!allergic!to!other!peanut!proteins.!!
The!Ara!h!2!predominant!Phenotype!is!defined!as:!
•!
Specific!IgE!to!Ara!h!2!>1.0!kUA/l!
•!
Specific!IgE!to!Ara!h!1!and!Ara!h!3!<1.0!kUA/l!
5.3.3!CONTROL!GROUP!
Subjects!randomized!to!the!control!group!will!receive!current!standard!care!according!to!best!practice!(as!per!British!
Society!for!Allergy!and!Clinical!Immunology!guidance).!This!includes:!
•!
A!food'allergy'management'plan!(Figure!5),!with!provision!of!rescue!medication!including!an!adrenaline!auto^
injector!device.!Families!and!participants!will!be!instructed!in!the!prompt!recognition!and!treatment!of!allergic!
reactions.!
•!
Contact'information!for!the!team,!which!will!include!telephone!contact!number!for!the!team!and!an!email!
address!which!will!be!checked!daily!by!the!research!team!from!Monday!to!Friday!for!non^urgent!queries.!
•!
Dietary'advice'on'peanut'avoidance.!Participants!will!not!be!allowed!to!ingest!peanut!for!the!whole!study!
duration!(52!weeks).!!!
•!
A!home'diary'sheet,!on!which!parents!will!log!all!accidental!reactions!experienced.!Participants!will!also!be!
offered!an!opportunity!to!‘opt^in’!to!using!an!electronic!‘mobile!app’!diary!in!parallel!to!the!paper^based!diary.!
Children!(and!their!parents)!will!undergo!quality^of^life!assessments!at!0,!3,!6!and!12!months!(see!5.7.1).!!
!
!

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5.3.4!ACTIVE!GROUP:!ORAL!IMMUNOTHERAPY!
Subjects!randomized!to!the!active!intervention!arm!will!continue!to!undergo!an!OPEN!(unblinded)!food!challenge!at!the!
same!visit,!to!determine!the!starting!dose!of!boiled!peanut.!This!is!because!some!children!may!exhibit!a!degree!of!de"
novo"tolerance!to!boiled!peanut,!and!thus!demonstration!of!tolerance!allows!for!individualization!of!the!updosing!
protocol.!The!open!challenge!will!utilize!the!following!protocol:!
!
Protocol'2:'
Open'OFC'to'boiled'PN'
Boiled'peanuts'(boiled'for'4'hours)'
If'dose'tolerated,'
commence'
updosing'at'STEP:'
TIME!POINT!(mins)!
No.!peanuts!
Peanut!protein!(mg)*!
(Already!given!in!5.3.1)!
¼!boiled!peanut!
30!
pre^A!
0!
¾!boiled!peanut!
100!
1!
30!
2!boiled!peanuts!
260!
1!
60!
4!boiled!peanuts!
520!
1!
90!
8!boiled!peanuts!
1040!
5!
Cumulative'dose'
15'boiled'peanuts'
1950'
'
2!hours!observation!period!following!last!dose!to!monitor!for!signs!of!reaction!
*Boiled"peanuts"contain"approximately"half"the"amount"of"protein"as"roasted"peanuts."
The!criteria!listed!in!Section!5.2.2!will!be!used!to!determine!outcome!of!this!food!challenge.!
Children!will!receive!daily!doses!of!peanut!at!home,!initially!using!boiled!peanut.!The!updosing!regime!is!shown!in!Table!
1.!Children!who!tolerate!at!least!1!boiled!peanut!will!commence!updosing!at!½!boiled!peanut,!unless!they!have!passed!
the!challenge!in!its!entirety!(i.e.!tolerates!15!boiled!peanuts)!in!which!case!they!will!commence!at!STEP!5.!Those!who!
tolerate!¼!boiled!peanut!only!will!commence!updosing!at!the!pre^A!step!(Table!1).!
Children!in!the!ACTIVE!group!(and!their!parents)!will!undergo!quality^of^life!assessments!at!0,!3,!6!and!12!and!24!
months!(see!section!5.7.1).!!
Prior!to!discharge!home,!each!family!will!be!provided!with:!!
•!
A!symptom'advice'sheet!(including!advice!on!avoiding!intense!physical!exercise!up!to!2!hours!after!the!dose!
intake).!
•!
A!food'allergy'management'plan!(Figure!6),!including!an!emergency!medicine!kit!containing!non^sedating!oral!
antihistamine!and!two!adrenaline!auto^injectors.!Where!the!child!has!a!history!of!asthma!or!prior!respiratory!
symptoms!to!a!food!allergen,!the!kit!will!also!include!a!salbutamol!inhaler!and!spacer!device.!Families!and!
participants!will!be!instructed!in!the!prompt!recognition!and!treatment!of!allergic!reactions,!including!
adrenaline!auto^injectors.!
•!
Contact'information!for!the!team,!which!will!includes!a!dedicated!mobile!phone!number!with!24/7!access!to!a!
senior!member!of!the!medical!team!for!urgent!queries,!and!an!email!address!which!will!be!checked!daily!by!
the!research!team!from!Monday!to!Friday!for!non^urgent!queries.!
•!
Dietary'advice'on'peanut'avoidance.!Participants!receiving!OIT!will!not!be!allowed!to!ingest!peanut!for!the!
whole!study!duration!(52!weeks)!excluding!the!OIT!doses.!!!
•!
A!home'diary'and'instruction'sheet,!which!will!specify!to!parents!what!dose!to!give!their!child,!and!on!to!
which!they!will!log!all!doses!taken!at!home!and!any!resulting!adverse!events.!Subjects!will!be!asked!to!record!
any!symptoms,!duration,!timing!in!relation!to!OIT!dose!and!any!exacerbating!factors!(e.g.!exercise,!excessive!
tiredness,!viral!illness).!In!the!event!of!any!symptoms,!the!family!needs!to!contact!the!research!team!for!
advice.!Participants!will!also!be!offered!an!opportunity!to!‘opt^in’!to!using!an!electronic!‘mobile!app’!diary!in!
parallel!to!the!paper^based!diary,!the!aim!being!to!facilitate!reporting!by!study!participants!and!validate!this!
approach!for!future!OIT!studies.!
!
!
!

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5.3.4.1!UPDOSING!
At!each!step!(i.e.!all!dose!increases),!the!dose!will!first!be!given!under!medical!supervision!on!the!Research!Unit,!
followed!by!observation!for!at!least!one!hour!(2!hours!if!participant!has!previously!experienced!a!delayed!reaction).!
Prior!to!a!dose!increase,!the!supervising!clinician!will!assess!the!participant!to!ensure:!!
•!
No!significant!allergic!reactions!to!doses!given!in!previous!2!weeks.!!
•!
No!acute!exacerbation!of!asthma!in!the!past!week.!!
•!
No!concurrent!systemic!illness.!!
The!dose!can!be!mixed!into!a!carrier!(such!as!low!fat!(rather!than!full!fat)!yoghurt,!for!example)!if!desired.!Children!will!
be!monitored!under!medical!supervision!for!one!hour!following!dose!administration.!Following!each!dose!increase,!that!
dose!will!be!given!to!participants!at!home!daily!for!a!minimum!of!2!weeks!until!the!next!increase!is!performed.!!
!
!
!
STEP!
PEANUT!
Boiling!time!
No.!of!
peanuts!/!day!
No.'weeks'
at'this'dose'
(minimum)'
Cumulative'
No.'of'weeks'
(minimum)'
Approximate'
Peanut'protein'
(mg)'
pre^A!
4!hours!
1/8!
2!
^!
15!
pre^B!
4!hours!
¼!
2!
^!
30!
1!
4!hours!
½!!
2!
2!
65!
2!
4!hours!
1!
2!
4!
130!
3!
4!hours!
2!
2!
6!
260!
4!
4!hours!
4!
2!
8!
520!
5!
4!hours!
8!
2!
10!
1040!
6!
2!hours!
4*!
2!
12!
520!
7!
2!hours!
8!
2!
14!
1040!
8!
1!hour!
2*!
2!
16!
260!
9!
1!hour!
4!
2!
18!
520'
10!
1!hour!
8!
2!
20!
1040'
11!
1/2!hour!
4*!
2!
22!
520'
12!
1/2!hour!
8!
4!
26!
1040!
!
Open!OFC!to!roasted!peanut!(to!determine!if!updosing!can!be!converted!to!roasted):!
•!
If!reacts!to!≤300mg!dose,!continue!maintenance!of!8!peanuts!up!to!Wk!52!
•!
If!tolerates!300mg!dose,!continue!updosing!as!follows:!
13!
n/a!
½!roasted!PN!
4!
30!
125!
14!
n/a!
1!roasted!PN!
4!
34!
250!
15!
n/a!
2!roasted!PN!
4!
38!
500!
16!
n/a!
4!roasted!PN!
4!
42!
1000!
Table'1:!Updosing!protocol!for!Peanut!(PN)!OIT!using!boiled!and!then!roasted!peanut.!!
!
*For!initial!(in^hospital)!updosing!at!the!time!points!marked,!the!dose!to!be!administered!will!be!split!into!2!doses,!
given!30!minutes!apart:!Step!6:!1!+!3!peanuts;!Step!8:!1!+!1!peanut;!Step!11:!1!+!3!peanuts.!
!
5.3.4.2!TRANSITION!TO!ROASTED!PEANUT!
After!STEP!12!(approximately!4^7!months!after!commencement),!the!next!updosing!step!involves!a!transition!to!roasted!
peanut.!This!will!involve!an!OPEN!(unblinded)!abbreviated!food!challenge!according!to!the!following!protocol:!
!

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Protocol'3:'
Open'OFC'to'roasted'PN'
Roasted'peanut'OFC'(using'defatted'flour)'
If'dose'tolerated,'
continue'at'STEP:'
TIME!POINT!(mins)!
Peanut!flour!(mg)!
Peanut!protein!(mg)!
0!
20!
10!
Do!not!transition!to!
roasted!PN:!continue!
at!8!boiled!PN!per!day!
30!
60!
30!
60!
200!
100!
90!
600*!
300*!
13!
150!
2000!
1000!
13!
180!
6000#!
3000#!
16!
Cumulative'dose'
'
4440mg'
'
2!hours!observation!period!following!last!dose!to!monitor!for!signs!of!reaction!
*Dose!to!be!given!as!1!whole!peanut!(25%!protein)!+!peanut!flour!to!make!a!total!dose!of!300mg!peanut!protein!
#Dose!to!be!given!as!4!whole!peanuts!+!peanut!flour!to!make!a!total!dose!of!3!gram!peanut!protein!
!
The!criteria!listed!in!Section!5.2.2!will!be!used!to!determine!outcome!of!this!food!challenge.!
!
Children!who!tolerate!at!least!300mg!peanut!protein!(i.e.!a!cumulative!dose!of!440mg)!will!continue!updosing!at!STEP!
13!using!roasted!peanut.!Those!who!tolerate!the!entire!dose!(4440mg)!will!continue!at!STEP!16.!This!is!equivalent!to!
continuing!OIT!at!a!minimum!of!one!half!roasted!peanut!BELOW!that!tolerated!at!this!open!challenge.!!Children!who!
are!unable!to!tolerate!the!300mg!dose!will!continue!maintenance!at!8!boiled!peanuts!(boiled!for!30mins)!until!the!1!
year!assessment.!
All!subjects!will!also!undergo!repeat!skin!prick!testing!to!commercial!crude!peanut!extract,!and!quality^of^life!
assessments!as!described!in!section!5.7.1.!
5.3.4.3!CHANGES!TO!THE!PROTOCOL!DUE!TO!REACTIONS!
In!the!event!of!an!allergic!reaction!to!a!dose!of!OIT!within!2!hours!of!a!dose,!either!at!updosing!in!hospital!or!after!a!
dose!given!at!home,!the!following!measures!will!be!taken:!
•!
For!a!single!reaction!consisting!of!wheeze,!persistent!cough,!difficulty!breathing,!stridor!or!marked!swallowing!
difficulties,!the!family!must!not!give!further!OIT!doses!without!contacting!the!research!team.!The!previous!lower!
dose!will!be!given!the!next!possible!day,!ideally!under!medical!observation!on!the!Research!Unit.!!
•!
For!skin!symptoms,!itchy!mouth,!rhinoconjunctivitis!or!mild!abdominal!symptoms,!reassurance!to!families!will!be!
provided!and!the!current!dose!will!be!continued,!with!daily!contact!with!the!study!team!as!needed.!
•!
For!persistent!reactions!for!5^7!days!(within!2!hours!of!the!OIT!dose)!consisting!of!abdominal!pain,!
rhinoconjunctivitis!or!skin!symptoms,!the!dose!will!be!reduced!to!the!previous!dose.!
•!
In!the!event!of!other!symptoms!that!prove!difficult!to!the!child,!the!dose!can!be!reduced!at!investigator’s!
discretion.!!!!
!
Where!a!dose!reduction!is!required,!the!subsequent!dose!increase!will!be!performed!at!least!2!weeks!later!at!the!
Research!Unit!in!hospital!under!supervision.!!!
!
In!the!event!of!omitted!doses:!
•!
If!a!single!dose!of!OIT!is!missed,!the!subject!can!continue!with!the!usual!dose.!
•!
If!2!^!4!days!of!OIT!are!missed,!give!the!previous!dose!until!the!subject!can!attend!the!research!unit!for!the!next!
updosing.!!
•!
If!more!than!4!days!are!missed,!daily!doses!should!stop!and!the!subject!must!attend!the!research!unit.!!
!
In!the!event!of!an!intercurrent!illness,!where!symptoms!occur!but!are!not!related!temporally!to!dose!administration,!
families!should!contact!the!research!team!to!discuss!reducing!the!dose!depending!on!symptoms!type!and!intensity.!!
!
!

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5.3.4.4!PREPARATION!OF!BOILED!AND!ROASTED!PEANUT!FOR!OIT!
Families!will!be!provided!with!blanched!raw!peanut!at!hospital!visits,!for!preparation!at!home.!Full!instructions!will!be!
provided!(as!part!of!the!home'diary'and'instruction'sheet).!Peanuts!(Holt!Runner!cultivar,!supplied!by!the!Peanut!
Company!of!Australia!Ltd)!will!be!supplied!in!125g!vacuum^packed!batches!to!families!on!an!as^needed!basis,!in!order!
to!monitor!peanut!consumption.!!
!
Families!will!be!provided!with!instructions!to!boil!the!peanuts!at!home!in!batches,!as!follows:!
•!
Boil!100g!quantity!of!peanuts!in!a!saucepan!in!~600ml!water!for!xx!hours!
•!
Drain!and!plunge!peanuts!into!cold!water,!then!drain!in!colander/sieve!
•!
Lay!peanuts!in!a!single!layer!on!a!baking!tray!lined!with!baking!paper!
•!
Place!tray!in!freezer!until!peanuts!are!'snap!frozen'!
•!
Transfer!peanuts!into!a!plastic!container!and!store!in!freezer!until!required.!
The!boiling!time!will!be!progressively!reduced!as!depicted!in!Table!1!above.!!
In!those!children!who!tolerate!roasted!peanuts,!families!will!be!instructed!to!use!commercial!roasted!peanuts!(KP!
roasted!peanuts)!sourced!from!a!UK!supermarket.!Alternatively,!peanut!M&Ms!may!be!substituted!for!roasted!peanut,!
where!this!is!desired!by!the!study!participant:!four!roasted!peanuts!is!equivalent!to!6!peanut!M&Ms.!
5.4!1!YEAR!ASSESSMENT!
All!subjects,!in!both!the!active!(OIT)!and!control!groups,!will!be!invited!to!undergo!a!further!DBPCFC!to!roasted!PN!at!12!
months.!Those!who!tolerate!>1.4g!of!peanut!protein!at!this!challenge!will!be!invited!back!for!a!further!open!challenge!
having!stopped!all!peanut!ingestion!(including!OIT!doses)!for!4!weeks.!The!challenges!and!outcomes!are!depicted!in!
summary!form!in!Figure!7.!
!
!
Figure'7:!Challenges!and!outcomes,!months!12^13!!
!
All!subjects!will!also!undergo!repeat!skin!prick!testing!to!commercial!crude!peanut!extract,!and!quality^of^life!
assessments!as!described!in!section!5.7.1.!
1000mg 
≤ 300 mg
3000mg or 
no reaction
Failed OIT 
(withdrawal)
Continue daily maintenance using roasted peanut
(2-4 peanuts)
“Tolerance check”
Open challenge to roasted peanut
Subject reacts to…
Stop OIT for 4 weeks
≤ 1000mg
3000mg
Recommence OIT 
(roasted PN) then
continue daily
maintenance
No reaction
Thrice weekly
dose (4 peanuts)
Thrice weekly
dose (4-8 peanuts)
“Tolerance check”
Open challenge 
to roasted peanut
Stop OIT 
for 4 weeks
≤ 1000 g
3000 g 
Continue daily PN
No reaction
Thrice weekly
dose (4 peanuts)
Thrice weekly
dose (4-8 peanuts)
DBPCFC to roasted peanut
Subject reacts to:
Month 24+
Month 12
Month 13

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5.4.1!12!MONTH!DBPCFC!
!The!DBPCFC!will!be!performed!as!per!Protocol!1!in!Section!5.2.2.!The!purpose!of!this!challenge!is:!
•!
In!those!who!have!undergone!OIT,!to!assess!for!desensitisation!to!roasted!peanut!and!a!resulting!change!in!
threshold!of!clinical!reactivity!(Primary!and!Secondary!outcome!measures).!
•!
In!the!control!group,!to!determine!the!rate!of!natural!resolution!of!peanut!allergy!and!for!those!continuing!
into!WP2!(where!they!will!undergo!OIT),!serve!as!the!baseline!threshold!of!clinical!reactivity!to!roasted!peanut.!
!
Protocol'1:'
DBPCFC'to'roasted'PN'
Roasted'peanut'DBPCFC'
(using'defatted'flour)'
OUTCOME'if'reacts'
TIME!POINT!(mins)!
Peanut!flour!
Peanut!protein!!
0!
6!
3!
OIT!unsuccessful:!
withdrawn!from!study*!
30!
20!
10!
60!
60!
30!
90!
200!
100!
120!
600!
300!
150!
2000!
1000!
Continue!daily!PN!at!previous!
maintenance!dose!
180!
6000!
3000!
STOP!peanut!for!4!weeks!and!
proceed!to!open!challenge!
Cumulative'dose'
'
4440mg'
If'no'reaction:'
STOP!peanut!for!4!weeks!and!
proceed!to!open!challenge'
2!hour!observation!period!following!last!dose!
*In!the!unlikely!event!that!a!child!reacts!to!the!300mg!dose!during!challenge!but!has!previously!tolerated!≥1!roasted!PN,!then!they!can!continue!daily!
peanut!at!the!previous!tolerated!dose!for!a!further!12!months,!within!this!protocol.!
5.4.2!TOLERANCE!CHALLENGE!AT!13!MONTHS!
Children!in!the!active!group!who!meet!the!primary!study!outcome!(desensitised!to!>1.4g!peanut!protein!at!DBPCFC)!
will!then!be!instructed!to!stop!all!peanut!exposure!(including!OIT!doses).!A!further!open!challenge!will!be!performed!
after!4!weeks,!according!to!protocol!3,!using!criteria!listed!in!Section!5.2.2!to!determine!outcome.!Children!who!
tolerate!at!least!1.4g!peanut!protein!at!this!challenge!will!continue!with!thrice!weekly!maintenance!peanut!therapy!(4^8!
peanuts).!Those!who!react!will!recommence!updosing!to!the!previously!tolerated!dose!and!then!continue!daily!
maintenance!peanut!until!the!24!months!time!point.!
!
Protocol'3:'
Open'OFC'to'roasted'PN'
Roasted'peanut'OFC'
'(using'defatted'flour)'
OUTCOME'if'reacts'
TIME!POINT!(mins)!
Peanut!flour!
Peanut!protein!!
0!
20!
10!
RECOMMENCE!OIT!and!updose!to!
previous!tolerated!dose.!
Then!continue!DAILY!maintenance!of!up!
to!4!peanuts.!Repeat!tolerance!OFC!at!24!
mths!!
30!
60!
30!
60!
200!
100!
90!
600!
300!
120!
2000!
1000!
150!
6000!
3000!
Change!to!minimum!thrice!weekly!
maintenance!dose!of!4!peanuts.!
Cumulative'dose'
'
4440mg'
If'no'reaction:'
Change!to!thrice!weekly!maintenance!
dose!of!4^8!peanuts'
2!hour!observation!period!following!last!dose!
!
!

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5.5!WP2:!YEAR!2!OF!STUDY!
Children!in!the!control!group!will!be!offered!OIT!using!boiled!PN!during!months!12^24.!An!identical!protocol!to!WP1!will!
be!used!(section!5.3.3).!
!
Children!in!the!active!group!(who!underwent!OIT!during!months!1^12)!will!be!offered!ongoing!maintenance!therapy,!as!
described!above!in!section!5.4.!!
!
!
5.6!2!YEAR!ASSESSMENT!
Children!who!were!originally!assigned!to!the!control!group!and!who!have!undertaken!OIT!during!months!12^24!will!
undergo!a!further!DBPCFC!to!roasted!PN!at!24!months.!The!DBPCFC!will!be!performed!as!in!Section!5.2.2.!The!purpose!
of!this!challenge!is!to!assess!for!the!development!of!sustained!unresponsiveness!to!roasted!peanut!following!OIT,!and!
the!resulting!change!in!threshold!of!clinical!reactivity.!
!
All!subjects!will!also!undergo!repeat!skin!prick!testing!to!commercial!crude!peanut!extract!and!boiled!peanut!slurry,!and!
quality^of^life!assessments!as!described!in!section!5.7.1.!
!
All!children!(in!both!control!and!active!groups),!apart!from!those!who!passed!the!tolerance!challenge!at!13!months,!will!
be!offered!a!further!tolerance!challenge!at!24!months,!to!be!performed!as!in!section!5.4.!
!
!
5.7!!YEAR!3/4!ASSESSMENTS!
All!children!(in!both!active!and!control!groups)!will!be!invited!to!return!at!the!3!year!timepoint!for!a!further!set!of!
challenges,!to!define!longer^term!tolerance!following!2^3!years!of!active!immunotherapy.!This!is!because!there!is!data!
to!suggest!that!longer!duration!of!OIT!is!associated!with!immune!memory!and!more!sustained!tolerance.!These!
assessments!will!consist!of:!
i.!
A!DBPCFC!at!the!year!3!timepoint!(3!years!following!randomisation)!(conducted!according!to!section!5.4.1)!
ii.!
Open!food!challenge!4!weeks!after!stopping!OIT!(identical!to!tolerance!challenge,!section!5.4.2)!
iii.!
In!participants!who!exhibit!sustained!unresponsiveness!at!4!weeks,!a!further!DBPCFC!(conducted!according!to!
section!5.4.1)!after!a!further!8!weeks!off!OIT,!to!assess!for!sustained!unresponsiveness!at!12!weeks.!
iv.!
In!participants!who!exhibit!sustained!unresponsiveness!at!12!weeks,!a!further!DBPCFC!(conducted!according!to!
section!5.4.1)!after!a!total!of!1!year!off!OIT,!to!assess!for!sustained!unresponsiveness!at!1!year.!
These!assessments!are!summarised!in!Figure!8.!
All!families!will!continue!to!receive!access!to!the!24/7!helpline!during!this!time.!Any!participant!who!reacts!at!challenge!
to!a!previously!tolerated!level!will!recommence!updosing.!
!

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Figure'8:!Year!3/4!Assessments!
!
Participants!who!go!on!to!stop!all!peanut!for!12!months!(i.e.!who!pass!the!12^week!DBPCFC!without!any!loss!of!
tolerance)!will!be!asked!to!eat!8!roasted!peanuts!on!a!monthly!basis!as!a!safety!measure,!to!ensure!ongoing!clinical!
non^reactivity!during!this!time.!Any!participant!who!begins!to!exhibit!symptoms!during!this!9!month!period!(prior!to!
final!DBPCFC)!to!the!monthly!dose!of!8!peanuts!will!be!reviewed!by!the!study!PI!who!may!take!the!decision!to!
recommence!peanut!and!not!to!proceed!to!the!12!month!challenge.!This!is!in!order!to!prevent!any!participant!from!
reverting!back!to!clinical!reactivity!that!cannot!be!remedied!easily.!
!
5.8!OTHER!ASSESSMENTS!
5.8.1!ALLERGY!SKIN!PRICK!TESTING!
Skin!prick!testing!(SPT)!to!commercial!peanut!extract,!histamine!positive!and!saline!negative!control!will!be!performed!
at!baseline,!6,!12,!24!months!after!starting!OIT,!and!the!year!3!assessments!(see!Fig!8),!according!to!local!standard!
operating!procedures!consistent!with!national!guidelines.13!The!baseline!SPT!will!include!a!modified!SPT!to!boiled!
peanut.!
At!the!open!food!challenges!(e.g.!6!month!challenge),!SPT!will!be!performed!by!an!investigator!independent!to!the!
challenge!so!as!not!to!influence!the!interpretation!of!challenge!outcome.!Additional!positive!controls!will!be!included!as!
needed!to!ensure!blinding!of!the!participant.!!
!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
13!http://www.bsaci.org/Guidelines/Skin_Prick_Testing.pdf!
Randomisation
ACTIVE'TREATMENT:
OIT-using-boiled-peanut
CONTROL'GROUP:
Standard-care-(no-OIT)
Year'1
Year'2
Year'3+
OFC-1m-
OFF-OIT
DBPCFC
DBPCFC
ACTIVE'TREATMENT:
OIT-using-boiled-peanut
MAINTENANCE'
OFC-1m-OFF-OIT
OFC-1-month-OFF-OIT
DBPCFC 3-months-off-OIT
DBPCFC
DBPCFC
MAINTENANCE'
MAINTENANCE'
DBPCFC 12-months-off-OIT
Original-BOPI-study:
!
"
#
$
2
+1m------+3m-----+12m
2
2
1
Questionnaire-
Skin-prick-test
Blood-test
Peanut-challenge-(1-visit)
(2-visits)
2
1

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5.8.2!QUALITY!OF!LIFE!ASSESSMENTS!
The!impact!of!OIT!on!participants’!quality!of!life!(QoL)!will!be!assessed!both!from!parents’!and!participants’!perspective!
using!abbreviated!versions!of!disease^specific!validated!“food^allergy!quality!of!life!questionnaire”!(FAQL^Q)!in!its!
parental,14!child15!and!teenage16!forms!at!baseline,!3,!6,!12,!24!and!36!months!in!both!the!active!and!control!groups.!
These!new!abbreviated!versions!have!been!validated!(data!submitted!for!publication).!We!will!also!assess!the!impact!of!
the!child’s!food!allergy!on!parent!QoL,!using!the!FAQL^Parent!Burden!form!(which!has!been!validated!in!a!UK!
population).17!QoL!assessments!will!be!done!both!prior!to!and!after!oral!challenges.!!
!
The!FAQL^questionnaires!are!based!on!a!7^point!Likert!scale!and!changes!greater!than!0.5!points!over!time!have!been!
defined!as!clinically!significant.18!Previous!studies!have!reported!a!positive!effect!on!QoL!following!OIT!to!peanut!from!
the!parents’!perspective,7!however,!there!are!no!controlled!studies!which!have!addressed!the!impact!on!QoL!as!
perceived!by!participants.!!This!is!a!significant!knowledge!gap,!since!there!is!a!concern!that!while!parents!report!an!
improved!QoL!when!their!child!undergoes!OIT,!the!child!themselves!may!experience!a!worsening!of!QoL!due!to!
frequent!side!effects!and!need!to!alter!their!activities!following!OIT!doses.!
!
In!line!with!current!expert!opinion,!and!to!ensure!the!ability!to!compare!responses!consistently!during!the!first!12!
months!of!OIT,!children!who!are!age!12!at!study!commencement!will!be!asked!to!complete!the!Teenage!versions!of!the!
QoL!assessments,!unless!there!are!difficulties!with!comprehension!which!preclude!this.!!
!
We!will!also!assess!parental!anxiety!before,!and!12!and!24!months!after!their!child!commencing!OIT,!using!the!
Perceived!Stress!Scale.19!!
!
In!subjects!who!fail!visit!3!(tolerance!check!to!boiled!peanut)!or!are!withdrawn!during!the!active!OIT!phase!due!to!a!
significant!allergic!reaction,!we!will!contact!the!family!at!1!and!6!months!after!the!event!to!repeat!the!QoL!assessments.!
This!will!allow!us!to!assess!the!impact!of!‘failing’!OIT!on!the!young!person!and!their!family.!In!addition,!at!both!time!
points,!we!will!ask!the!family!if!we!can!arrange!a!convenient!time!when!we!can!undertake!a!limited!structured!
telephone!interview!(10^15!minutes)!with!the!parent/guardian(s)!and!their!child,!to!explore!any!issues!which!might!
have!been!raised!as!a!result!of!the!reaction,!following!the!outline!in!Appendix!3.!The!answers!to!these!questions!will!be!
documented!and!analysed!using!the!framework!method.20!
!
5.8.3!LABORATORY!ASSESSMENTS!
The!development!of!tolerance!in!immunotherapy!(whether!to!food!or!aeroallergens)!is!associated!with!several!
immunological!changes,!including!decreases!in!peanut^specific!IgE!levels!with!concomitant!increases!in!IgG4!levels,!
reduced!basophil!and!TH2!cytokine!responses!to!peanut!stimulation!and!upregulation!of!IL^10^producing!T^regulatory!
cells.21!However,!many!of!these!appear!to!be!transient,!and!there!remain!significant!gaps!in!knowledge,!particularly!in!
understanding!why!many!subjects!require!ongoing!exposure!to!the!allergen!(i.e.!maintenance!dosing)!to!maintain!
sustained!unresponsiveness.!!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
14DunnGalvin!A,!Cullinane!C,!Daly!DA,!FlokstraNde!Blok!BM,!Dubois!AE,!Hourihane!JO.!Longitudinal!validity!and!responsiveness!of!the!Food!
Allergy!Quality!of!Life!Questionnaire!N!Parent!Form!in!children!0N12!years!following!positive!and!negative!food!challenges.!Clin!Exp!Allergy.!
2010;40:476N85.!
15FlokstraNde!Blok!BM,!DunnGalvin!A,!VliegNBoerstra!BJ,!et!al.!Development!and!validation!of!a!selfNadministered!Food!Allergy!Quality!of!Life!
Questionnaire!for!children.!Clin!Exp!Allergy.!2009;39:127N37.!
16FlokstraNde!Blok!B,!DunnGalvin!A,!VliegNBoerstra!BJ,!et!al.!Development!and!validation!of!the!selfNadministered!Food!Allergy!Quality!of!Life!
Questionnaire!for!adolescents.!J!Allergy!Clin!Immunol.!2008;122:139N44,!144.e1N2.!
17Knibb!RC,!Stalker!C.!Validation!of!the!Food!Allergy!Quality!of!LifeNParental!Burden!Questionnaire!in!the!UK.!Qual!Life!Res.!2013;22:1841N9.!
18Jaeschke!R,!Singer!J,!Guyatt!GH.!Measurement!of!health!status.!Ascertaining!the!minimal!clinically!important!difference.!
Control!Clin!Trials!1989;!10:407–15.!
19!Cohen,!S.,!Kamarck,!T.,!and!Mermelstein,!R.!(1983).!A!global!measure!of!perceived!stress.!Journal!of!Health!and!Social!Behavior,!24,!386N396.!
20!Gale!NK,!Heath!G,!Cameron!E,!Rashid!S,!Redwood!S.!Using!the!framework!method!for!the!analysis!of!qualitative!data!in!multiNdisciplinary!
health!research.!BMC!Med!Res!Methodol.!2013!Sep!18;13:117.!
21Gorelik!M,!Narisety!SD,!Guerrerio!AL,!et!al.!Suppression!of!the!immunologic!response!to!peanut!during!immunotherapy!is!often!transient.!J!
Allergy!Clin!Immunol.!2014;!doi:!10.1016/j.jaci.2014.11.010.!

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It!is!therefore!important!for!this!study!to!include!mechanistic!assessments!to!allow!for!markers!of!successful!
desensitisation!to!be!assessed,!in!order!to!improve!the!efficacy!of!future!OIT!protocols.!We!will!include!a!series!of!
laboratory!assessments!in!subjects!undergoing!OIT,!allowing!longitudinal!comparisons!to!be!made!in!those!undergoing!
OIT!(vs!controls)!to!assess!the!following:!!
!
•!
Changes!in!serum!specific!antibodies!pre^!and!post^OIT:!Total!IgE;!specific!IgE,!IgG4!to!whole!peanut!and!
peanut!components!(Ara!h!1,!2,!3,!8!and!9)!and!their!ability!to!cause!an!effector!cell!response!will!be!measured!
•!
IgE^immunoblot!using!patient!sera!to!identify!in!vitro!the!binding!of!participants!IgE!to!peanut!proteins,!and!
how!this!varies!during!OIT.!
•!
Identification!of!serum!factors!associated!with!the!development!of!oral!tolerance!during!peanut!OIT,!by!means!
of!a!validated!IgE!facilitated^binding!assay.!
•!
Changes!in!basophil!responses!(assessed!by!CD63!and!CD203c!expression!by!flow!cytometry)!following!in"vivo!
and!ex"vivo!peanut!stimulation,!and!how!these!vary!during!OIT.!Confirmatory!work!will!be!performed!in!a!
subset!of!patients!using!purified!basophils!isolated!from!whole!blood.!
•!
Biomarkers!that!may!identify!successful!tolerance!induction!to!peanut!!
•!
Changes!in!T!and!B!cell!populations!and!their!immune!profile!during!OIT,!including!allergen^specific!
proliferation!of!T^cell!subtypes!(including!T!helper!and!regulatory!T!cells)!and!changes!in!immunoglobulin!
repertoire!by!peanut^specific!B^cells.!
•!
mRNA!expression!and!methylation!of!proteins!(such!as!forkhead!box!protein!3!(FOXP3)!sites)!on!T!cell!subsets!
which!may!predict!the!presence!of!sustained!unresponsiveness.!
!
These!assessments!will!be!performed!on!blood!samples!taken!at!baseline,!3,!6,!12,!13!and!24!months,!as!well!as!at!the!3!
year!assessments!(outlined!in!Figure!8)!after!commencement!of!OIT.!Laboratory!work!will!be!initially!performed!at!the!
National!Heart!&!Lung!Institute,!Imperial!College!London,!although!some!assays!may!be!performed!elsewhere!in!the!UK!
or!abroad,!where!lack!of!local!expertise!necessitates!this).!Specimens!may!also!be!stored!for!future!use!in!new!assays!to!
measure!immune!responses!or!biomarkers,!as!research!tests!are!developed.!!
!
5.9!STUDY!COMPLETION!!
The!study!duration!is!for!up!to!4!years!following!randomisation,!as!outlined!in!section!5.7.!The!study!will!be!considered!
complete!following!enrolment!of!the!last!patient!and!completion!of!the!study!procedures!in!that!patient.!!
!
At!the!end!of!the!study,!children!will!be!re^integrated!into!the!routine!clinical!allergy!service!for!ongoing!care.!
!
5.9.1!EARLY!STUDY!TERMINATION!
An!Independent!Data!Monitoring!Committee!(IDMC)!will!assess!study!safety!on!a!regular!basis.!The!IDMC!has!the!
authority!to!suspend!the!study,!or!request!withdrawal!of!a!particular!participant,!at!any!stage!if!it!concludes!there!are!
significant!safety!concerns!affecting!a!single!participant!or!the!study!as!a!whole.!
Recruitment!to!the!study,!and!further!peanut!challenges!and!updosing,!will!be!suspended!pending!review!by!the!IDMC!
in!the!event!of:!!
^!
any!death!
^!
a!participant!being!admitted!to!the!intensive!care!unit!for!a!study^related!adverse!event!!
^!
a!participant!experiencing!a!life^threatening!anaphylactic!reaction!to!an!OIT!dose.!
!
The!IDMC!will!consider!the!circumstances!and!make!a!recommendation!as!to!whether!to!terminate!the!study,!or!
continue!with!or!without!a!protocol!amendment.!!
'

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6.'ADVERSE'EVENT'REPORTING'
6.1!DEFINITIONS!
An!adverse'event!is!any!occurrence!or!worsening!of!an!undesirable!or!unintended!sign,!symptom,!laboratory!finding,!or!
disease!that!occurs!during!participation,!including!occurrences!that!are!not!necessarily!caused!by!or!related!to!a!study!
intervention.!An!adverse!event!will!be!followed!until!it!resolves!or!until!30!days!after!a!participant!terminates!from!the!
study,!whichever!comes!first.!!
A!serious'adverse'event!(SAE)!is!defined!as!any!adverse!event!that!suggests!a!significant!hazard.!This!includes!but!is!not!
limited!to!any!of!the!following:!!
1.!Death:!Any!death!that!occurs!during!the!study!must!be!reported!whether!considered!treatment!related!or!
not.!!
2.!A!life^threatening!event:!Any!adverse!therapy!experience!that,!in!the!view!of!the!investigator,!places!the!
participant!at!immediate!risk!of!death!from!the!reaction!as!it!occurred.!!
3.!Inpatient!hospitalization!or!prolongation!of!existing!hospitalization.!!
4.!Persistent!or!significant!disability.!!
5.!An!event!that!requires!intervention!to!prevent!permanent!impairment!or!damage.!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.!!
6.!Important!AEs!that!are!not!immediately!life^threatening!or!do!not!result!in!death!or!hospitalization!but!may!
jeopardise!the!subject!or!may!require!intervention!to!prevent!one!of!the!other!outcomes!listed!in!the!
definition!above,!should!also!be!considered!serious.!
The!adverse!event!can!be!described!as!‘expected’!if!it!caused!symptoms!and/or!signs!that!could!be!reasonably!
described!as!a!consequence!of!an!allergic!reaction!to!peanut!exposure!within!the!protocol.!Symptoms!of!an!allergic!
reaction!are!defined!as!any!described!within!this!protocol.!
An!adverse!event!is!considered!“unexpected”!when!its!nature!or!severity!is!not!consistent!with!the!investigator’s!
protocol.!!
An!adverse!event!is!defined!as!“related”!when!it!has!resulted!from!the!administration!of!any!of!the!research!
procedures.!Related!adverse!events!are!defined!as!“adverse'reactions”.!!
Any'symptoms'requiring'treatment'for'anaphylaxis'(adrenaline,!steroids,!salbutamol)!following!an!OIT!dose'will'be'
classified'as'a'SERIOUS'ADVERSE'REACTION.!!
6.2!DOCUMENTATION!OF!ADVERSE!EVENTS!
All!adverse!events!will!be!recorded!on!a!specifically!designated!case!report!form!(CRF)!from!the!time!the!participant!
provides!consent!until!the!time!the!event!resolves!or!until!30!days!after!the!participant!completes!study!treatment.!
Adverse!events!may!be!discovered!through!observing!and!questioning!the!participant!or!receiving!an!unsolicited!
complaint!and!questioning!the!participant!in!an!objective!manner.!All!adverse!events!will!be!recorded,!regardless!of!
their!severity!or!relation!to!study!medication!or!procedures.!!

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All!serious!adverse!events!(SAEs)!will!be!reported!on!a!SAE!report!form!in!addition!to!CRFs.!Safety!data!will!be!reviewed!
at!least!every!four!months!by!the!Independent!Data!Monitoring!Committee!(IDMC).!The!IDMC!has!the!authority!to!
recommend!withdrawal!of!a!study!participant!or!termination!of!the!trial!because!of!safety!findings.!
All!SAEs!should!be!reported!to!the!Research!Ethics!Committee,!where!in!the!opinion!of!the!Chief!Investigator,!the!event!
was:!
•!
‘related’,!ie!resulted!from!the!administration!of!any!of!the!research!procedures;!and!
•!
‘unexpected’,!ie!an!event!that!is!not!listed!in!the!protocol!as!an!expected!occurrence!
Reports!of!related!and!unexpected!SAEs!should!be!submitted!within!15!days!of!the!event,!using!the!NRES!SAE!form!for!
non^IMP!studies.!!The!Chief!Investigator!must!also!notify!the!Sponsor!of!all!SAEs.!
6.3!GRADING!AND!ATTRIBUTION!OF!ADVERSE!EVENTS!
The!study!site!will!grade!the!severity!of!adverse!events!experienced!by!study!participants!according!to!the!criteria!set!
forth!in!the!NCI^CTCAE!Version!3.0.22!This!document!provides!a!common!language!to!describe!levels!of!severity,!to!
analyse!and!interpret!data,!and!to!articulate!the!clinical!significance!of!all!adverse!events.!
Adverse!events!will!be!graded!on!a!scale!from!1!to!5!according!to!the!following!standards!in!the!NCI^CTCAE!manual:!!
Grade!1!=!mild!adverse!event.!!
Grade!2!=!moderate!adverse!event.!!
Grade!3!=!severe!and!undesirable!adverse!event.!!
Grade!4!=!life^threatening!or!disabling!adverse!event.!!
Grade!5!=!death.!!
All!adverse!events!will!be!recorded!and!graded!whether!they!are!or!are!not!related!to!disease!progression!or!
treatment.!The!NCI^CTCAE!grades!will!be!the!primary!source!for!scoring.!
Allergic!reactions!will!be!graded!according!to!World!Allergy!Organisation!(WAO)!criteria!for!allergic!reactions!to!
immunotherapy,!modified!for!use!with!food^triggered!allergic!reactions.!These!can!be!used!to!inform!as!to!the!
appropriate!NTI^CTCAE!grade!(Table!2).!!
The!relation,!or!attribution,!of!an!adverse!event!to!study!participation!will!be!determined!by!the!investigator!and!
recorded!on!CRF!and/or!SAE!reporting!form.!The!assignment!of!the!causality!should!be!made!by!the!investigator!
responsible!for!the!care!of!the!participant!using!the!definitions!in!the!table!below!(Table!3).!If!any!doubt!about!the!
causality!exists!the!investigator!will!discuss!with!the!Chief!Investigator.!!In!the!case!of!discrepant!views!on!causality!
between!the!investigator!and!others,!all!parties!will!discuss!the!case.!!
!
!
!
!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
22http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf!

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Grade!1!
Grade!2!
Grade!3!
Grade!4!
Grade!5!
Symptom(s)/sign(s)(of(GI(and/or(
1(organ(system(present(
Cutaneous'
Generalized!pruritus,!urticaria,!
flushing,!or!sensation!of!heat!or!
warmth!
or'
Angioedema!(not!laryngeal)!
or'
Gastrointestinal'
Abdominal!cramps,!vomiting,!or!
diarrhoea!
or'
Upper'respiratory'
Rhinitis!^!(eg,!sneezing,!
rhinorrhoea,!nasal!pruritus!
and/or!nasal!congestion)!
or'
Throat^clearing!(itchy!throat)!
or'
Cough!perceived!to!originate!in!
the!upper!airway,!not!the!lung,!
larynx,!or!trachea!
or'
Conjunctival'
Erythema,!pruritus!or!tearing!
Other'
Nausea,!metallic!taste,!or!
headache!
Symptom(s)/sign(s)(of(2(or(
more((not(including(GI)(
organ(system(present(
"
or'
!
Lower'respiratory'
Asthma:!cough,!wheezing,!
shortness!of!breath!(e.g.!
fall!in!PEF!or!FEV1!<40%,!
salbutamol^responsive!
wheeze)!
!
or'
!
Other'
Uterine!cramps!
Lower'respiratory'
Asthma!(e.g.!fall!in!
PEF!or!FEV1!>40%,!
wheeze!not!
responsive!to!
salbutamol)!
!
or'
!
Laryngeal'oedema!
with!or!without!
stridor!
Lower'or'upper'
respiratory'
Respiratory!failure!
with!or!without!loss!
of!consciousness!
!
or'
!
Cardiovascular'
Hypotension!with!or!
without!loss!of!
consciousness!
Death!
Table'2:!World!Allergy!Organisation!(WAO)!Grading!System!for!allergic!reactions!(modified!for!applicability!for!food^
triggered!reactions)!adapted!from!J!Allergy!Clin!Immunol!2010;!125:569^74.!
'
Relationship'
Description'
Unrelated'
There!is!no!evidence!of!any!causal!relationship!
Unlikely'
There!is!little!evidence!to!suggest!there!is!a!causal!relationship!(e.g.!the!
event!did!not!occur!within!a!reasonable!time!after!administration!of!the!
trial!medication).!!There!is!another!reasonable!explanation!for!the!event!
(e.g.!the!participant’s!clinical!condition,!other!concomitant!treatment).!
Possible'
There!is!some!evidence!to!suggest!a!causal!relationship!(e.g.!because!
the!event!occurs!within!a!reasonable!time!after!administration!of!the!
trial!medication).!!However,!the!influence!of!other!factors!may!have!
contributed!to!the!event!(e.g.!the!participant’s!clinical!condition,!other!
concomitant!treatments).!
Probable'
There!is!evidence!to!suggest!a!causal!relationship!and!the!influence!of!
other!factors!is!unlikely.!
Definitely'
There!is!clear!evidence!to!suggest!a!causal!relationship!and!other!
possible!contributing!factors!can!be!ruled!out.!
Not'assessable'
There!is!insufficient!or!incomplete!evidence!to!make!a!clinical!
judgement!of!the!causal!relationship.!
'
Table'3:'Assignment!of!causality!for!adverse!event!
!

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7.'STATISTICS'AND'DATA'ANALYSIS'
7.1!SAMPLE!SIZE!ESTIMATION!
Current!data!from!Europe!and!North!America!indicates!that!at!least!80^85%!of!peanut^allergic!children!will!react!to!1.4g!
peanut!protein.!The!incidence!of!natural!resolution!of!peanut!allergy!over!a!12!month!period!is!typically!<10%,!on!the!
basis!of!data!arising!from!our!clinical!service.!
For!the!purpose!of!this!study,!we!have!assumed!a!conservative!estimate!of!10%!for!natural!resolution,!and!a!20%!drop^
out!rate.!We!note!that!such!is!the!demand!for!OIT!that!in!the!published!studies,!drop^out!rates!have!been!consistently!
<10%.!
We!propose!to!recruit!46!peanut^allergic!children!to!the!study,!who!will!be!randomized!2:1!to!active!(n=30)!or!control!
(n=16)!groups.!This!will!allow!us!to!detect!a!rate!of!successful!desensitisation!of!60%!in!participants!undergoing!OIT,!
with!80%!power!using!a!two^sided!significance!level!of!0.05!and!with!continuity!correction,!whilst!allowing!for!a!20%!
loss^to^follow^up.!
These!figures!for!desensitisation!rate!and!resolution!are!based!on!published!data!relating!to!the!UK.7!
!
7.2!STATISTICAL!ANALYSIS!PLAN!
Data!will!be!collected!on!paper!CRFs!which!include!the!patients!name,!DOB!and!hospital!number.!Participants!will!be!
assigned!a!study!number,!which!will!be!noted!on!the!paper!record.!Data!will!then!be!entered!on!to!a!password^
protected!computer!database!on!the!secure!hospital!IT!system;!only!the!study!number!will!be!used!to!identify!the!
patient!data.!
De^identified!data!and!all!appropriate!documentation!will!be!stored!for!a!minimum!of!10!years!after!the!completion!of!
the!study,!including!the!follow^up!period.!!!
The!primary!analysis!will!be!performed!on!an!intention!to!treat!basis:!all!subjects!allocated!to!each!arm!will!be!analysed!
together!as!representing!that!treatment!arm,!irrespective!of!compliance!and!whether!or!not!they!have!completed!the!
prescribed!regimen.!A!secondary!analysis!will!also!be!performed!on!a!per!protocol!basis.!
Subjects!who!are!withdrawn!from!active!treatment!will!remain!in!the!study!for!assessment!of!outcome!relating!to!QoL!
measures.!
!
7.2.1!ANALYSIS!OF!PRIMARY!ENDPOINT!
The!primary!analysis!will!compare!the!proportion!of!subjects!who!tolerate!1.4g!(or!more)!roasted!peanut!protein!in!the!
active!and!control!groups,!12!months!after!randomization,!using!a!two^sided!Fisher's!exact!test!at!a!p<0.05!level!of!
significance.!!
!
!

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7.2.2!ANALYSIS!OF!SECONDARY!ENDPOINTS!
The!following!secondary!analyses!will!be!performed,!using!two^sided!testing!for!non^parametric!data!at!a!p<0.05!level!
of!significance:!
•!
Relative!change!in!clinical!threshold!(NOAEL,!LOAEL)!to!roasted!peanut!at!6!and!12!months!in!active!vs!control,!
using!Mann^Whitney!U!test.!
•!
Proportion!of!subjects!who!tolerate!1.4g!(or!more)!roasted!peanut!protein!in!the!active!and!control!groups,!12!
months!after!randomization!and!following!cessation!of!all!peanut!intake!for!4!weeks!after!1!and!3!years!of!OIT,!
using!a!two^sided!Fisher's!exact!test!at!a!p<0.05!level!of!significance.!!
•!
Change!in!quality!of!life!assessments!before,!and!at!6!and!12!months!after!OIT,!as!assessed!by!FAQL^
Questionnaire!in!children,!teenagers!and!their!parents!–!in!the!active!vs!control!groups!–!using!paired!and!
group!comparisons!by!non^parametric!testing.!
•!
The!incidence!of!adverse!events!experienced!between!active!and!control!groups.!!Statistical!differences!will!be!
determined!using!Fisher’s!exact!test!for!proportions!or!using!non^parametric!tests!for!graded!reactions.!
Logistic!regression!will!be!used!to!assess!the!influence!of!age,!gender,!asthma!status!and!prior!history!of!
anaphylaxis!on!incidence!of!adverse!events.!
•!
Immunological!outcome!measures!pre^,!during!and!post^!12!months!of!OIT,!using!Mann^Whitney!U!test!(for!
paired!comparisons)!or!Friedman’s!test!(for!trends!over!time).!
!
7.2.3!INTERIM!ANALYSIS!
There!will!be!no!formal!interim!analysis,!however!the!IDMC!will!review!safety!data!at!least!every!4!months.!

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8.'ADMINISTRATIVE'AND'REGULATORY'ISSUES'
8.1!ETHICS!APPROVAL!
The!Chief!Investigator!will!obtain!the!required!approvals!from!the!relevant!Research!Ethics!Committee.!!The!study!will!be!
submitted!for!Site!Specific!Assessment!(SSA)!at!each!participating!NHS!Trust.!!The!Chief!Investigator!will!require!a!copy!
of!the!Trust!R&D!approval!letter!before!accepting!participants!into!the!study.!!The!study!will!be!conducted!in!accordance!
with!the!recommendations!for!physicians!involved!in!research!on!human!subjects!adopted!by!the!18th!World!Medical!
Assembly,!Helsinki!1964!and!later!revisions.!
8.2!INFORMED!CONSENT!AND!PARTICIPANT!ASSENT!
Consent! to! enter! the! study! must! be! sought! for! each! participant! only! after! a! full! explanation! has! been! given,! an!
information!leaflet!offered!and!time!allowed!for!consideration.!Signed!consent!from!the!parent/legal!guardian!should!be!
obtained.!!Participant!assent!will!also!be!sought.!The!right!of!the!parent/guardian!to!refuse!to!participate!without!giving!
reasons!must!be!respected.!!After!the!participant!has!entered!the!trial!the!clinician!remains!free!to!give!alternative!
treatment!to!that!specified!in!the!protocol!at!any!stage!if!he/she!feels!it!is!in!the!participant’s!best!interest,!but!the!
reasons!for!doing!so!should!be!recorded.!!In!these!cases!the!participants!remain!within!the!study!for!the!purposes!of!
follow^up!and!data!analysis.!!All!participants!are!free!to!withdraw!at!any!time!from!the!protocol!treatment!without!giving!
reasons!and!without!prejudicing!further!treatment.!
8.3!MHRA!EXEMPTION!
Following! discussions! with! MHRA,! it! has! been! confirmed! that! this! study! is! not! a! Clinical! Trial! of! an! Investigational!
Medicinal!Product!(IMP)!as!defined!by!the!EU!Directive!2001/20/EC,!thus!no!submission!to!the!Clinical!Trials!Unit!at!the!
MHRA!is!required.!The!peanuts!are!a!food!product!and!are!not!presented!as!a!medicine!(eg!in!a!pharmaceutical!form).!
The!study!is!therefore!exempt!from!MHRA!requirements!for!a!clinical!trial.!This!confirmation!is!reproduced!in!Appendix!
4.!
8.4!CONFIDENTIALITY!
The!Chief!Investigator!will!preserve!the!confidentiality!of!participants!taking!part!in!the!study!under!the!Data!Protection!
Act.!
8.5!INDEMNITY!
Imperial!College!London!holds!negligent!harm!and!non^negligent!harm!insurance!policies!which!apply!to!this!study.!
8.6!SPONSOR!
Imperial!College!London!will!act!as!the!main!Sponsor!for!this!study.!!
!
!

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8.7!FUNDING!
Funding!has!been!secured!from!the!NIHR!Biomedical!Research!Centre!at!the!Imperial!Academic!Health!Sciences!Centre!
(AHSC),!a!partnership!between!Imperial!College!Healthcare!NHS!Trust!and!Imperial!College!London.!
8.8!AUDITS!
The!study!may!be!subject!to!inspection!and!audit!by!Imperial!College!London!under!their!remit!as!sponsor!and!other!
regulatory!bodies!to!ensure!adherence!to!GCP!and!the!NHS!Research!Governance!Framework!for!Health!and!Social!Care!
(2nd!edition).!
!
9'STUDY'MANAGEMENT'
The!day^to^day!management!of!the!study!will!be!co^ordinated!through!Dr!Paul!Turner!(CI).!!
!
10'PUBLICATION'POLICY''
Results!of!this!study!will!be!published!in!scientific!peer^reviewed!literature!relevant!to!allergic!disease.!Members!of!the!
Trial!Management!Group!and!the!Data!Monitoring!Committee!will!be!listed!and!contributors!will!be!cited!by!name!if!
published!in!a!journal!where!this!does!not!conflict!with!the!journal’s!policy.!!
!
!
!
!

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APPENDIX'1:'MANAGEMENT'OF'ANAPHYLAXIS'
In!the!unlikely!event!of!a!participant!requiring!treatment!for!anaphylaxis!beyond!an!initial!dose!of!IM!adrenaline,!the!
UK!Resuscitation!Council!guidelines!for!anaphylaxis!will!be!followed:!!
!

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In!the!event!of!refractory!anaphylaxis!(requiring!over!2!doses!of!IM!adrenaline!or!at!investigator!initiation),!
consideration!will!be!given!to!initiate!an!adrenaline!infusion!according!to!a!published!protocol!(reproduced!below).!This!
will!be!initiated!ONLY!under!the!direct!supervision!of!a!consultant!experienced!in!the!management!of!anaphylaxis.!
The!adrenaline!infusion!should!be!delivered!by!a!syringe!pump!and!not!via!a!volumetric!pump.!The!infusion!can!be!
administered!through!a!dedicated!peripheral!line!(to!avoid!inadvertent!bolus!dosing!with!other!drugs/fluids),!but!the!
cannula!should!be!sited!in!a!large!vein.!
!
!
!
!
!

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APPENDIX'2'MHRA'EXEMPTION'
!
From
O'Kane, Martin
Date    29/05/2014 22:08:21
To
Turner, Paul J
Cc
Subject
RE: SCOPE - Food allergy study
Dear%Paul,
Following%our%‘scope’%mee6ng%today%I%can%conﬁrm%that%your%study%would%not%be%considered%as%a%CTIMP
under%the%Clinical%Trials%Direc6ve%2001/20%EC.%%The%peanuts%are%a%food%product%and%are%not%presented%as%a
medicine%(eg%in%a%pharmaceu6cal%form).
%
Best%regards,
Mar6n
%
%
Dr E Martin O'Kane
Pharmaceutical Assessor & Acting Manager
Clinical Trials Unit
MHRA
Buckingham Palace Road, London, SW1W 9SZ, UK
Telephone: 020 3080 6659
Stay connected: mhra.gov.uk/stayconnected
MHRA is a centre of the Medicines and Healthcare Products Regulatory Agency
%
%
%
%
From: Turner, Paul J [mailto:p.turner@imperial.ac.uk]
Sent: 22 May 2014 23:19
To: O'Kane, Martin
Subject: RE: SCOPE - Food allergy study
 
Dear Martin,
I hope you are keeping well. You may recall that back in January, we had a conversation about the need
for a CTA for various discussions regarding food allergy studies. Given those discussions (see your email
below), I was hoping to pick your brain again on a closely-related matter.
We wish to conduct a clinical trial to desensitise patients with peanut allergy. This approach is standard
practice in some European countries, and involves giving small amounts of the food to which the person is
allergic to build up a level of tolerance (in much the same way that someone planning to run a marathon
needs to train to get fit).
A recent study (in Cambridge, which made BBC news etc) used powered peanut flour to acheive this end,
and I understand from colleagues that this would be considered as medicinal product as the flour was not
presented as food and was used to treat a medical condition (ie food allergy).
In our proposal, we wish to use peanuts (out of a packet, like you might purchase in any shop) for
desensitisation. The novel aspect is that we have data from Australia that cooking the peanut (something
which is routine in Asian cuisine) results in many peanut-allergic people tolerating the peanut (interesting!).
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We want to provide peanuts (from a packet purchased in a supermarket) for families to boil at home and
then use as part of a desensitisation protocol, under strict medical supervision. I am unclear as to whether
such a study would qualify as a CTIMP; it is a clinical trial, but the product (peanut) is presented as exactly
that - a whole peanut, without any form of modification or processing at our end. In fact, the only reason
we are providing the peanuts (rather than the patients purchasing them direct) is to reduce cost to
participants, ensure that we are using a similar 'cultivar' of peanut throughout, and help us monitor patient
compliance (from how long the packet lasts).
Given this, would the product be classified as a "food product not presented as a medicine" and thus not
be subject to MHRA oversight? Or, if it is considered to be an IMP, what information would you need in our
CTA application, given that we are providing subjects with packets of peanut purchased from a
supermarket? Would the MHRA adopt the same 'pragmatic' approach as you outlined below "accept a bare
minimum package (<1 page) essentially saying how the product is made" - as this product would not have
been 'made' as such, it is peanut!
Just in case you need, here are further details of what we are planning:
Trial Design: An open, randomised 2 phase cross-over study in subjects with peanut allergy. During the
first phase, subjects in the active group will be provided with peanuts (commercial source, from
supermarket, in sealed packets as purchased) to use as part of a protocol. The protocol will provide
instructions to the subjects to boil the peanuts at home (in water) for set amounts of time, and then
consume the peanut under medical oversight. Subjects in the control group will undergo no intervention
other than routine care, until 12 months when they will be offered to receive peanut desensitisation as per
the active group.
Purpose of Trial: To investigate whether low dose exposure to boiled peanuts results in tolerance to
roasted peanut after 12 months of treatment.
Products Administered: Supermarket-sourced peanuts, in original (unopened) packaging as purchased.
Key Parameters:  Amount of peanut tolerated pre- and post-protocol, as determined at formal food
challenge (as per routine clinical practice)
Many thanks for your help and advice.
With kind regards,
Paul
Dr Paul Turner
MRC Clinician Scientist, Senior Lecturer and Honorary Consultant in Paediatric Allergy &
Immunology
Imperial College London / Imperial College Healthcare NHS Trust
E: p.turner@imperial.ac.uk
F: +44 (0) 20 3312 7571
 
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APPENDIX'3'STRUCTURED'TELEPHONE'INTERVIEW'FOR'STUDY'PARTICIPANTS'WHO'FAIL'THE'
OIT'PROTOCOL'
!
In!participants!who!fail!the!OIT!protocol!(either!due!to!allergy!to!¼!boiled!peanut,!or!who!are!withdrawn!due!to!adverse!
events!during!updosing),!we!will!contact!the!family!at!1!and!6!months!after!the!event,!to!ask!if!we!can!arrange!a!
mutually!convenient!time!to!undertake!a!limited!structured!telephone!interview!(10^15!minutes)!with!the!parent/!
guardian(s)!and!their!child.!The!aim!is!to!explore!any!issues!which!might!have!been!raised!as!a!result!of!the!reaction,!
following!the!following!outline:!
!
Guide'to'telephone'interview:'
'
1.! Confirm!interviewee’s!identity!
!
2.! Introduce!yourself:!
“I"am"<name>,"from"the"BOPI"Study."We"arranged"to"speak"briefly"today"to"discuss"any"issues"or"questions"you"may"
have,"following"your"<participant’s"name>"involvement"in"the"BOPI"study.""
"
3.! “First,"do"you"have"any"questions"about"the"study"or"your"allergy?”"
"
4.! “Has"your"understanding"of"food"allergy,"and"peanut"allergy"in"particular,"changed"as"a"result"of"the"study?”""
[In!what!ways?!Explore!views!on!significance!/!perceived!severity!/!future!care]!
!
5.! “Has"taking"part"in"the"study"changed"how"you"feel"about"your"peanut"allergy?"Is"there"anything"that"now"worries"
you"or"bothers"you?”"
"
6.! “How"do"you"feel"about"taking"part"in"the"study?"Did"it"help"you?”"
[Do!you!think!it!was!good!/!bad!/!waste!of!time!/!unsure?]!
"
7.! "“If"you"were"taking"part"in"the"study"again,"is"there"anything"you"would"suggest"that"we"do"differently?”"
"
8.! “Thank"you"for"taking"part"in"the"study,"please"do"let"us"know"if"there"is"anything"else"you"would"like"to"ask"us.”"
!