Conditions: Peanut Hypersensitivity Food Allergy Food Hypersensitivity Peanut Allergy
Keywords: Peanut Food Allergy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: no

Brief summary:
Primary Objective: To determine if 36 months of peanut SLIT as an early intervention in subjects ages 1 to 4 years induces clinical desensitization. The primary outcome of this objective will be a statistically significant difference in challenge scores between the treatment group versus the placebo group during DBPCFC (Double blind placebo controlled food challenge) performed after 36 months of peanut SLIT (desensitization). Challenge scores are measured by the amount of peanut protein participants are able to ingest successfully without symptoms of an allergic reaction. \[Time Frame: Baseline, 36 months\]

Secondary Objectives:

A secondary outcome of this objective will be a statistically significant difference in the challenge score of the treatment group versus the placebo group during the DBPCFC performed 3 months after discontinuing therapy (tolerance).

To examine the change in immune parameters associated with peanut SLIT and the development of clinical tolerance. Through this objective, the investigators will seek to understand the molecular processes by which SLIT affects the immune system through evaluation of immune mechanisms in relationship to clinical findings of desensitization and tolerance. The investigators will delineate the impact of peanut SLIT on the subsequent cellular and humoral responses to peanut protein.

\[Time Frame: Baseline, 39 months\]

Detailed description:
Peanut allergy is one of the most common food allergies; most children develop this allergy early in life, do not outgrow it and are at risk for severe and life-ending anaphylactic reactions. There is a critical need for a proactive treatment for peanut allergy and the investigators along with others are developing specific types of immunotherapy that will act as disease-modifying therapies.

This SLIT study is a randomized, blinded, placebo-controlled study. The primary outcome of this objective will be a statistically significant difference in challenge scores between the treatment group versus the placebo group during DBPCFC performed after 36 months of peanut SLIT (desensitization). A secondary outcome of this objective will be a statistically significant difference in the challenge score of the treatment group versus the placebo group during the DBPCFC performed 3 months after discontinuing therapy (tolerance).

Upon enrollment into the study, all subjects will undergo a qualifying entry DBPCFC with peanut protein to confirm the diagnosis of peanut allergy and establish a baseline threshold level. Following a positive DBPCFC, each subject will be randomized 1:1 to receive peanut SLIT therapy versus placebo for a duration of 36 months. DBPCFC will be repeated for both active and placebo subjects at 36 months to assess desensitization and at 39 months to assess tolerance.

Outcome variables of interest include peanut specific IgE, IgG, and IgG4, basophil activation, mast cell responses through skin prick testing, and specific T-cell cytokine responses and T regulatory cell (TReg) activation.

COVID-19 SAFETY MEASURES- Reflected in Protocol V4.0- April 2020

In March of 2020, State and National emergencies were declared over the global pandemic coronavirus COVID-19.

As such, any 36 month Desensitization DBPCFC will be postponed while the safety measures surrounding COVID-19 are in place. Subjects who choose to remain in the study will continue on study drug at the maintenance dose level beyond the originally planned 36 months until such time that the Desensitization DBPCFC is conducted.

Subjects who are scheduled to undergo the 39 month Tolerance DBPCFC while the COVID-19 safety measures are in place will have their DBPCFC cancelled. Additional time off of study drug therapy would potentially increase the risk of allergic reaction during the DBPCFC and would not be acceptable.

For subjects whose Desensitization DBPCFC is postponed, a followup visit to review safety and subject dosing diaries would be conducted. This visit would be conducted remotely by telephone. Additional study drug would be sent direct-to-patient as necessary to continue on maintenance dosing. Lab sample collection and mechanistic studies would be deferred and be completed at the time that the Desensitization DBPCFC is completed. The Tolerance DBPCFC would be completed 3 months after the Desensitization DBPCFC is completed.

For subjects whose Tolerance DBPCFC is canceled, an exit visit would be conducted to review safety. The subject would be unblinded to treatment allocation and end of study instructions would be reviewed with the subject.

As the situation is changing daily, we are unable to provide a time frame for extension. We hope to limit the number of subjects who will need to utilize this option and preserve the endpoint data parameters. Previous SLIT studies have not shown any additional risk with peanut SLIT dosing beyond 3 years up to a total of 5 years of dosing.

Arms:
arm 1: After the entry DBPCFC, subjects will be randomized 1:1 to active or placebo drug product. Subjects randomized to peanut SLIT therapy will dose for 36 months and undergo a second DBPCFC. The subjects will stop dosing for three months and repeat a DBPCFC at 39 months. arm 2: After the entry DBPCFC, subjects will be randomized 1:1 to active or placebo drug product. Subjects randomized to placebo glycerin SLIT will dose for 36 months and undergo a second DBPCFC. The subjects will stop dosing for three months and repeat a DBPCFC at 39 months.

Interventions: intervention 1: Liquid Peanut Extract intervention 2: Placebo Glycerin SLIT
Intervention descriptions: intervention 1: 5000mcg/ml peanut protein intervention 2: pure glycerinated saline solution with caramel coloring to match color

Protocol document:
Prot_SAP_000.pdf: 
Title:  Pea n ut S u bli n g ual I m m u n ot hera p y I n d ucti o n of Cli nical T olera nce i n Ne wl y Dia g n ose d 
Pea n ut Aller gic 1 2 t o 4 8 M o nt h Ol d C hil dre n  
 
Cli nicaltrials. g o v : N C T 0 2 3 0 4 9 9 1  
 
D oc u me nt date : Marc h  1 8 , 2 0 20  
 
 


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C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2  of 5 7  
* See a p pe n di x 6 . 0 
 
P R O T O C O L  
P E A N U T S U B LI N G U A L I M M U N O T H E R A P Y  I N D U C TI O N O F 
C LI NI C A L T O L E R A N C E I N N E W L Y DI A G N O S E D P E A N U T 
A L L E R GI C 1 2 T O 4 8 M O N T H O L D C HI L D R E N  
P e a n ut S LI T a n d E arl y T ol er a n c e  I n d u cti o n  
Ve rsi o n  4. 0 M a r c h 1 8, 2 0 2 0  
I N D # 1 4 3 2 6  
T hi s cli ni c al st u d y i s s u p p o rt e d b y F o o d All e r g y R e s e a r c h a n d E d u c ati o n ( F A R E ) a n d 
c o n d u ct e d at T h e Di vi si o n of P e di at ri c All e r g y a n d I m m u n ol o g y at U N C -C h a p el Hill  
a n d T h e Di vi si o n of All e r g y a n d I m m u n ol o g y at t h e U ni v e r sit y of T e x a s S o ut h w e st e r n.  
P RI N CI P A L IN V E S TI G A T O R  [ PR O T O C O L C H AI R ] 
A.  Wesley B urks, M D  
Pr ofess or  of Pe di atrics  
T he U niversity of N ort h C ar oli n a  
C h a pel Hill , N C 2 7 5 9 9  
P h o ne: 9 1 9 -9 6 6 -4 4 2 7  
E -mail: wesle y. b ur ks @ u nc .e d u 
 
C o nfi de nti ality St ate me nt  
T his d oc u me nt is c o nfi de nti al a n d is t o be distri b ute d f or revie w o nly t o i nvesti g at ors, 
p ote nti al i nvesti g at ors, c o ns ult a nts, st u dy st aff, a n d a p plic a ble i n de pe n de nt et hics 
c o m mittees or i nstit uti o n al revie w b o ar ds.  T he c o nte nts of t his d oc u me nt s h all n ot be 
discl ose d t o ot hers wit h o ut writte n a ut h oriz ati o n fr o m Dr . B urks, u nless it is necess ary 
t o o bt ai n i nf or me d c o nse nt fr o m p ote nti al st u dy p artici p a nts. 
 
 
 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
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F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3  of 5 7  
* See a p pe n di x 6 . 0 
 
 
 
Pr ot oc ol A p pr o v al  
 
 
 
 
 
 
 
 
Pr ot oc ol #  1 4 -0 6 4 8  
Versi o n/ Date: 4. 0 / Marc h 1 8, 2 0 2 0  
I N D: 1 4 3 2 6  
Pri nci pal I n vesti gat or:  A. Wesle y B ur ks, M D  
S h ort Title:  Pe a n ut S LI T a n d E arly T oler a nce  I n d ucti o n 
 
 
I h ave re a d pr ot oc ol # , a n d I a p pr ove it.  As t he pri nci p al i nvesti g at or, I a gree t o          c o n d uct 
t his  pr ot oc ol  acc or di n g  t o  g o o d  cli nic al  pr actices,  w hic h  are  deli ne ate d  i n  t he  I nter n ati o n al 
C o nfere nce  o n  H ar m o niz ati o n  (I C H)  of  Tec h nic al  Re q uire me nts 
f or  Re gistr ati o n  of 
P h ar m ace utic als  f or  H u m a n  Use 
“ G ui da nce  f or  I n d ustr y:  E 6  G o o d  Cli nical  Practice 
C o ns oli date d G ui da nce” ( M ay 1 9 9 6), a n d acc or di n g t o t he criteri a s pecifie d i n t his pr ot oc ol. 
 
 
   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                                     
   Pri nci pal I n vesti gat or ( Pri nt)                                                                 
 
 
   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                                    _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
   Pri nci pal I n vesti gat or ( Si g nat ure)                                                          Date  


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F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4  of 5 7  
* See a p pe n di x 6 . 0 
 
S y n o psis  
Title  
Pe a n ut S u bli n g u al I m m u n ot her a py I n d ucti o n of Cli nic al T oler a nce i n Ne wly 
Di a g n ose d  Pe a n ut Aller gic  1 2 t o 4 8 m o nt h ol d  C hil dre n  
S h ort Title  
Pea n ut S LI T a n d Earl y  T olera nce  I n d ucti o n 
Cli nic al P h ase  
P hase II –  Safet y a n d Efficac y  
I N D 
1 4 3 2 6  
S p o ns or  
A.  Wesle y B ur ks, M D  
Pri nci p al I n vesti g at or  
C hair - A. Wesle y B ur ks , M D  
P artici p ati n g Site s 
U N C -C ha pel Hill  ( pri mar y), U T S o ut h wester n Me dical Ce nter (sec o n dar y) 
Accr u al O bjecti ve  
5 0  s u bjects (3 5  at pri mar y site, 1 5  at sec o n dar y site)  
Accr u al Peri o d  
3 0 m o nt hs  
St u d y Desi g n  
A pr os pecti ve, ra n d o mize d, d o u ble -bli n d, place b o c o ntr olle d st u d y t o deter mi ne t he 
efficac y of pea n ut s u bli n g ual i m m u n ot hera p y ( S LI T) i n i n d uci n g cli nical 
dese nsitizati o n  after 3 6 m o nt hs *  of treat me nt.  
St u d y D ur ati o n  
D ose escalati o n ( 5  m os); Mai nte na nce ( 3 1  m os); Wit h dra wal ( 3  m os).  
Pri m ar y E n d p oi nt  
T he pri mar y cli nical e n d p oi nt of t his trial is t o e val uate t he prese nce/a bse nce of  
cli nical dese nsitizati o n  t o pea n ut after 3 6 m o nt hs of pea n ut s u bli n g ual i m m u n ot hera p y 
( S LI T). 
Sec o n d ar y E n d p oi nts  
T he sec o n dar y cli nical efficac y e n d p oi nt of t his trial is t o e val uate t he 
prese nce/a bse nce of persiste nt cli nical t olera nce t o pea n ut 3 m o nt hs f oll o wi n g 
wit h dra wal of acti ve/ place b o S LI T.   A mec ha nistic e n d p oi nt will deter mi ne i m m u ne 
para meters of s u bjects w h o ac hie ve a state of cli nical t olera nce vers us t h ose w h o fail 
t o pr o gress be y o n d a state of dese nsitizati o n.   
I ncl usi o n Criteri a 
•  Writte n i nf or me d c o nse nt fr o m partici pa nt’s pare nt/ g uar dia n . 
•  A ge 1 2 -4 8 m o nt hs  of eit her se x, a n y race, a n y et h nicit y . 
•  1) A pea n ut aller g y w it h a c o n vi nci n g cli nical hist or y of pea n ut aller g y a n d  a 
pea n ut -s pecific I g E [ U ni C A P] >  0. 3 5  k U A / L a n d  a p ositi ve s ki n pric k test t o 
pea n ut ( >3 m m t ha n t he ne gati ve c o ntr ol) or  2) are se nsitize d t o pea n u t ( base d o n 
an  I g E [ U ni C A P] t o pea n ut of >  5 k U A/ L ) a n d  a p ositi ve s ki n pric k test t o pea n ut 
(>  3 m m t ha n t he ne gati ve c o ntr ol) a n d  n o k n o w n hist or y of i n gesti o n of pea n ut.  
•  A p ositi ve D B P C F C t o 1 0 0 0 m g of pea n ut at e nr oll me nt . 
E xcl usi o n Criteri a  
•  Hist or y of se vere a na p h yla xis t o pea n ut , defi ne d as  h y p o xia, h y p ote nsi o n, or 
ne ur ol o gic  c o m pr o mise (c ya n osis or S p O 2 < 9 2 % at a n y sta ge, h y p ote nsi o n, 
c o nf usi o n, c olla pse or  l oss of c o nsci o us ness). 
•  Partici pati o n i n a n y i nter ve nti o nal st u d y f or t he treat me nt of f o o d aller g y i n t he 
past 6 m o nt hs . 
•  K n o w n oat, w heat , or gl yceri n aller g y. 
•  E osi n o p hilic or ot her i nfla m mat or y (e. g. celiac) gastr oi ntesti nal disease . 
•  Se vere ast h ma ( 2 0 0 7 N H L BI Criteria Ste ps 5 or 6  –  A p pe n di x 2 ). 
•  I na bilit y t o disc o nti n ue a nti hista mi nes f or s ki n testi n g a n d D B P C F C s. 
•  Use of o maliz u ma b or ot her n o n -tra diti o nal f or ms of aller ge n i m m u n ot hera p y (e. g., 
oral or s u bli n g ual) or i m m u n o m o d ulat or t hera p y ( n ot i ncl u di n g c ortic oster oi d s) or 
bi ol o gic t hera p y wit hi n t he past year . 


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V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5  of 5 7  
* See a p pe n di x 6 . 0 
 
•  Use of b -bl oc kers ( oral), a n gi ote nsi n -c o n verti n g e nz y me ( A C E) i n hi bit ors, 
a n gi ote nsi n-rece pt or bl oc kers ( A R B) or calci u m c ha n nel bl oc kers. 
•  Si g nifica nt me dical c o n diti o n (e. g., li ver, ki d ne y, gastr oi ntesti nal, car di o vasc ular, 
he mat ol o gic, or p ul m o nar y disease) w hic h w o ul d ma ke t he s u bject u ns uita ble f or 
i n d ucti o n of f o o d reacti o ns. 
Tre at me nt Descri pti o n  
T he st u d y is a pr os pecti ve , ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d trial base d o n 
pre vi o us e x perie nce  at D u ke U ni versit y  a n d at U N C C ha pel Hill  wit h pea n ut -aller gic 
s u bjects.  A t otal of 5 0 s u bjects at 2 sites will be e nr olle d  t o recei ve 3 6 m o nt hs *  of 
pea n ut S LI T  vers us place b o (ra n d o mize d 1 : 1 treat me nt: place b o). 
 
( * U nless affecte d b y C O VI D-1 9)  
 
T he d osi n g f or t he st u d y is o utli ne d bel o w.  
(1: 1 = f ull c o nce ntrati o n = 5 0 0 0 mc g/ ml; 1 p u m p = 0. 0 5 ml)  
 
After c o m pleti n g t he d osi n g escalati o n  p has e, s u bjects will c o nti n ue o n a dail y 
mai nte na nce d ose of 4 0 0 0 mc g of pea n ut pr otei n.  F oll o wi n g 3 6  m o nt hs *  of t otal 
treat me nt, s u bjects will u n der g o a D B P C F C t o verif y dese nsitizati o n (i.e. a n i ncrease 
i n reacti o n t hres h ol d w hile recei vi n g acti ve treat me nt).  All s u bjects will be 
dis c o nti n ue d fr o m pea n ut S LI T t hera p y after 3 6 m o nt hs of treat me nt * .  S u bjects w h o 
D ose #  
 
Pe a n ut 
Dil uti o n  
 
P u m ps  
D ose of 
Pe a n ut 
Pr otei n  
I nter v al i n 
Wee ks  
%  I ncre ase  
1  
1 :1 0 0  
1  
2. 5 mc g  
 
- 
2  
1 :1 0 0  
2  
5 mc g  
1  
1 0 0 %  
3  
1 :1 0 0  
4  
1 0 mc g  
1  
1 0 0 %  
4  
1 :1 0 0  
8  
2 0 mc g  
1  
1 0 0 %  
5  
1 :1 0  
1  
2 5 mc g  
1  
2 5 %  
6  
1 :1 0  
2  
5 0 mc g  
1  
1 0 0 %  
7  
1 :1 0  
4  
1 0 0 mc g  
1  
1 0 0 %  
8  
1 :1 0  
8  
2 0 0 mc g  
1  
1 0 0 %  
9  
1: 1  
1  
2 5 0 mc g  
2  
2 5 %  
1 0  
1: 1  
2  
5 0 0 mc g  
2  
1 0 0 %  
1 1  
1: 1  
4  
1 0 0 0 mc g  
2  
1 0 0 %  
1 2  
1: 1  
8  
2 0 0 0 mc g  
2  
1 0 0 %  
1 3  
1: 1  
1 2  
3 0 0 0 mc g  
2  
5 0 %  
1 4  
1: 1  
1 6  
4 0 0 0 mc g  
2  
3 3 %  


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C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
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M arc h 1 8, 2 0 2 0  
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* See a p pe n di x 6 . 0 
 
t olerate > 4 4 3 m g of pea n ut pr otei n  at t he 3 6 m o nt h *  D B P C F C  will wit h h ol d treat me nt 
f or 3 m o nt hs a n d ret ur n a n d u n der g o  a D B P C F C t o assess cli nical  t olera nce u p t o t he 
a m o u nt t olerate d at t he 3 6 m o nt h *  D B P C F C  (i.e. mai ntai ni n g a n i ncrease i n reacti o n 
t hres h ol d after disc o nti n ui n g acti ve treat me nt).  S u bjects  will be u n bli n de d  after t he 
t olera nce c halle n ge a n d will c o m plete t he st u d y. S u bjects t hat c o m plete t he  t olera nce 
D B P C F C wit h o ut s y m pt o ms will be i nstr ucte d t o i ntr o d uce pea n ut i nt o t he diet a d 
li bit u m.  S u bjects t hat fail eit her t he dese nsitizati o n or t olera nc e D B P C F C (t olerati n g < 
4 4 3 m g of pea n ut pr otei n)  or ca n n ot t olerate t he e ntire 4 4 4 3 m g of pea n ut pr otei n 
wit h o ut s y m pt o ms  will be gi ve n t he o pti o n t o ta ke a dail y pea n ut f o o d e q ui vale nt t o 
mai ntai n t he dese nsitize d state or t o strictl y a v oi d all pea n ut.  S u bjects w h o fail t he 
dese nsitizati o n D B P C F C at 3 6 m o nt hs *  will be u n bli n de d t o t heir st u d y treat me nt.  
St u d y Pr oce d ures  
T he f oll o wi n g pr oce d ures will be perf or me d  acc or di n g t o t he sc he d ule i n A p pe n di x 1:  
•  
Me dical a n d aller g y hist or y (i ncl u di n g dietar y his t or y) 
•  
P h ysical e xa mi nati o n  
•  
S ki n pric k testi n g  t o pea n ut 
•  
Bl o o d  a nal ysis f or pea n ut -s pecific i m m u n o gl o b uli ns (I m m u n oC A P)  
•  
W h ole bl o o d f or bas o p hil acti vati o n  a n d T-cell st u dies  ( U N C-C H)  
•  
Sali va c ollecti o n f or i m m u n o gl o b uli n st u dies  
•  
St o ol c ollecti o n f or  micr o bi o me a n d i m m u n o gl o b uli n st u dies  
•  
S u bli n g ual I m m u n ot hera p y ( S LI T)  
•  
D o u ble -bli n d, place b o -c o ntr olle d, f o o d c halle n ge t o pea n ut  
 
St u d y St o p pi n g R ule s 
•  
A n y deat h relate d t o pea n ut S LI T  d osi n g . 
•  
Greater t ha n 2 se vere a na p h ylactic reacti o ns relate d t o pea n ut S LI T  d osi n g at 
a n y sta ge of t he pr ot oc ol.  
•  
Greater t ha n 3 s u bjects t hat re q uire m ore t ha n 1 i ntra m usc ular i njecti o n of 
e pi ne p hri ne d uri n g d ose escalati o n or mai nte na nce d osi n g of pea n ut  st u d y 
pr o d uct.  
C O VI D -1 9  
I n Marc h of 2 0 2 0 a nati o nal e mer ge nc y was declare d o ver t he gl o bal pa n de mic 
c or o na vir us C O VI D -1 9. S ocial dista nci n g meas ures were p ut i n place i n or der t o st o p 
t he s prea d a n d miti gate i nfecti o n rates t hat w o ul d o ver w hel m h os pitals. U N C’s V ice-
C ha ncell or f or Researc h i m ple me nte d pla ns t o re d uce s u bjects c o mi n g t o ca m p us a n d 
halt n o n -esse ntial researc h. W hile t he F o o d Aller g y I nitiati ve gr o u p’s researc h was 
dee me d esse ntial  a n d all o we d t o c o nti n ue, meas ures are bei n g i m ple me nte d t o e ns ure 
safet y. 
•  
I n-pers o n f oll o w u p visits will be c o n verte d t o p h o ne visits  
•  
St u d y dr u g will be pr o vi de d direct t o patie nt as feasi ble  
•  
A ll oral  f o o d c halle n ges will be halte d  d uri n g t he U ni versities’ safet y 
meas ures d ue t o C O VI D -1 9 d ue t o t he ris k of a na p h yla xis p ossi bl y re q uiri n g 
e mer ge nc y c o de tea m res p o nse ser vices a n d/ or a n E mer ge nc y De part me nt 
( E D) visit. T his is i n a n eff ort t o re d uce a n y n o n-C O VI D b ur de n o n  U N C 
e mer ge ncy ser vices  d uri n g t his u ncertai n ti me.   
•  
S u bjects w h ose 3 6 m o nt h oral f o o d c halle n ge has bee n deferre d will c o nti n ue 
dail y d osi n g of st u d y dr u g  past t he 3 6 m o nt h ti me peri o d. T his is t o mai ntai n 
a n y p ote ntial treat me nt effect u ntil s uc h ti me t hat t he oral f o o d c halle n ge is 
resc he d ule d. 
•  
S u bjects w h ose 3 9 m o nt h oral f o o d c halle n ge has bee n deferre d will c o m plete 
t he st u d y at t hat ti me a n d be u n bli n de d t o treat me nt all ocati o n. 
 
 


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C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 7  of 5 7  
* See a p pe n di x 6 . 0 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 8  of 5 7  
* See a p pe n di x 6 . 0 
 
T a bl e of C o nt e nt s  
1 . B A C K G R O U N D A N D R A TI O N A L E  ............................................................................... 1 0  
1.  
B A C K G R O U N D A N D R A TI O N AL E  ................................................................................................. 1 2  
1. 1  
B A C K G R O U N D  ................................................................................................................................ 1 2  
1. 2  
R A TI O N AL E  .................................................................................................................................... 1 2  
1. 3  
R A TI O N AL E F O R S EL E C TI O N OF S T U D Y P O P UL A TI O N  ............................................................................. 1 5  
1. 4  
K N O W N A N D P O T E N TI AL R I S K S A N D B E N E FI T S T O H U M A N P A R TI CI P A N T S  ................................................ 1 5  
1. 4. 1  
Ris ks  ................................................................................................................................... 1 5  
1. 4. 2  
B e n efits  .............................................................................................................................. 1 6  
2.  
O BJ E C TI V E S  ................................................................................................................................ 1 7  
2. 1  
P RI M A R Y A N D S E C O N D A R Y O BJ E C TI V E S  .............................................................................................. 1 7  
3.  
S T U D Y D E SI G N  ............................................................................................................................ 1 9  
3. 1  
S T U D Y E N D P OI N T S  .......................................................................................................................... 1 9  
3. 1. 1  
Pri m ary E n d p oi nt  ............................................................................................................... 1 9  
3. 1. 2  
S ec o n d ary E n d p oi nts  .......................................................................................................... 1 9  
3. 2  
C RI T E RI A F O R P R E M A T U R E T E R MI N A TI O N OF T H E S T U D Y : S T U D Y S T O P PI N G R UL E S  .................................... 2 0  
4.  
S EL E C TI O N A N D WI T H D R A W AL O F P A R TI CI P A N T S  ...................................................................... 2 1  
4. 1  
IN CL USI O N C RI T E RI A  ....................................................................................................................... 2 1  
4. 2  
E X CL USI O N C RI T E RI A  ....................................................................................................................... 2 1  
4. 3  
P R E M A T U R E P A R TI CI P A N T T E R MI N A TI O N F R O M T H E S T U D Y  ................................................................... 2 1  
4. 3. 1  
Crit eri a  ............................................................................................................................... 2 1  
5.  
S T U D Y M E DI C A TI O N  ................................................................................................................... 2 3  
5. 1  
F O R M UL A TI O N , P A C K A GI N G , A N D LA B ELI N G  ....................................................................................... 2 3  
5. 2  
P R E P A R A TI O N , A D MI NI S T R A TI O N , A N D D OS A G E  .................................................................................. 2 3  
5. 3  
D R U G A C C O U N T A BILI T Y  ................................................................................................................... 2 3  
5. 4  
A S S E S S M E N T OF C O M PLI A N C E WI T H S T U D Y T R E A T M E N T A N D M O NI T O RI N G  ............................................ 2 4  
5. 5  
M O DI FI C A TI O N OF S T U D Y T R E A T M E N T  ............................................................................................... 2 4  
5. 6  
C O N C O MI T A N T M E DI C A TI O NS  .......................................................................................................... 2 4  
5. 7  
P R O P H YL A C TI C M E DI C A TI O NS  ........................................................................................................... 2 4  
5. 8  
R E S C U E M E DI C A TI O NS  .................................................................................................................... 2 4  
5. 9  
P R O HI BI T E D M E DI C A TI O NS  .............................................................................................................. 2 5  
6.  
S T U D Y D E FI NI TI O N S A N D P R O C E D U R E S  ...................................................................................... 2 6  
6. 1  
S T U D Y D E FI NI TI O NS  ........................................................................................................................ 2 6  
6. 1. 1  
A n a p hyl axis  ........................................................................................................................ 2 6  
6. 1. 2  
Crit eri a f or Di a g n osis  .......................................................................................................... 2 6  
6. 1. 3  
A n a p hyl axis St a gi n g Syst e m  ............................................................................................... 2 6  
6. 2  
E N R OLL M E N T  ................................................................................................................................ 2 7  
6. 3  
S C R E E NI N G V I SI T ............................................................................................................................ 2 7  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 9  of 5 7  
* See a p pe n di x 6 . 0 
 
6. 4  
B AS ELI N E V I SI T/ EN T R Y F O O D C H ALL E N G E  .......................................................................................... 2 7  
6. 5  
S T U D Y T R E A T M E N T V I SI T S ............................................................................................................... 2 8  
6. 6  
D O U BL E B LI N D P L A C E B O C O N T R OLL E D F O O D C H ALL E N G E ( D B P C F C) ..................................................... 3 1  
6. 7  
S KI N P RI C K T E S TI N G  ........................................................................................................................ 3 2  
6. 8  
S ALI V A C OLL E C TI O N  ........................................................................................................................ 3 2  
6. 9  
S T O OL C OLL E C TI O N  ........................................................................................................................ 3 2  
6. 1 0  
V I SI T W I N D O WS ............................................................................................................................. 3 2  
6. 1 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N P R O C E D U R E S  .......................................................................... 3 3  
6. 1 1. 1  
R e q uir e m e nts f or U n bli n di n g  ............................................................................................. 3 3  
7.  
S A F E T Y M O NI T O RI N G  ................................................................................................................. 3 4  
7. 1  
P R O C E D U R E S A N D M O NI T O RI N G  ....................................................................................................... 3 4  
7. 2  
D E FI NI TI O NS  .................................................................................................................................. 3 4  
7. 2. 1  
A dv ers e Ev e nt ( A E) or M e dic al Ev e nt  ................................................................................. 3 4  
7. 2. 2  
S eri o us A dv ers e Ev e nt ( S A E)  ............................................................................................... 3 5  
7. 2. 3  
U n ex p ect e d A dv ers e Ev e nt  ................................................................................................. 3 5  
7. 3  
T O XI CI T Y G R A DI N G  ......................................................................................................................... 3 5  
7. 3. 1  
R el ati o ns hi p t o Pr oc e d ur e D efi niti o ns  ................................................................................ 3 6  
7. 4  
A D V E R S E E V E N T S C OLL E C TI O N P R O C E D U R E S  ....................................................................................... 3 7  
7. 4. 1  
R ec or di n g a n d R e p orti n g Pr oc e d ur es  ................................................................................. 3 7  
7. 4. 2  
S A E R ec or di n g a n d R e p orti n g  ............................................................................................. 3 8  
7. 5  
S E RI O US A D V E R S E E V E N T N O TI FI C A TI O N  ............................................................................................ 3 8  
7. 5. 1  
N otifyi n g t h e F D A, I R B, a n d DS M B  ..................................................................................... 3 8  
7. 5. 2  
R e p orti n g Crit eri a  ............................................................................................................... 3 8  
8.  
M E C H A NI S TI C A S S A Y S  ................................................................................................................ 3 9  
8. 1  
B L O O D S P E CI FI C IG E,  IG G,  IG G 4,  A N D IG A  ......................................................................................... 3 9  
8. 2  
S ALI V A R Y S P E CI FI C IG G,  IG A,  IG E,  A N D S E C R E T O R Y IG A  ........................................................................ 4 0  
8. 3  
C Y T O KI N E M E AS U R E M E N T S  .............................................................................................................. 4 0  
8. 4  
T R E G AS S A Y  ..................................................................................................................................... 4 0  
8. 5  
B AS O P HIL A C TI V A TI O N AS S A Y  ............................................................................................................ 4 0  
8. 6  
S T O OL  .......................................................................................................................................... 3 8  
9.  
S T A TI S TI C AL C O N SI D E R A TI O N S  ................................................................................................... 4 2  
9. 1  
S T U D Y E N D P OI N T A S S E S S M E N T ........................................................................................................ 4 2  
9. 1. 1  
Pri m ary E n d p oi nt  ............................................................................................................... 4 2  
9. 1. 2  
S ec o n d ary E n d p oi nts  .......................................................................................................... 4 2  
9. 2  
S U BJ E C T A N D D E M O G R A P HI C D A T A  ................................................................................................... 4 2  
9. 2. 1  
B as eli n e C h ar act eristics a n d D e m o gr a p hics  ...................................................................... 4 2  
9. 2. 2  
St u dy C o m pl eti o n  ............................................................................................................... 4 3  
9. 3  
IN T E RI M A N AL Y S E S T O E NS U R E P A TI E N T S A F E T Y  .................................................................................. 4 3  
1 0.  
I D E N TI FI C A TI O N A N D A C C E S S T O S O U R C E D A T A ..................................................................... 4 4  
1 0. 1  
D A T A M A N A G E M E N T  ...................................................................................................................... 4 4  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 0  of 5 7  
* See a p pe n di x 6 . 0 
 
1 0. 2  
A C C E S S T O D A T A  ............................................................................................................................ 4 4  
1 1.  
Q U ALI T Y C O N T R OL A N D Q U ALI T Y A S S U R A N C E  ....................................................................... 4 5  
1 1. 1  
D A T A H A N DLI N G  ............................................................................................................................ 4 5  
1 2.  
E T HI C AL C O N SI D E R A TI O N S A N D C O M PLI A N C E WI T H G O O D CLI NI C AL P R A C TI C E  ..................... 4 6  
1 2. 1  
S T A T E M E N T OF C O M PLI A N C E  ........................................................................................................... 4 6  
1 2. 2  
INF O R M E D C O NS E N T A N D A S S E N T ..................................................................................................... 4 6  
1 2. 3  
P RI V A C Y A N D C O NFI D E N TI ALI T Y  ........................................................................................................ 4 6  
1 3.  
R E S O U R C E S H A RI N G  ............................................................................................................... 4 7  
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 1  of 5 7  
* See a p pe n di x 6 . 0 
 
Gl oss ar y of A b bre vi ati o ns  
A E  
A d verse E ve nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C R F  
Case Re p ort F or m  
C T C  
C o m m o n T o xicit y Criteria  
D B P C F Cs = O F C  
D o u ble -Bli n d, Place b o -C o ntr olle d F o o d C halle n ges  
D S M B  
Data Safet y M o nit ori n g B oar d  
E C  
Et hics C o m mittee  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D S 
I n vesti gati o nal Dr u g Ser vice 
I N D 
I n vesti gati o nal Ne w Dr u g A p plicati o n 
I R B 
I nstit uti o nal Re vie w B oar d 
I T 
I m m u n ot hera p y 
k U/ L  
Kil o u nits per Liter  
NI AI D  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases  
OI T  
Oral I m m u n ot hera p y  
P B M C  
Peri p heral Bl o o d M o n o n uclear Cells  
PI  
Pri nci pal I n vesti gat or  
S A E  
Seri o us A d verse E ve nt  
S L I T 
S u bli n g ual I m m u n ot hera p y  
S P T  
S ki n Pric k Tests  
T Re g  
T re g ulat or y cell 
U N C -C H  
U ni versit y of N ort h Car oli na at C ha pel Hill  
U T S W  
U ni versit y of Te xas S o ut h wester n  
 
 
 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 2  of 5 7  
* See a p pe n di x 6 . 0 
 
1.  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
B a c k g r o u n d  
Pea n ut aller g y is o ne of t he m ost c o m m o n f o o d aller gies; m ost c hil dre n de vel o p t his aller g y earl y 
i n life, d o n ot o ut gr o w it a n d are at ris k f or se vere a n d life-e n di n g a na p h ylactic reacti o ns.  T here 
is a critical nee d f or a pr oacti ve treat me nt f or pea n ut aller g y a n d we al o n g wit h ot hers are 
de vel o pi n g s pecific t y pes of i m m u n ot hera p y t hat will act as disease -m o dif yi n g t hera pies.  
Pr os pecti ve st u dies i n dicate t hat 6 -8 % of c hil dre n less t ha n 4 years of a ge e x perie nce I g E -
me diate d f o o d aller gic reacti o ns  [1 ], a n d a rece nt s ur ve y i n t he U. S. f o u n d t hat 1. 3 % of t he 
p o p ulati o n is aller gic t o pea n uts or tree n uts [2 ].  Des pite i ncrease d rec o g niti o n a n d 
u n dersta n di n g of f o o d aller gies, f o o d -i n d uce d a na p h yla xis is t he si n gle m ost c o m m o n f or m of 
a na p h yla xis see n i n h os pital e mer ge nc y de part me nts, acc o u nt i n g f or a b o ut o ne t hir d of 
a na p h yla xis cases see n [3 ].  It is esti mate d t hat a b o ut 3 0, 0 0 0 f o o d-i n d uce d a na p h ylactic e ve nts 
are see n i n U. S. e mer ge nc y de part me nts eac h year a n d t hat a b o ut 2 0 0 of t hese are ulti matel y 
fatal; eit her pea n uts or tree n uts ca use t he maj orit y of t hese deat hs [4 , 5 ].  Pri or trials of aller g y 
i m m u n ot hera p y (I T) usi n g tra diti o nal a n d r us h aller ge n pr ot oc ols i n patie nts wit h pea n ut aller g y 
s h o we d partial rates of res p o nse b ut, u nf ort u natel y, res ulte d i n hi g h rates of a d verse reacti o ns, 
i ncl u di n g a na p h yla xis [6 , 7 ].  R ece nt brea kt hr o u g h st u dies ha ve s h o w n s uccess i n dese nsitizi n g 
pea n ut -aller gic c hil dre n t o pea n ut via oral I T ( OI T) pr ot oc ols [8 , 9 ].  O ur gr o u p was t he first t o 
s h o w e vi de nce of dese nsitizati o n a n d t olera nce t o pea n ut wit h a s u bli n g ual ( S LI T) a p pr oac h [1 0 ]. 
1. 2  
R ati o n al e  
S u bc uta ne o us aller ge n i njecti o n I T is hi g hl y effecti ve i n caref ull y selecte d patie nts wit h I g E -
me diate d res pirat or y disease a n d i nsect sti n g aller g y, a n d re prese nts t he o nl y r o uti nel y 
a d mi nistere d a nti ge n -s pecific i m m u n o m o d ulat or y treat me nt gi ve n f or i m m u n ol o gic disease of 
a n y ki n d.  I T has bee n s h o w n t o be effecti ve f or ve n o m a na p h yla xis a n d f or aller gic r hi nitis a n d 
ast h ma ca use d b y i n hala nt aller ge ns , a n d c o nfers l o n g -ter m be nefit f or at least t hree years after 
disc o nti n uati o n  [1 1 ].  I n s pite of its effecti ve ness, t here re mai ns a si g nifica nt k n o wle d ge ga p 
re gar di n g t he u n derl yi n g basis f or aller ge n I T a n d t he de vel o p me nt of e ve nt ual t olera nce [1 2 ].  
Tra diti o nal aller ge n i njecti o n I T has n ot bee n s h o w n t o be effecti ve f or t he treat me nt of f o o d 
aller g y beca use of t he si g nifica nt si de effects of t he t hera p y relate d t o s yste mic aller gic e ffects 
[6 , 7 ]. 
Alt h o u g h its use has bee n li mite d i n t he U nite d States, S LI T has bee n use d c o m m o nl y i n E ur o pe 
as a n alter nati ve t o S CI T f or aller gic r hi nitis.   It offers a n o vel mea ns of treat me nt f or f o o d 
aller g y a n d see ms well s uite d f or se veral reas o ns.   First, oral La n ger ha ns cells t hat ta ke u p 
a nti ge n wit hi n t he m o ut h ha ve bee n s h o w n t o ha ve t oler o ge nic pr o perties, p ote ntiall y acc o u nti n g 
f or t he efficac y of aer oaller ge n S LI T  [1 3 ].  Sec o n d, S LI T is easil y a d mi nistere d, es peciall y w he n 
c o m pare d wit h recei vi n g i njecti o ns, s uc h as wit h S CI T, or i n gesti n g lar ge a m o u nts of f o o d, as 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 3  of 5 7  
* See a p pe n di x 6 . 0 
 
wit h OI T a n d is m uc h safer.  Fi nall y, s yste mic reacti o ns ha ve bee n u nc o m m o n  [1 4 ], w hic h mi g ht 
be sec o n dar y t o t he relati vel y s mall d oses use d t o ac hie ve cli nical efficac y.  T his a p pears t o gi ve 
S LI T a fa v ora ble si de effect pr ofile, w he n c o m pare d t o ot her I T a p pr oac hes.  
T he pr o p ose d st u d y  is hi g hl y i n n o vati ve i n t he f oll o wi n g wa ys: ( 1 ) U ni q ue e m p hasis o n t he 
ne wl y dia g n ose d y o u n g pea n ut -aller gic p o p ulati o n, w h o ma y be m ore s uita ble f or t olera nce 
i n d ucti o n, (2 ) Mec ha nis ms of bas o p hil h y p ores p o nsi ve ness d uri n g t he earl y sta ges ( da ys t o 
wee ks) o f S LI T a n d later d uri n g mai nte na nce p hase of S LI T; p ossi bl y deli neati n g dese nsitizati o n 
vers us l o n g -li ve d t olera nce (I g G-me diate d or i n v ol ve me nt of S y k or b ot h), ( 3 ) Tec h n ol o g y bei n g 
use d t o i n vesti gate, f or t he first ti me, c ha n ges i n fre q ue ncies a n d p he n o t y pes of C D 4 T cells 
d uri n g t he c o urse of S LI T, a n d ( 4 ) E pit o pe s pecificities of aller ge n-s pecific I g E, G 4, a n d I g A i n 
bl o o d  a n d sali va. 
O n g oi n g St u dies  
T hr o u g h t he e n d of A pril 2 0 1 3, t here were 3 3 acti ve s u bjects a n d 9 c o m plete d s u bjects a ge d 1 - 
1 1 years i n t he first bli n de d pr ot oc ol of pea n ut S LI T ( A D o u ble-bli n de d, Place b o -c o ntr olle d 
St u d y of Pea n ut S u bli n g ual I m m u n ot hera p y i n C hil dre n, cli nicaltrials. g o v # N C T 0 0 5 9 7 7 2 7).  
T his st u d y, usi n g a pe a n ut S LI T mai nte na nce d ose of 2 m g, is place b o -c o ntr olle d t hr o u g h t he 
first 1 2 m o nt hs of t hera p y, a n d t he n a f o o d c halle n ge is perf or me d t o assess efficac y; t he i nteri m 
res ults of t his i nitial e n d p oi nt ha ve bee n p u blis he d [1 0 ], de m o nstrati n g statisticall y si g nifica nt 
dese nsitizati o n a n d i m m u ne m o d ulati o n i n t he acti ve gr o u p c o m pare d t o t he place b o gr o u p.  It 
s h o ul d be n ote d t hat t here was a wi de ra n ge of reacti o n t hres h ol ds i n t he treat me nt gr o u p 
s u g gesti n g t hat t he dese nsitizati o n effect at t he 1 2-m o nt h ti me p oi nt was o nl y partial.   T he 
pri mar y si de effect re p orte d was tra nsie nt m o ut h or or o p har y n geal itc hi n g a n d n o e pi ne p hri ne 
a n d o nl y rare di p he n h y dra mi ne was use d d uri n g h o me or o bser ve d d osi n g de m o nstrati n g t he 
safet y of t he S LI T treat me nt.  
T hese preli mi nar y res ults s h o w t hat pea n ut S LI T is ver y safe, eas y t o use, a n d ca n i n d uce cli nical 
dese nsitizati o n wit h ass ociate d i m m u n ol o gic c ha n ges i n mast cell, bas o p hil, a n d T cell res p o nses 
t o pea n ut wit hi n 1 2 m o nt hs. 
A sec o n dar y e n d p oi nt of t he st u d y was t o deter mi ne t he perce nta ge of pea n ut -aller gic patie nts 
t hat de vel o p t olera nce t o pea n ut after 3 6 m o nt hs of treat me nt as defi ne d b y passi n g a pea n ut oral 
f o o d c halle n ge 1 m o nt h after disc o nti n ui n g S LI T t hera p y.  T he first 1 2 patie nts t o reac h t his ti me 
p oi nt u n der we nt pea n ut oral f o o d c halle n ges t o d o u ble t he a m o u nt of pea n ut ( 4 4 4 3  m g) 
pre vi o usl y teste d w hile still o n treat me nt.  Si x  of t hese patie nts ( 5 0 %) s uccessf ull y c o m plete d 
t his f o o d c halle n ge a n d were c o nsi dere d f ull y dese nsitize d.  After 1 m o nt h off of t hera p y, 5 of 
t hese 6 patie nts ( 4 2 % of t otal) a gai n s uccessf ull y c o m plete d a n i de ntical pea n ut oral f o o d 
c halle n ge a n d were c o nsi dere d t olera nt.  T he 6 patie nts w h o were n ot f ull y dese nsitize d after 3 6 
m o nt hs of treat me nt all c o ns u me d m ore pea n ut t ha n at t he 1 2 -m o nt h ti me p oi nt ( me dia n 3 7 5 0 
m g; ra n ge 1 7 5 0 –  3 7 5 0 m g).  T hree  of t hese partiall y dese nsitize d patie nts o pte d t o c o nti n ue 
S LI T t hera p y.  T his u n p u blis he d data was prese nte d at t he 2 0 1 3 A A A AI a n n ual meeti n g i n 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 4  of 5 7  
* See a p pe n di x 6 . 0 
 
Marc h [1 5 ].  Mec ha nistic st u dies o n t his s mall c o h ort of s u bjects i n dicate d t hree ke y fact ors i n 
t he t olera nt gr o u p vers us t he n o n-t olera nt gr o u p.  First, t hese s u bjects ha d l o wer pea n ut -s pecific 
I g E at baseli ne ( me dia n t olera nt 1 4. 0 k U/ L, n o n-t olera nt 4 0. 4 k U/ L) a n d at 3 6 m o nt hs ( me dia n 
t olera nt 6. 1 8 k U/ L, n o n-t olera nt 2 0. 1 k U/ L; Sec o n d, t olera nt s u bjects ha d l o wer I g E a gai nst Ara 
h 1 a n d Ara h 2 b ot h at baseli ne a n d at 3 6 m o nt hs  [1 6 ]; T hir d, t olera nt s u bjects ha d l o wer 
bas o p hil acti vati o n i n res p o nse t o f o ur l o g -f ol d d oses of pea n ut a nti ge n i n a n e x vi v o assa y [1 7 ]. 
T hese fi n di n gs are i m p orta nt si nce it has bee n s h o w n t hat t he f o o d-s pecific I g E le vels are l o wer 
i n y o u n ger c hil dre n (see disc ussi o n bel o w) s uc h t hat t hese s u bjects ma y ha ve a hi g her li keli h o o d 
of de vel o pi n g t olera nce via S LI T t ha n t he s u bjects e val uate d a n d re p orte d at A A A AI 2 0 1 3.  
I n s u m mar y, o ur preli mi nar y data s u g gests t hat pea n ut S LI T has t he p ote ntial f or f ut ure use as a  
treat me nt t o pr otect a gai nst acci de ntal e x p os ures a n d reacti o ns i n pea n ut-aller gic c hil dre n, a 
fi n di n g wit h si g nifica nt cli nical i m pact.  I n a d diti o n, t olera nce ma y be p ossi ble i n s u bjects o n 
l o n g-ter m pea n ut S LI T wit h l o wer pea n ut-s pecific a n d pea n ut-c o m p o ne nt I g E a n d bas o p hil 
res p o nses, fi n di n gs e x pecte d i n y o u n ger, ne wl y dia g n ose d aller gic patie nts, p ossi bl y pre dicti ve 
of s uccessf ul t ole ra nce i n d ucti o n.  
E arly Life I m m u ne Res p o nses t o Pe a n ut  
T here is n o w e vi de nce fr o m m ulti ple st u dies [1 8 -2 0 ] t hat i m m u nit y t o pea n ut c o m me nces i n t he 
first year of life.  H o we ver, t he nasce nt T cell res p o nses i n t hese c hil dre n a p pear t o be wea k [2 0 ], 
re q uiri n g years t o f ull y mat ure [2 1 ]; a n d si milarl y, i n a rece nt st u d y of o ver 7 0 0 pea n ut-aller gic 
c hil dre n f oll o we d i n a tertiar y care ce nter, pea n ut -I g E le vels te n de d t o start l o w a n d i ncrease o ver 
t he first fi ve years of life bef ore reac hi n g stea d y-state [2 2 ].  T he c urre nt pr o p osal  will test S LI T 
as a n earl y i nter v e nti o n d uri n g t his de vel o p me ntal peri o d b y f oc usi n g recr uit me nt o n c hil dre n 
a ge d 1-4 years .  T his s h orte ns t he peri o d of dietar y a v oi da nce, mi ni mizes ris k of a na p h yla xis, 
a n d be gi ns treat me nt at l o wer I g E le vels, w hic h i n pre vi o us st u dies was ass ociate d wit h 
i m pr o ve d cli nical o utc o mes.  T his earl y i nter ve nti o n c o nce pt  is c urre ntl y bei n g pil ote d i n a n 
o n g oi n g st u d y of OI T f or y o u n g pea n ut -aller gic c hil dre n t hat use s t he sa me e ntr y criteria.  It has 
bee n  s h o w n t hat recr uit me nt of s uc h a y o u n g p o p ulati o n is n ot o nl y feasi ble, b ut acc o m plis hes a 
maj or g oal of t he strate g y b y esta blis hi n g a c o h ort wit h l o wer baseli ne pea n ut-s pecific I g E le vels 
t ha n i n pre vi o us st u dies [2 3 ].  I n a d diti o n, it has bee n s h o w n t hat earl y i nter ve nti o n 
i m m u n ot hera p y has a s u peri or safet y pr ofile, ver y hi g h rete nti o n rates, e nc o ura gi n g preli mi nar y 
cli nical res ults, a n d i m m u n o m o d ulat or y effects si milar t o pre vi o us trials [2 4 ].  Q ualitati vel y, it 
has bee n  o bser ve d t hat y o u n g c hil dre n are e xcelle nt st u d y partici pa nts w h o r ea dil y c o ns u me t heir 
d oses wit h o ut  t he a versi o ns t hat li mit t he partici pati o n of ol der s u bjects i n t his t y pe of 
i m m u n ot hera p y researc h.  T his is t he first pr oject t o a p pl y t hese i n n o vati ve c o nce pts t o a S LI T 
trial.  T he e xcelle nt safet y pr ofile of pea n ut S LI T ma kes it a ver y attracti ve ca n di date f or t hera p y, 
b ut t o date t he cli nical efficac y has bee n varia ble i n st u dies of ol der c hil dre n a n d a d ults.  B y 
tar geti n g y o u n g c hil dre n, we ai m t o i nterr u pt o n g oi n g aller gic pri mi n g pri or t o t he i nte nsificati o n 
of t h e I g E a n d T H 2 me m or y res p o nse, w hic h i n m ost pea n ut -aller gic c hil dre n will persist 
t hr o u g h o ut life.  I n d oi n g s o, we belie ve t hat earl y i nter ve nti o n i m m u n ot hera p y will be safer a n d 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 5  of 5 7  
* See a p pe n di x 6 . 0 
 
m ore s uccessf ul i n re pr o gra m mi n g relati vel y wea k i m m u ne res p o nses t o pea n ut , t h us i ncreasi n g 
t he li keli h o o d of t olera nce i n d ucti o n.  T hese n o vel c o nce pts e xte n d t he a d v a nces of first -
ge ner ati o n S LI T pil ot st u dies a n d pr o mise t o re defi ne t he c urre nt st a n d ar d of c are.  
1. 3  
R ati o n al e f o r S el e cti o n of St u d y P o p ul ati o n  
S u bjects bet wee n 1 2  a n d 4 8  m o nt hs of a ge  w h o ha ve bee n dia g n ose d wit h pea n ut aller g y base d 
o n a c o n vi nci n g cli nical hist or y of pea n ut aller g y a n d a n  I g E [ U ni C A P T M] t o pea n ut of > 0. 3 5 
k U A / L a n d a p ositi ve s ki n pric k test t o pea n ut ( > 3 m m t ha n t he ne gati ve c o ntr ol) or w h o are 
se nsitize d t o pea n ut ( base d o n an  I g E [ U ni C A P T M] of > 5 k UA / L a n d a p ositi ve s ki n pric k test t o 
pea n ut ( > 3 m m t ha n t he ne gati ve c o ntr ol) a n d n o k n o w n hist or y of i n gesti o n of pea n ut  will be 
e nr olle d.  T he a ge gr o u p f or st u d y was selecte d base d o n all t he pre vi o us st u dies o n a n y t y pe of 
I T f or f o o d aller g y ha vi n g s h o w n t hat t he s u bjects w h o beca me t olera nt te n de d t o be y o u n ger a n d 
ha d l o wer pea n ut I g E le vels at t he be gi n ni n g of t he st u d y.   
1. 4  
K n o w n a n d P ot e nti al Ris ks a n d B e n efits t o H u m a n P a rti ci p a nts  
1. 4. 1  Ris ks  
T he b uil d -u p a n d dail y mai nte na nce d oses of S LI T ma y ca use aller gic s y m pt o ms i ncl u di n g 
s neezi n g, r hi n orr hea, urticaria, a n gi oe de ma, fl us hi n g, flares of ecze ma, oc ular, nasal, oral a n d/ or 
t hr oat pr urit us, t hr oat ti g ht ness, na usea, v o miti n g, a b d o mi nal disc o mf ort, c o u g h, w heezi n g, 
a n d/ or s h ort ness of breat h i n a d diti o n t o se vere a na p h yla xis.  T he m ost c o m m o n s y m pt o m 
ass ociate d wit h S LI T d osi n g is or o p har y n geal itc hi n g  prese nt i n 9. 3 % of all d os es.  T o date, n o 
s u bject i n t he o n g oi n g S LI T st u d y has ha d d osi n g -relate d a na p h yla xis re q uiri n g treat me nt wit h 
e pi ne p hri ne  [1 0 ].  T he li keli h o o d of a s u bject e x perie nci n g aller gic s y m pt o ms will be lesse ne d 
b y starti n g at s mall a m o u nts of t he pea n ut pr otei n f or d osi n g per t he S LI T pr ot oc ol.   
D o u ble -bli n d, place b o -c o ntr olle d f o o d c halle n ges ( D B P C F C)  ma y i n d uce a n aller gic res p o nse  
wit h s y m pt o ms si milar t o t h ose descri be d f or S LI T d osi n g .  T he ris k of a se vere aller gic reacti o n 
is re d uce d b y c o n d ucti n g t he c halle n ge i n a m o nit ore d cli nic setti n g, i nitiati n g t he c halle n ge wit h 
a ver y s mall a m o u nt of t he f o o d, gra d uall y i ncreasi n g t he d os e, a n d st o p pi n g t he c halle n ge at t he 
first si g n of a reacti o n.  If s u bjects ha ve a n aller gic reacti o n d uri n g t he c halle n ges, t he y ma y nee d 
oral  or  i ntra m usc ular me dicati o ns.  Trai ne d pers o n nel, i ncl u di n g a p h ysicia n, as well as 
me dicati o ns a n d e q ui p me nt, w ill be i m me diatel y a vaila ble t o treat a n y reacti o n. 
Ot her ris ks i ncl u de t h ose relate d t o bl o o d dra wi n g a n d s ki n testi n g.  Bl o o d dra wi n g ma y 
a g gra vate a pre -e xisti n g a ne mic c o n diti o n, b ut t his ris k is mi ni mize d b y restricti n g t he v ol u me 
dra w n t o a ma xi m u m o f 3 ml /k g i n acc or da nce wit h U nite d States De part me nt of Healt h a n d 
H u ma n Ser vices rec o m me n dati o ns.  A d diti o nal ris ks are t h ose atte n da nt t o a n y nee dle p u nct ure, 
i ncl u di n g sli g ht br uisi n g, l ocal i nfecti o n, or t he p ossi bilit y of t he s u bject fai nti n g.  S ki n pric k 
tests ( n ot i ntra der mal) will be perf or me d b y tec h ni q ues reflecti n g ge neral sta n dar d of care a n d 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 6  of 5 7  
* See a p pe n di x 6 . 0 
 
ca use mi ni mal disc o mf ort (t he se nsati o n of a scratc h a n d a pr uritic, tra nsie nt hi ve ma y res ult).  
S uc h tests c o ul d t he oreticall y i n d uce a s yste mic aller gic reacti o n, b ut t his is e xcee di n gl y rare.  
1. 4. 2  B e n efits   
 
T he i m me diate be nefits f or t he s u bject i ncl u de t he p ossi bilit y of a decrease i n cli nical reacti vit y 
t o pea n ut a n d di mi nis he d aller gic reacti o n f oll o wi n g a n acci de ntal i n gesti o n of pea n ut, as well as 
t he p ossi bilit y of alteri n g t he nat ural c o urse of t he pea n ut aller g y.  A d diti o nall y, s u bjects ma y 
bec o me cli nicall y a n d i m m u n ol o gicall y t olera nt t o pea n ut, w hic h is ot her wise n ot li kel y t o 
ha p pe n.  S h o ul d t olera nce occ ur, s u bjects w o ul d ha ve t he a bilit y t o br oa de n t heir diet a n d 
e x perie nce a n i m pr o ve d q ualit y of life  wit h o ut t he restricti o ns i m p ose d b y a life-t hreate ni n g f o o d 
aller g y.  T his st u d y will als o hel p t o e x pa n d t he k n o wle d ge of f o o d aller g y i n ge neral a n d ma y 
lea d t o ne w ma na ge me nt a n d t hera pe utic pr ot oc ols f or i n di vi d uals wit h ot her f o o d aller gies. 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 7  of 5 7  
* See a p pe n di x 6 . 0 
 
2.  
O B J E C T I V E S  
2. 1  
P ri m a r y a n d S e c o n d a r y O bj e cti v es  
O ur ce ntr al hy p ot hesis  is t hat pea n ut S LI T as a n earl y i nter ve nti o n will i n d uce cli nical 
dese nsitizati o n  i n 8 0 % of s u bjects after 3 6  m o nt hs of t hera p y.  We will a d dress o ur h y p ot hesis 
t hr o u g h i n vesti gati o ns f oc use d o n t he f oll o wi n g o bjectives :  
O bjecti ve # 1: T o deter mi ne if 3 6  m o nt hs of pea n ut S LI T as a n earl y i nter ve nti o n i n s u bjects a ges 
1 t o 4 years i n d uces cli nical dese nsitizati o n .  
O bjecti ve # 2: T o e xa mi ne t he c ha n ge i n i m m u ne para meters ass ociate d wit h pea n ut S LI T a n d t he 
d e vel o p me nt of cli nical dese n sitizati o n.  
Pri m ary o bjective:   
T o deter mi ne if 3 6  m o nt hs of pea n ut S LI T as a n earl y i nter ve nti o n i n s u bjects a ges 1 t o 4 years 
i n d uces cli nical dese nsitizati o n .  T he pri m ary o utc o me  of t his o bjecti ve will be a statisticall y 
si g nifica nt differe nce i n c halle n ge sc ore s bet wee n  t he treat me nt gr o u p vers us t he place b o gr o u p 
d uri n g D B P C F C  perf or me d after 3 6 m o nt hs of pea n ut S LI T  (dese nsitizati o n ).  A sec o n d ary 
o utc o me  of t his o bjecti ve will be a statisticall y si g nifica nt differe nce i n t he c halle n ge sc ore  of t he 
treat me nt gr o u p vers us t he place b o gr o u p d uri n g t he D B P C F C perf or me d 3 m o nt hs after 
disc o nti n ui n g t hera p y (t olera nce). 
P ur p ose a n d ex pect ati o ns :   
T his o bjecti v e is desi g ne d t o test t he effecti ve ness of usi n g pea n ut S LI T as a n earl y i nter ve nti o n 
t o i n d uce cli nical dese nsitizati o n  i n pea n ut aller gic c hil dre n.  We e x pect t o de m o nstrate t he 
i n d ucti o n of dese nsitizati o n  b y s h o wi n g t hat s u bjects w h o ha ve c o m plete d 3 6  m o nt hs of 
treat me nt will ha ve si g nifica ntl y hi g her c halle n ge sc ores  o n D B P C F C c o m pare d t o s u bjects 
ra n d o mize d t o place b o.  Details of t his statistical a nal ysis are descri be d i n secti o n 9 bel o w.  
T he st u dies u n der O bjecti ve # 1 will deter mi ne t he efficac y of utilizi n g S LI T t o i n d uce 
dese nsitizati o n  i n y o u n g, ne wl y dia g n ose d pea n ut aller gic s u bjects.  At prese nt, strict dietar y 
a v oi da nce of f o o d aller ge ns a n d rea d y access t o self -i njecta ble e pi ne p hri ne is t he sta n dar d of care 
f or f o o d aller g y.  H o we ver, the u bi q uit y of pea n ut c o ntai ni n g f o o ds ma kes a v oi da nce diffic ult 
a n d t he p ossi bilit y of i na d verte nt i n gesti o n great.  W hile it has bee n s h o w n t hat dail y d osi n g wit h 
pea n ut S LI T res ults i n dese nsitizati o n a n d li kel y pr o vi des li mite d pr otecti o n fr o m acci de ntal 
pea n ut i n gesti o n [1 0 ], t hese res ults were q uite varia ble.  T his st u d y will de m o nstrate w het her 
pea n ut S LI T ca n ha ve a m ore r o b ust effect i n y o u n ger, ne wl y -dia g n ose d s u bjects.  T he st u d y will 
als o i n vesti gate w het her pea n ut S LI T ma y als o pr o vi de a n a ve n ue t o ca use pea n ut aller gic 
i n di vi d uals t o l ose t heir aller gic reacti vit y t o pea n uts (t olera nce).  
Sec o n d ary O bjectives:  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 8  of 5 7  
* See a p pe n di x 6 . 0 
 
O bjective # 2 : T o e xa mi ne t he c ha n ge i n i m m u ne para meters ass ociate d wit h pea n ut S LI T a n d t he 
de vel o p me nt of cli nical t olera nce.  
P ur p ose a n d Ex pect ati o ns:  
T hr o u g h O bjecti ve # 2, we will see k t o u n dersta n d t he m olec ular pr ocesses b y w hic h S LI T 
affects t he i m m u ne s yste m t hr o u g h e val uati o n of i m m u ne mec ha nis ms i n relati o ns hi p t o cli nical 
fi n di n gs of dese nsitizati o n a n d t olera nce.  We will de li neate t he i m pact of pea n ut S LI T o n t he 
s u bse q ue nt cell ular a n d h u m oral res p o nses t o pea n ut pr otei n: 1) pea n ut s pecific I g E, I g G, a n d 
I g G 4 res p o nse, 2) pea n ut  s pecific bas o p hil acti vati o n, 3) mast cell res p o nses t hr o u g h s ki n pric k  
testi n g, a n d 4) s pecific T-cell c yt o ki ne res p o nses a n d T re g ulat or y cell ( TRe g ) acti vati o n.  We 
a ntici pate t hat t he effect of pea n ut S LI T will occ ur b y i n d ucti o n of T Re gs , c o n versi o n of T cells 
fr o m a n aller gic ( TH 2) t o a n o n -aller gic ( TH 1) l y m p h oc yte res p o nse ( meas ure d b y c yt o ki nes, 
a nti b o d y le vels, a n d s ki n pr ic k test size), a c ha n ge i n pea n ut-s pecific bas o p hil acti vati o n, or 
t hr o u g h a c o m bi nati o n of t he a b o ve .   
Base d o n mec ha nistic st u dies of s u bc uta ne o us i m m u n ot hera p y f or aller gic r hi nitis [1 2 ], OI T f or 
f o o d aller gies [8 ], a n d pre vi o us w or k wit h S LI T f or pea n ut aller gies [1 0 ], our e x pectati o n is t hat 
t he i m m u n o gl o b uli n res p o nse will c ha n ge o ver ti me  res ulti n g i n a decrease i n pea n ut-s pecific 
I g E a n d a n i ncrease i n pea n ut -s pecific I g G a n d I g G 4.  We a ntici pate a n i ncrease i n TRe g   s pecific 
c yt o ki nes, s uc h as I L -1 0 a n d T G F -beta, t hat will parallel earl y cli nical res p o nses a n d i n dicate 
i m m u ne de viati o n t o war d t olera nce.  T he c o n versi o n fr o m TH 2 t o T H 1 c yt o ki ne res p o nses 
w o ul d ha ve a si milar cli nical effect of ma ki n g a s u bject less se nsiti ve t o pea n uts, b ut t his w o ul d 
li kel y occ ur t hr o u g h a n alter nati ve mec ha nis m or a mec ha nis m c o m bi ni n g TRe g  acti vati o n wit h 
ot her T cell c ha n ges.  A c ha n ge i n bas o p hil acti vati o n w o ul d i n dicate t hat s u bjects w o ul d be less 
se nsiti ve t o pea n ut, a n d we a ntici pate t hat res p o nse w o ul d be i n parallel t o t he fi n di n g of cli nical 
dese nsitizati o n b ut ma y n ot i n dicate cli nical t olera nce de vel o p me nt.  O verall, we will assess 
t hese im m u ne para meters o ver ti me a n d i n c o nj u ncti o n wit h cli nical le vels of reacti vit y t o 
deter mi ne w hic h mec ha nis m(s) is rele va nt f or effecti ve pea n ut S LI T i n dese nsitizati o n a n d 
ulti matel y t olera nce.  F oll o wi n g c ha n ges i n t he i m m u ne para meters of t he place b o s u bjects will 
be t he m ost i nf or mati ve a n d ma y pr o vi de i nsi g ht i nt o s pecific i m m u ne mar kers t hat heral d t he 
l oss of dese nsitizati o n or t he de vel o p me nt of cli nical t olera nce.  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 1 9  of 5 7  
* See a p pe n di x 6 . 0 
 
3.  
S T U D Y D E S I G N  
T his S LI T st u d y is  a ra n d o mize d, bli n de d, place b o -c o ntr olle d st u d y bas e d o n o ur pre vi o us 
e x perie nce at D u ke U ni versit y Me dical Ce nter a n d t he U ni versit y of N ort h Car oli na at C ha pel  
H ill usi n g OI T a n d S LI T i n f o o d aller gic s u bjects.  T he st u d y will e nr oll 5 0  c hil dre n a ges 1 t o 4 
years wit h pea n ut aller g y.  U p o n e nr oll me nt i nt o t he st u d y, all s u bjects will u n der g o a  q ualif yi n g  
e ntr y D B P C F C t o 1 0 0 0  m g  of pea n ut pr otei n t o c o nfir m t he dia g n osis of pea n ut aller g y  a n d 
esta blis h a baseli ne t hres h ol d le vel .  F oll o wi n g a p ositi ve D B P C F C , eac h s u bject will be 
ra n d o mize d 1: 1 t o recei ve pea n ut S LI T t hera p y vers us place b o. St u d y dr u g d osi n g will be gi n at a 
starti n g d ose of 1 p u m p of a 1:1 0 0  dil uti o n of pea n ut S LI T or place b o  (2 . 5 mc g pea n ut pr otei n  or 
place b o ).  D uri n g t he b uil d-u p p hase , w hic h lasts a p pr o xi matel y 2 0  wee ks  ( Ta ble 1), s u bjects 
will d ose dail y a n d i ncrease t he n u m ber of p u m ps e ver y 1 -2 wee ks as per t he d osi n g sc he d ule.  
S u bjects will ret ur n t o t he researc h u nit f or o bser ve d d osi n g wit h eac h c ha n ge i n st u d y dr u g 
dil uti o n  ( 1:1 0 0, 1 :1 0, 1: 1 ) a n d wit h e ver y ot her d ose i ncrease o n 1: 1  u ntil t he mai nte na nce d ose 
of 1 6  p u m ps of 1: 1  st u d y dr u g ( 40 0 0 mc g pea n ut pr otei n  or place b o ) is ac hie ve d.  S u bjects will 
t he n c o nti n ue dail y a d mi nistrati o n of t he mai nte na nce d ose a n d ret ur n e ver y 6 m o nt hs f or foll o w -
u p.  After 3 6  m o nt hs *  of treat me nt, s u bjects will u n der g o a D B P C F C t o 4 4 4 3  m g  of pea n ut 
pr otei n t o assess f or  dese nsitizati o n.  All s u bjects  will t he n disc o nti n ue pea n ut  S LI T  or place b o 
t hera p y f or 3  m o nt hs .  T h ose s u bjects w h o are a ble t o t olerate >  4 4 3 m g of pea n ut pr otei n at t he 
3 6 m o nt h *  D B P C F C will be as ke d t o  ret ur n f or a D B P C F C  at 3 9 m o nt hs *  ( or 3 m o nt hs after t he 
i nitial D B P C F C) t o t he a m o u nt of pea n ut pr otei n pre vi o usl y t olerate d at t he 3 6 m o nt h*  D B P C F C  
t o assess f or t olera nce.  All s u bjects will be u n bli n de d after t he t olera nce D B P C F C a n d will ha ve 
c o m plete d t he st u d y.   S u bjects u na ble t o t olerate >  4 4 3 m g of pea n ut pr otei n at t he 3 6 m o nt h 
D B P C F C will be  u n bli n de d a n d  gi ve n t he o pti o n t o strictl y a v oi d all pea n uts or, if a p pr o priate, 
be offere d a f o o d e q ui vale nt.    
* See C O VI D safet y meas ure i nf or mati o n i n A p pe n di x 6  
3. 1  
St u d y E n d p oi nts   
3. 1. 1  P ri m a r y E n d p oi nt  
T he pri m ary o utc o me  of t his st u d y will be a statisticall y si g nifica nt differe nce i n t he c halle n ge 
sc ore of t he treat me nt gr o u p vers us t he place b o gr o u p d uri n g D B P C F C after 3 6 m o nt hs of pea n ut 
S LI T  (dese nsitizati o n ). 
3. 1. 2  S e c o n d a r y E n d p oi nt s  
T he sec o n dar y o utc o me meas ures are as f oll o ws:  
1.  A stati sticall y si g nifica nt differe nce i n t he c halle n ge sc ore of t he treat me nt gr o u p vers us 
t he place b o gr o u p d uri n g t he D B P C F C perf or me d 3 m o nt hs after disc o nti n ui n g t hera p y  
(t olera nce). 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 0  of 5 7  
* See a p pe n di x 6 . 0 
 
2.  T he c ha n ge i n i m m u ne para meters o ver ti me ass ociate d wit h t he i n d ucti o n of cli nical 
dese nsitizati o n  c o m pare d t o t he fail ure t o ac hie ve cli nical dese nsitizati o n .  T hese i ncl u de 
h u m oral res p o nses, bas o p hil/effect or cell res p o nses, a n d c yt o ki ne res p o nses t o p ea n uts. 
3.  I nci de nce of all seri o us a d verse e ve nts d uri n g t he st u d y. 
 
3. 2  
C rit e ri a f o r P r e m at u r e T e r mi n ati o n of t h e St u d y: St u d y St o p pi n g R ul es  
T he st u d y will be st o p pe d a n d will u n der g o a n e x pe dite d re vie w b y t he Pri nci pal I n vesti gat or , 
I R B, a n d data safet y m o nit ori n g b oar d ( D S M B) if a n y of t he f oll o wi n g occ urs:  
•  A n y deat h relate d t o pea n ut S LI T d osi n g  
•  M ore t ha n 2 se vere a na p h ylactic reacti o n relate d t o pea n ut S LI T d osi n g at a n y sta ge of 
t he pr ot oc ol 
•  M ore t ha n 3 s u bjects w h o re q uire m ore t ha n 1 i njecti o n of i ntra m usc ular e pi ne p hri ne 
d uri n g d ose escalati o n or mai nte na nce d osi n g of t he pea n ut st u d y pr o d uct  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 1  of 5 7  
* See a p pe n di x 6 . 0 
 
4.  
S E L E C T I O N A N D W
I T H D R A W A L O F P A R T I C I P A N T S  
4. 1  
I n cl usi o n C rit e ri a  
S u bjects w h o meet all  of t he f oll o wi n g criteria are eli gi ble f or e nr oll me nt as st u d y partici pa nts:  
•  Writte n i nf or me d c o nse nt fr o m partici pa nt’s pare nt/ g uar dia n . 
•  A ge 1 2 -4 8 m o nt hs of eit her se x, a n y race, a n d a n y et h nicit y. 
•  1) A pea n ut aller g y dia g n osis wit h a c o n vi nci n g cli nical hist or y of pea n ut aller g y A N D  a 
pea n ut -s pecific I g E [ U ni C A P] >  0. 3 5  k U A / L A N D  a p ositi ve s ki n pric k test t o pea n ut ( > 3 
m m t ha n t he ne gati ve c o ntr ol) O R  2 ) are se nsitize d t o pea n ut ( base d o n a n  I g E [U ni C A P] 
t o pea n ut of >  5 k U A / L) A N D  a p ositi ve s ki n pric k test t o pea n ut ( >  3 m m t ha n t he 
ne gati ve c o ntr ol) A N D  n o k n o w n hist or y of i n gesti o n of pea n ut.  
•  A p ositi ve D B P C F C t o 1 0 0 0 m g of pea n ut at e nr oll me nt. 
4. 2  
E x cl usi o n C rit e ri a  
S u bjects w h o meet a ny of t hese criteria are n ot  eli gi ble f or e nr oll me nt as st u d y partici pa nts:  
•  H ist or y of se vere a na p h yla xis t o pea n ut, defi ne d as h y p o xia, h y p ote nsi o n, or ne ur ol o gic 
c o m pr o mise (c ya n osis or S p O 2 < 9 2 % at a n y sta ge, h y p ote nsi o n, c o nf usi o n, c olla pse or 
l oss of c o nsci o us ness). 
•  Partici pati o n i n a n y i nter ve nti o nal st u d y f or t he treat me nt of f o o d aller g y i n t he past 6 
m o nt hs.  
•  K n o w n oat, w heat, or gl yceri n aller g y.  
•  E osi n o p hilic or ot her i nfla m mat or y (e. g. celiac) gastr oi ntesti nal diseas e. 
•  Se vere ast h ma ( 2 0 0 7 N H L BI Criteria Ste ps 5 or 6 –  A p pe n di x 2).  
•  I na bilit y t o disc o nti n ue a nti hista mi nes f or s ki n testi n g a n d D B P C F Cs. 
•  Use of o maliz u ma b or ot her n o n -tra diti o nal f or ms of aller ge n i m m u n ot hera p y (e. g., oral 
or s u bli n g ual) or i m m u n o m o d ulat or  t hera p y ( n ot i ncl u di n g c ortic oster oi ds) or bi ol o gic 
t hera p y wit hi n t he past year. 
•  Use of b eta-bl oc kers ( oral), a n gi ote nsi n -c o n verti n g e nz y me ( A C E) i n hi bit ors, 
a n gi ote nsi n -rece pt or bl oc kers ( A R B) or calci u m c ha n nel bl oc kers. 
•  Si g nifica nt me dical c o n diti o n ( e. g., li ver, ki d ne y, gastr oi ntesti nal, car di o vasc ular, 
he mat ol o gic, or p ul m o nar y disease) t hat w o ul d ma ke t he s u bject u ns uita ble f or i n d ucti o n 
of f o o d reacti o ns.  
4. 3  
P r e m at u r e P a rti ci p a nt T e r mi n ati o n f r o m t h e St u d y  
4. 3. 1  C rit e ri a  
N o s u bject i nitiati n g t hera p y i n t hi s trial will be re place d. 
Partici pa nts ma y be re m o ve d fr o m t his st u d y if:  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 2  of 5 7  
* See a p pe n di x 6 . 0 
 
•  Si g nifica nt cli nical s y m pt o ms (res pirat or y, GI, s ki n) are e x perie nce d at h o me after ta ki n g 
t he dail y d ose of pea n ut pr otei n. 
•  T he  partici pa nt has a n acci de ntal pea n ut i n gesti o n wit h a na p h yla xis d uri n g t he st u d y. 
•  T he  partici pa nt de vel o ps  p o or c o ntr ol or persiste nt acti vati o n of sec o n dar y at o pic disease 
(e. g. at o pic der matitis , ast h ma). 
•  Circ u msta nces (e. g. c o nc urre nt ill ness, s uc h as gastr oe nteritis) re q uire misse d 
mai nte na nce d osi n g of > 1 4 c o nsec uti ve da ys (t his d oes n ot i ncl u de s u bjects i nte nti o n all y 
re m o ve d fr o m t hera p y i n pre parati o n f or t he t olera nce D B P C F C). 
•  T here is a patter n of n o n -a d here nce wit h t he h o me d osi n g pr ot oc ol ( i.e., e xcessi ve misse d 
d osi n g da ys  or misse d a p p oi nt me nts ) t hat w o ul d create a safet y iss ue warra nti n g 
disc o nti n uati o n . 
•  T he partici pa nt is s tarte d o n A R Bs, A C E i n hi bit ors, beta-bl oc kers, or ot her pr o hi bite d 
me dicati o ns a n d t here are n o alter nati ve o pti o ns pe r t he prescri bi n g p h ysicia n. 
Partici pa nts ma y pre mat urel y wit h dra w fr o m t he st u d y if: 
•  T he partici pa nt elects t o wit h dra w c o nse nt fr o m all f ut ure st u d y acti vities, i ncl u di n g 
f oll o w-u p . 
•  T he partici pa nt is “l ost t o f oll o w -u p” (i.e., n o f urt her f oll o w -u p is p o ssi ble beca use 
atte m pts t o reesta blis h c o ntact wit h t he partici pa nt ha ve faile d) . 
•  T he partici pa nt dies . 
 
 
 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 3  of 5 7  
* See a p pe n di x 6 . 0 
 
5.  
S T U D Y M
E D I C A T I O N  
5. 1  
F o r m ul ati o n, P a c k a gi n g, a n d L a b eli n g  
T he pea n ut S LI T st u d y dr u g will be li q ui d pea n ut e xtract ( 5 0 0 0 mc g/ ml pea n ut pr otei n)  
ma n ufact ure d b y a n d c o m merciall y p urc hase d fr o m Greer La b orat ories , I nc. i n Le n oir, N C.  T he 
place b o will c o nsist of p ure gl yceri nate d sali ne s ol uti o n wit h cara mel c ol ori n g t o matc h c ol or.  
T he pea n ut S LI T s t u d y dr u g will be deli vere d t o t he pri ma r y site la b orat or y at U N C-C H ( PI, 
B ur ks) .  It will be dil ute d as a p pr o priate ( Ta ble 1) a n d b ottle d a n d t he n be s u b mitte d t o t he 
i n vesti gati o nal dr u g ser vices (I D S) at U N C-C H  a n d U T S W res pecti vel y f or la beli n g, a n d 
distri b uti o n .  A certificate of a nal ysis f or t he pea n ut e xtract is o n file i n Dr. B ur ks’ la b orat or y.   
Gl yceri nate d sali ne s ol uti o n will be a d de d t o ma ke t he a p pro priate dil uti o ns  of b ot h t he pea n ut 
S LI T st u d y dr u g a n d place b o ( Ta ble 1).  T he pea n ut S LI T st u d y dr u g a n d place b o will be 
aliq u ote d  i nt o 3 2. 6 ml plastic vials wit h eac h p u m p dis pe nsi n g 5 0 micr oliters of st u d y dr u g.  
I n di vi d ual vials will be la bele d wit h t he s u bject I D a n d ra n d o mizati o n n u m ber, descri pti o n of 
pr o d uct, l ot n u m ber, e x pirati o n date, dil uti o n , a n d t he n u m ber of p u m ps t o be dis pe nse d dail y.  
U p o n recei vi n g t he st u d y dr u g fr o m I D S , t he st u d y c o or di nat or will verif y t hat t he dil uti o n a n d 
t he n u m ber of dail y p u m ps matc h t he partici pa nt’s c urre nt prescri pti o n.  T he s u bject’s I D a n d 
ra n d o mizati o n n u m ber will als o be c o nfir me d pri or t o gi vi n g t he vials t o t he partici pa nt or 
partici pa nt’s care pr o vi der.  
5. 2  
P r e p a r ati o n, A d mi nist r ati o n, a n d D o s a g e 
F or h o me a d m i nistrati o n t he fa mil y will be pr o vi de d wit h i n di vi d ual 3 2. 6 ml vials of t he 
a p pr o priate dil uti o n al o n g wit h i nstr ucti o ns  re gar di n g t he n u m ber of p u m ps t o dis pe nse.  
Partici pa nts will be gi ve n a n a de q uate s u p pl y f or t he i nter val bet wee n sc he d ule d visits wi t h a n 
a d diti o nal s u p pl y t o be use d i n t he e ve nt of misse d or ca ncelle d st u d y visits.  T he p u m ps are t o 
be a d mi nistere d bel o w t he t o n g ue a n d hel d i n place f or as l o n g as p ossi ble f or u p t o  2 mi n utes 
bef ore s wall o wi n g.  T he s u bjects s h o ul d ha ve n ot hi n g t o ea t or dri n k 1 5 mi n utes bef ore or  3 0 
mi n utes after d osi n g .  At least 1 2 h o urs s h o ul d pass bet wee n d oses.  F or y o u n ger s u bjects w here 
t he v ol u me of li q ui d is t o o lar ge t o be hel d u n der t he t o n g ue as a si n gle d ose, d oses ma y be s plit 
i nt o 2 d oses wit h 5 mi n utes bet wee n eac h a d mi nistrati o n.  
5. 3  
D r u g A c c o u nt a bilit y  
U n der Title 2 1 of t he C o de of Fe deral Re g ulati o ns ( 2 1 C F R § 3 1 2. 6 2) t he i n vesti gat or is re q uire d 
t o mai ntai n a de q uate rec or ds of t he dis p ositi o n of t he i n vesti gati o nal a ge nt, i ncl u di n g t he date 
a n d q uantit y of t he dr u g recei ve d, t o w h o m t he dr u g was dis pe nse d ( partici pa nt -b y -partici pa nt 
acc o u nti n g), a n d a detaile d acc o u nti n g of a n y dr u g acci de ntall y or deli beratel y destr o ye d.  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 4  of 5 7  
* See a p pe n di x 6 . 0 
 
Rec or ds f or recei pt, st ora ge, use, a n d dis p ositi o n will be mai ntai ne d b y t he s t u d y site.  Eac h 
partici pa nt will ha ve a c urre nt dr u g -dis pe nsi n g l o g.  T his l o g will c o ntai n t he i de ntificati o n of 
eac h partici pa nt a n d t he date a n d q ua ntit y of dr u g dis pe nse d.  
All rec or ds re gar di n g t he dis p ositi o n of t he i n vesti gati o nal pr o d uct will be a v aila ble f or 
i ns pecti o n b y t he trial m o nit or. 
5. 4  
Ass ess m e nt of C o m pli a n c e wit h St u d y T r e at m e nt a n d M o nit o ri n g  
Fa milies will d oc u me nt dail y d osi n g of t he st u d y pr o d uct a n d a n y reacti o n fr o m h o me d osi n g 
t hr o u g h diar y l o gs.  A d diti o nall y, t he fa milies will be i ns tr ucte d t o ret ur n all e m pt y vials  as well 
as all u n use d st u d y dr u g at eac h visit. Fa milies will be pr o vi de d 2 4 -h o ur e mer ge nc y c o ntact 
i nf or mati o n. 
5. 5  
M o difi c ati o n of St u d y T r e at m e nt  
If t he s u bject is u na ble t o t olerate t he sc he d ule d d ose i ncrease d uri n g b uil d -u p , the st u d y 
c o or di nat or or PI  ma y c h o ose t o dela y or a dj ust d ose escalati o n .  O pti o ns i ncl u de le n gt he ni n g t he 
i nter val bet wee n sc he d ule d d ose i ncreases, decreasi n g t o a pre vi o usl y t olerate d d ose, or 
wit h dra wi n g fr o m t he st u d y.   
5. 6  
C o n c o mit a nt M e di c at i o ns  
All s u bjects ma y c o nti n ue t heir us ual me dicati o ns, i ncl u di n g t h ose ta ke n f or ast h ma, aller gic 
r hi nitis a n d at o pic der matitis, d uri n g t he st u d y.  H o we ver, t he y m ust be a ble t o te m p oraril y 
disc o nti n ue a nti hista mi nes ( 5 half-li ves of t he a nti hista mi ne) pri or t o s ki n pric k testi n g a n d 
D B P C F Cs .  Re g ular t o pical ster oi d use is per mitte d at t he ti me of s ki n testi n g.  Mai nte na nce 
aller ge n i m m u n ot hera p y f or e n vir o n me ntal aller gies ma y be c o nti n ue d d uri n g t he st u d y b ut 
s u bjects s h o ul d n ot start or escalate aller ge n i m m u n ot hera p y f or e n vir o n me ntal aller gies d uri n g 
t he st u d y. 
5. 7  
P r o p h yl a cti c M e di c ati o ns  
N o ne  
5. 8  
R es c u e M e di c ati o ns   
Treat me nt of i n di vi d ual aller gic reacti o ns d uri n g pea n ut S LI T t hera p y s h o ul d be wit h a n 
a nti hista mi ne a n d/ or e pi ne p hri ne, al o n g wit h I V fl ui ds, al b uter ol , ster oi ds, a n d H 2 bl oc kers as 
i n dicate d.  All s u bjects a n d/ or fa mil y me m ber m ust  ha ve a n a p pr o priate self -i njecta ble 
e pi ne p hri ne de vice a vaila ble t hr o u g h o ut t he st u d y f or e mer ge nc y use.  Pre scri pti o ns will be 
pr o vi de d f or s u bjects w h o d o n ot ha ve a n e pi ne p hri ne a ut o -i nject or.  S u bjects a n d pare nts will be 
trai ne d i n pr o per use of t he de vice a n d m ust  be a ble t o de m o nstrate pr o per tec h ni q ue.   


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 5  of 5 7  
* See a p pe n di x 6 . 0 
 
5. 9  
P r o hi bit e d M e di c ati o ns   
1.  O maliz u ma b ( X ol air ) 
2.  S yste mic c ortic oster oi ds of l o n ger t ha n 3 wee ks d urati o n at a n y ti me t hr o u g h o ut t he  st u d y 
3.  Beta -bl oc kers ( oral)  
4.  A n gi ote nsi n -c o n verti n g e nz y me ( A C E) i n hi bit ors  
5.  A n gi ote nsi n -rece pt or bl oc kers ( A R B) 
6.  Calci u m c ha n nel bl oc kers  
 
 
 
 
 
 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 6  of 5 7  
* See a p pe n di x 6 . 0 
 
6.  
S T U D Y D E F I N I T I O N S A N D P R O C E D U R E S  
6. 1  
St u d y D efi niti o ns  
6. 1. 1  A n a p h yl a xi s  
A na p h yla xis is a ge neralize d aller gic reacti o n t hat is ra pi d i n o nset a n d ma y pr o gress t o deat h.  
6. 1. 2  C rit e ri a f o r Di a g n o si s   
A na p h yla xis is li kel y w he n a n y o ne  of t he t hree f oll o wi n g sets of criteria is f ulfille d: 
1.  Ac ute o nset of a n ill ness ( mi n utes t o h o urs) wit h i n v ol ve me nt of:  
•  S ki n/ m uc osal tiss ue (e. g., ge ner alize d  hi ves, itc h or fl us h, s w olle n li ps/t o n g ue/ u v ula)   
A N D  
•  Re d uce d B P or ass ociate d s y m pt o ms (e. g., h y p ot o nia, s y nc o pe, i nc o nti ne nce)  
2.  T w o or m ore of t he f oll o wi n g t hat occ ur ra pi dl y after e x p os ure t o a li kel y aller ge n f or 
t h at s u bject ( mi n utes t o h o urs): 
•  S ki n/ m uc osal tiss ue (e. g., ge ner alize d  hi ves, itc h/fl us h, s w olle n li ps/t o n g ue/ u v ula)  
•  Air wa y c o m pr o mis e (e. g., d ys p nea, stri d or w heeze/ br o nc h os pas m, h y p o xia, re d uce d 
P E F)  
•  Re d uce d B P or ass ociate d s y m pt o ms (e. g., h y p ot o nia, s y nc o pe, i nc o nti ne nce)  
•  Persiste nt  GI s y m pt o ms (e. g., na usea, v o miti n g, cra m p y a b d o mi nal pai n)  
3.  Re d uce d B P after e x p os ure t o k n o w n aller g e n f or t hat s u bject ( mi n utes t o h o urs):  
•  I nfa nts a n d C hil dre n: l o w s yst olic B P (a ge-s pecific) or > 3 0 % dr o p i n s yst olic B P * 
•  A d ults: s yst olic B P < 9 0  m m H g or > 3 0 % dr o p fr o m t heir baseli ne  
 
*  L o w s yst olic B P f or c hil dre n is defi ne d as < 7 0 m m H g fr o m 1 m o nt h t o 1 year; less t ha n 
( 7 0 m m H g + [ 2 x a ge]) fr o m 1-1 0 years; a n d < 9 0 m m H g fr o m a ge 1 1 -1 7 years.  
 
6. 1. 3  A n a p h yl a xi s St a gi n g S y st e m  
St a gi n g S yste m of Se verit y of A n a p h yl a xis  
St a ge  
Defi ne d B y  
1. Mil d  (s ki n & s u bc uta ne o us tiss ues, 
GI, &/ or mil d res pirat or y)  
Fl us hi n g, urticaria, peri or bital or facial 
a n gi oe de ma; mil d d ys p nea, w heeze or u p per 
res pirat or y s y m pt o ms; mil d a b d o mi nal pai n 
a n d/ or e mesis  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 7  of 5 7  
* See a p pe n di x 6 . 0 
 
2. M o der ate  ( mil d s y m pt o ms + feat ures 
s u g gesti n g m o derate res pirat or y, 
car di o vasc ular or GI s y m pt o ms)  
Mar ke d d ys p ha gia, h oarse ness, a n d/ or stri d or; 
S O B, w heezi n g & retracti o ns; cra m p y 
a b d o mi nal pai n, rec urre nt v o miti n g a n d/ or 
diarr hea; a n d/ or mil d dizzi ness  
3. Sever e ( h y p o xia, h y p ote nsi o n, or 
ne ur ol o gical c o m pr o mise)  
C ya n osis or S p O 2 <  9 2 % at a n y sta ge, 
h y p ote nsi o n, c o nf usi o n, c olla pse, l oss of 
c o nsci o us ness; or i nc o nti ne nce  
 
6. 2  
E n r oll m e nt  
A t otal of 5 0 c hil dre n will be e nr olle d i n t he st u d y ( 4 0  c hil dre n at U N C -C H  a n d 1 0 c hil dre n at 
U T S W ).  Acc o u nti n g f or a 1 0 % dr o p o ut rate, we a ntici pate ha vi n g 4 5  c hil dre n eli gi ble f or t he 
dese nsitizati o n D B P C F C after 3 6 m o nt hs of treat me nt . 
6. 3  
S c r e e ni n g Visit  
T he scree ni n g visit will i ncl u de t he f oll o wi n g pr oce d ur es: 
•  C o nse nt  
•  Me dical hist or y  
•  Diet a n d aller g y q uesti o n naire  
•  P h ysical e xa mi nati o n  
•  Bl o o d dra w f or pea n ut -s pecific I g E meas ure me nt a n d a d diti o nal mec ha nistic st u dies  
•  S ki n pric k testi n g t o pea n ut  
•  Sali va c ollecti o n f or i m m u n o gl o b uli n testi n g  
•  St o ol c ollecti on f or micr o bi o me a n d i m m u n o gl o b uli n st u dies 
 
6. 4  
B as eli n e Visit / E nt r y F o o d C h all e n g e 
S u bjects w h o meet eli gi bilit y criteria will ret ur n f or a baseli ne visit  wit hi n 4 wee ks of t he 
scree ni n g visit.  T his visit ma y be c o m bi ne d wit h t he scree ni n g visit i n s u bjects w h o m t he 
i n vesti gat or belie ves will q ualif y f or t he st u d y.  T his visit will i ncl u de t he f oll o wi n g pr oce d ures: 
•  P h ysical e xa mi nati o n  
•  Q ualif yi n g D B P C F C  t o 1 0 0 0 m g of pea n ut  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 8  of 5 7  
* See a p pe n di x 6 . 0 
 
* Mec ha nistic bl o o d dra w ma y be re peate d d ue t o i na de q uate T a n d n o n -T cell se parati o n b ut n ot 
t o e xcee d t he less or of 3 5  m l or 3 ml / k g per bl o o d dra w wit hi n a n ei g ht ( 8) wee k peri o d.  T his 
w o ul d n ot be re peate d i n s u bjects wit h k n o w n c hr o nic a ne mia.   
6. 5  
St u d y T r e at m e nt Visits  
 
* C O VI D -1 9 S afety Me as ures  
Details o n c ha n ges t o st u d y dr u g d osi n g d urati o n, st u d y visits , la b orat or y sa m ple c ollecti o n a n d 
D B P C F Cs d ue t o t he gl o bal C O VI D -1 9 pa n de mic are descri be d i n detail i n A p pe n di x 6.  T hese 
c ha n ges are als o hi g hli g hte d t hr o u g h o ut t he f oll o wi n g secti o ns.  
D ose Esc al ati o n  
F oll o wi n g t he q ualif yi n g e ntr y D B P C F C t o pea n ut, s u bjects will ret ur n t o t he researc h u nit t o 
be gi n t he d ose escalati o n p hase of t he st u d y pr ot oc ol  ( Ta ble 1) wit hi n 7 da ys of c o m pleti n g t he 
e ntr y D B P C F C .  Acc or di n g t o t heir ra n d o mizati o n, s u bjects will a d mi nister o ne p u m p of a 1 :1 0 0 
dil uti o n of eit her pea n ut S LI T st u d y dr u g or place b o  u n der t heir t o n g ues a n d wait 2 mi n utes 
bef ore s wall o wi n g.  S u bjects will be o bser ve d f or a mi ni m u m of 3 0 mi n utes a n d t h ose wit h 
mi ni mal  (e. g.,or o p har y n geal itc hi n g) or n o  s y m pt o ms will be disc har ge d .  T he i de ntical d ose will 
be a d mi nistere d at h o me dail y f or 1 wee k.  Ta ble 1 s h o ws t he sc he d ule f or s u bse q ue nt d ose 
escalati o n, w hic h i ncl u des b ot h h o me d ose escalati o n as well as cli nic visits f or o bser ve d d ose 
escalati o n.  O bser ve d d ose escalati o n at t he researc h u nit will occ ur wit h eac h i ncrease i n st u d y 
dr u g dil uti o n a n d e ver y 4 wee ks w hile o n 1: 1 f ull c o nce ntrati o n u ntil mai nte na nce d osi n g ( 4 0 0 0 
mc g pea n ut pr otei n) is ac hie ve d.  T h ose wit h mil d s y m pt o ms re q uiri n g treat me nt d uri n g 
o bser ve d d ose escalati o n will be o bser ve d f or at least 2 h o ur s or u ntil s y m pt o ms res ol ve.   A n y 
s u bject t hat de vel o ps m o derate or se vere s y m pt o ms re q uiri n g e pi ne p hri ne will be o bser ve d f or at 
least 4 h o urs or u ntil s y m pt o ms res ol ve .  S u bse q ue nt d osi n g after a treata ble reacti o n will  be 
deter mi ne d b y t he PI usi n g his b est cli nical j u d g me nt.  O pti o ns w o ul d i ncl u de re peati n g t he 
i de ntical d ose t he f oll o wi n g da y, dela yi n g escalati o n a n d c o nti n ui n g o n t he pri or d ose f or a n 
a d diti o nal 1-2 wee ks, decreasi n g t he d ose t o t he hi g hest s y m pt o m free d ose  or a n ar bitrar y safe 
d ose , or disc o nti n ui n g d osi n g.  S u bjects will be gi ve n c o ntact n u m bers f or st u d y pers o n nel, 
i ncl u di n g e mer ge nc y c o ntact i nf or mati o n.  Fa milies will be i nstr ucte d t o c o ntact st u d y pers o n nel 
wit h a n y ne w or si g nifica nt  si de effects wit h h o me d osi n g. 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 2 9  of 5 7  
* See a p pe n di x 6 . 0 
 
 
 
 
M ai nte n a nce  d osi n g  
After c o m pleti n g t he escalati o n sc he d ule, s u bjects will c o nti n ue t o a d mi nister 1 6 p u m ps of t he 
1: 1 dil uti o n of pea n ut S LI T st u d y dr u g ( 4 0 0 0 mc g) or place b o  dail y f or a t otal of 3 6 m o nt hs.  
S u bjects will ret ur n t o t he researc h u nit e ver y 6 m o nt hs  f or a f oll o w u p visit w hic h w o ul d i ncl u de 
T a ble 1. D ose  Esc al ati o n  Sc he d ule  
 
D ose 
#  
 
Pe a n ut 
Dil uti o n  
 
P u m ps  
D ose of 
Pe a n ut 
Pr otei n  
I nter v al 
i n Wee ks 
%  I ncre ase  
 
St u d y Visit  
( O bser ve d 
d osi n g)  
1  
1 :1 0 0  
1  
2. 5 mc g  
 
- 
ü   
2  
1 :1 0 0  
2  
5 mc g  
1  
1 0 0 %  
 
3  
1 :1 0 0  
4  
1 0 mc g  
1  
1 0 0 %  
 
4  
1 :1 0 0  
8  
2 0 mc g  
1  
1 0 0 %  
 
5  
1: 1 0  
1  
2 5 mc g  
1  
2 5 %  
ü   
6  
1 :1 0  
2  
5 0 mc g  
1  
1 0 0 %  
 
7  
1 :1 0  
4  
1 0 0 mc g  
1  
1 0 0 %  
 
8  
1 :1 0  
8  
2 0 0 mc g  
1  
1 0 0 %  
 
9  
1: 1  
1  
2 5 0 mc g  
2  
2 5 %  
ü   
1 0  
1: 1  
2  
5 0 0 mc g  
2  
1 0 0 %  
 
1 1  
1: 1  
4  
1 0 0 0 mc g  
2  
1 0 0 %  
ü   
1 2  
1: 1  
8  
2 0 0 0 mc g  
2  
1 0 0 %  
 
1 3  
1: 1  
1 2  
3 0 0 0 mc g  
2  
5 0 %  
ü   
1 4  
1: 1  
1 6  
4 0 0 0 mc g  
2  
3 3 %  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 0  of 5 7  
* See a p pe n di x 6 . 0 
 
vitals si g ns, a p h ysical e xa m, re vie w of s y m pt o m diaries, c ollecti o n of ol d vials a n d distri b uti o n 
of ne w vials of st u d y dr u g.  S ki n testi n g, sali va c ollecti o n a n d bl o o d m ec ha nistic st u dies  are 
sc he d ule d at e nr oll me nt, a n n uall y, a n d at t he 3 6 m o nt h dese nsitizati o n D B P C F C a n d 3 9 -m o nt h  
t olera nce D B P C F C.  S u bjects wit h ne w or si g nifica nt s y m pt o ms wit h d osi n g will ret ur n t o t he 
researc h unit  as s o o n as is reas o na bl y p ossi ble f or re vie w of t he s y m pt o ms a n d li kel y o bser ve d 
d osi n g.   * S u bjects w h ose Dese nsitizati o n D B P C F C, n or mall y sc he d ule d f or 3 6 m o nt hs, has bee n 
deferre d d ue t o t he C O VI D -1 9 safet y meas ures, will  re mai n o n mai nte na nce st u d y dr u g d osi n g 
be y o n d 3 6 m o nt hs u ntil t he ti me t hat t he Dese nsitizati o n D B P C F C is a ble t o be c o m plete d. A 
f oll o w u p visit t o re vie w safet y a n d s u bject diaries w o ul d be perf or me d i n place of t he D B P C F C 
a n d be c o m plete d re m otel y b y t ele p h o ne wit h a d diti o nal st u d y dr u g pr o vi de d direct -t o-patie nt. 
Sa m ple c ollecti o n a n d mec ha nistic st u dies sc he d ule d f or t he 3 6 m o nt h visit w o ul d be deferre d 
u ntil t he ti me of t he Dese nsitizati o n D B P C F C. F ull details of t hese c ha n ges are a vaila ble i n 
A p pe n d i x 6. 
Dese nsitiz ati o n Assess me nt by D B P C F C  
All s u bjects will u n der g o a D B P C F C t o 4 4 4 3  m g of pea n ut pr otei n after 3 6 m o nt hs of treat me nt.  
T he pr oce d ure f or t he D B P C F C is descri be d i n secti o n 6. 6.  All s u bjects will t he n disc o nti n ue 
pea n ut S LI T or place b o t hera p y.  T h ose s u bjects w h o are a ble t o t olerate >  4 4 3 m g of pea n ut 
pr otei n at t he 3 6 m o nt h D B P C F C will be as ke d t o ret ur n f or a D B P C F C at 3 9 m o nt hs , t o t he 
a m o u nt of pea n ut pr otei n pre vi o usl y t olerate d at t he 3 6 m o nt h D B P C F C t o assess f or t olera nce.  
All s u bjects will be u n bli n de d  n o s o o ner t ha n 3 6 m o nt hs ( u nless safet y u n bli n di n g is re q uire d)  at 
t heir c o m pleti o n p oi nt i n t he st u d y.  S u bjects u na ble to t olerate >  4 4 3 m g of pea n ut pr otei n at t he 
3 6 m o nt h D B P C F C will be gi ve n t he o pti o n t o strictl y a v oi d all pea n uts or, if a p pr o priate, 
alter nati ve treat me nt o pti o ns t hat ma y be a vaila ble t o t he m via researc h or F D A a p pr o ve d 
me dicati o ns .  * S u bjects w h ose D ese nsitizati o n D B P C F C w o ul d be sc he d ule d t o fall d uri n g t he 
i m ple me ntati o n of t he C O VI D-1 9 safet y meas ures w o ul d ha ve t heir D B P C F C deferre d a n d a 
f oll o w u p visit perf or me d i n its place. T he s u bject w o ul d re mai n o n mai nte na nce st u d y dr u g 
d osi n g be y o n d 3 6 m o n t hs u ntil t he safet y meas ures are lifte d a n d t he Dese nsitizati o n D B P C F C is 
a ble t o be c o m plete d.  F ull details of t hese c ha n ges are a vaila ble i n A p pe n di x 6.  
T oler a nce Assess me nt by D B P C F C  
After  disc o nti n u i n g st u d y dr u g d osi n g f or 3 m o nt hs, t h ose s u bjects w h o are a ble t o t olerate >  4 4 3 
m g of pea n ut pr otei n at t he 3 6 m o nt h D B P C F C will be as ke d t o ret ur n f or a D B P C F C at 3 9 
m o nt hs t o t he a m o u nt of pea n ut pr otei n pre vi o usl y t olerate d at t he 3 6 m o nt h D B P C F C t o assess 
f or t olera nce.   All s u bjects will be u n bli n de d after t he D B P C F C a n d t he st u d y will c o ncl u de f or 
t hese s u bjects.  S u bjects w h o c o m plete t his D B P C F C wit h o ut s y m pt o ms  at 4 4 4 3 m g of pea n ut 
pr otei n will be c o nsi dere d t olera nt a n d will be i nstr ucte d t o i ntr o d uce pea n ut i nt o t heir diet a d 
libit u m.  S u bjects w h o d o n ot pass t he D B P C F C will be gi ve n t he o pti o n t o ta ke a dail y f o o d 
e q ui vale nt of pea n ut t o mai ntai n t he dese nsitize d state or  t o strictl y a v oi d pea n ut.  * S u bjects 
w h ose T olera nce D B P C F C w o ul d be sc he d ule d t o fall d uri n g t he i m ple me nt ati o n of t he C O VI D -
1 9 safet y meas ures w o ul d ha ve t heir D B P C F C. As f urt her st u d y dr u g a v oi da nce be y o n d t his ti me 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 1  of 5 7  
* See a p pe n di x 6 . 0 
 
p oi nt w o ul d ha ve t he p ote ntial t o i ncrease t he ris k of reacti o n d uri n g t he D B P C F C, t he D B P C F C 
w o ul d n ot be resc he d ule d f or a later date. T he s u b ject will c o m plete t he st u d y at t hat ti me wit h a 
re m ote tele p h o ne e xit visit perf or me d t o re vie w safet y, u n bli n d t he s u bject t o treat me nt 
all ocati o n a n d re vie w st u d y c o m pleti o n i nstr ucti o ns. F ull details of t hese c ha n ges are a vaila ble i n 
A p pe n di x 6.  
6. 6  
D o u bl e  Bli n d Pl a c e b o C o nt r oll e d  F o o d C h all e n g e ( D B P C F C)  
D B P C F Cs will be c o n d ucte d at t he researc h u nit at e ntr y, 3 6  m o nt hs * , a n d at 3 9 m o nt hs *  (f or 
t h ose a ble t o t olerate >  4 4 3 m g pea n ut pr otei n  at t he 3 6 m o nt h *  c halle n ge) .  Pri or t o t he f o o d 
c halle n ge, s u bjects will be as ke d t o restrict t he use of a nti hista mi nes (s h ort acti n g, 7 2 h o urs: l o n g 
acti n g, 7 da ys), beta -a g o nists ( 1 2 h o urs), t he o p h ylli ne ( 1 2 h o urs), a n d cr o m ol y n ( 1 2 h o urs).  T he 
D B P C F C c o nsists of 2 c halle n ges.  T h e or der of t he 2 c halle n ges  will be ra n d o ml y deter mi ne d 
b y  I D S.  T he B ur ks la b will pre pare d oses a n d t he n s u b mit t he m t o t he res pecti ve I D S at U N C-
C H a n d U T S W f or  la beli n g a n d distri b ut i o n.  O ne c halle n ge will c o nsist of gra de d d oses of 
pea n ut fl o ur gi ve n e ver y 1 0 -2 0 mi n utes u p t o a c u m ulati ve d ose of 1 0 0 0 m g  (3  m g, 1 0  m g, 3 0 
m g, 1 0 0 m g, 3 0 0 m g, 5 5 7  m g)  of pea n ut pr otei n d uri n g  t he e ntr y c halle n ge a n d 4 4 4 3  m g  (3 m g , 
1 0  m g, 3 0  m g, 1 0 0  m g, 3 0 0  m g, 1 0 0 0  m g , 3 0 0 0 m g) of pea n ut pr otei n f or t he 3 6  m o nt h *  
dese nsitizati o n D B P C F C  a n d 3 9 m o nt h t olera nce D B P C F C.   T he B ur ks la b will s u p pl y I D S wit h 
la bels f or t he c halle n ge d oses t o reflect t he t otal wei g ht i n oat a n d pea n ut fl o ur ( 6 m g, 2 0 m g, 
6 0 m g, 2 0 0 m g,  6 0 0 m g, a n d 1 1 1 4 m g f or e ntr y c halle n ge a n d 6 m g, 2 0 m g, 6 0 m g, 2 0 0 m g, 6 0 0 m g, 
2 0 0 0 m g, a n d 6 0 0 0 m g f or t he 3 6 a n d 3 9 m o nt h c halle n ges).   T he d osi n g sc he d ule is base d o n 
rece nt P R A C T A L L g ui deli nes[2 5 ].  T he ot her c halle n ge w ill c o nsist of place b o i n t he f or m of 
oat fl o ur a d mi nistere d i n i de ntical gra de d d oses b y wei g ht ( 1 0 0 0 m g of pea n ut pr otei n = 2 0 0 0 m g 
of pea n ut fl o ur b y wei g ht).   T here will be a mi ni m u m 1 0 mi n ute o bser vati o n peri o d b et wee n 
d oses t o m o nit or f or s y m pt o ms.  Pri or t o eac h c halle n ge, t he patie nt will ha ve a p h ysical e xa m 
a n d f ull vital si g ns.  All f o o d c halle n ges will be perf or me d u n der p h ysicia n s u per visi o n.  T he 
c halle n ge will be a d mi nistere d b y a n urse , n urse practiti o ner, or p h ysicia n w h o is bli n de d t o t he 
testi n g material.  T he s u per visi n g i n vesti gat or will als o be bli n de d t o testi n g material.  After  t he 
i nitial c halle n ge, t he s u bject will be o bser ve d f or a mi ni m u m peri o d of 1 h o ur pri or t o starti n g t he 
sec o n d c halle n ge. T he f o o d c halle n ge s ma y be c o n d ucte d o ver t w o se parate da ys .  Reacti o ns will 
be sc ore d usi n g a F o o d C halle n ge S y m pt o m Sc ore s heet.   Fre q ue nt assess me nts wi ll be ma de f or 
s y m pt o ms affecti n g t he s ki n, gastr oi ntesti nal tract, a n d/ or res pirat or y tract.  If t he s u bject 
prese nts wit h eit her o ne maj or or t w o mi n or criteria  ( A p pe n di x 4), t he f o o d c halle n ge will be 
ter mi nate d a n d t he s u bject will be gi ve n a p pr o priate treat me nt.  F o o d c halle n ges ma y be 
ter mi nate d at t he discreti o n of a st u d y p h ysicia n f or a n y safet y st o p.  T he s u bjects w h o are 
s y m pt o matic will be o bser ve d f or a mi ni m u m of 2 h o urs after t he c halle n ges are c o m plete d 
bef ore bei n g disc har ge d fr o m t he researc h u nit. 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 2  of 5 7  
* See a p pe n di x 6 . 0 
 
6. 7  
S ki n P ri c k T est i n g 
Aller g y s ki n pric k testi n g t o pea n ut aller ge n will be perf or me d at e nr oll me nt, o nce yearl y , a n d at 
t he dese nsitizati o n a n d  t olera nce D B P C F Cs (if nee de d).  T he s ki n testi n g will be perf or me d 
usi n g  a Greer pic k a n d sta n dar d pea n ut e xtract 1:2 0 wt/ v ol ( Greer, I nc, Le n oir, N C) wit h a 
p ositi ve hista mi ne c o ntr ol a n d a ne gati ve sali ne c o ntr ol.  Reacti o ns will be rea d after 1 5 mi n utes 
a n d t he w heal will be o utli ne d i n i n k a n d tra nsferre d t o t he per ma ne nt r ec or d usi n g tra ns pare nt 
ta pe.  T he reacti o n size will be calc ulate d as t he mea n w heal dia meter of pea n ut less t he mea n 
w heal dia meter of t he sali ne ne gati ve c o ntr ol.  T he mea n w heal dia meter is defi ne d as t he 
avera ge of t he lar gest dia meter a n d t he c orres p o n di n g mi d p oi nt dia meter.  
6. 8  
S ali v a C oll e cti o n  
Sali va c ollecti o n will be perf or me d at e nr oll me nt, o nce yearl y, a n d at t he  dese nsitizati o n a n d  
t olera nce D B P C F Cs (if nee de d).  If t he s u bject is a ble t o s pit, sali va will be c ollecte d i n a 5 0 ml 
c o nical t u be a n d st ore d o n ice u ntil pr ocessi n g b y t he la b orat or y.  If t he s u bject is u na ble t o s pit, 
sali va ma y be c ollecte d ma n uall y usi n g a 3-5 ml s yri n ge a n d tra nsferre d t o a c ollecti o n de vice, or 
sali va ma y be c ollecte d wit h a s oft-ti p pe d cat heter attac he d t o vac u u m s ucti o n. T he c ollecti o n 
de vice f or t he s ucti o n met h o d s h o ul d be a cl ose d m uc us s peci me n tra p.   A mi ni m u m of 2 ml of 
sali va s h o ul d be c ollecte d.  All sa m ples s h o ul d be st ore d o n ice u ntil pr ocesse d b y t he 
la b orat or y.  Sali va s h o ul d be c ol lecte d pri or t o pea n ut S LI T d osi n g if p ossi ble. 
 
6. 9  
St o ol C oll e cti o n  
St o ol c ollecti o n will be perf or me d at e nr oll me nt, o nce yearl y, a n d at t he dese nsitizati o n a n d 
t olera nce D B P C F Cs (if nee de d).  If t he s u bject is i n dia pers, pare nts will be gi ve n s u p plies a n d 
will be i nstr ucte d o n h o w t o c ollect a st o ol sa m ple fr o m h o me.  F or t oilet trai ne d c hil dre n, 
pare nts will be gi ve n s u p plies a n d i nstr ucti o ns as t o h o w t o c ollect a st o ol sa m ple fr o m h o me.  
6. 1 0  Visit Wi n d o ws  
D osi n g sc he d ule s h o ul d be a d here d t o strictl y.  T w o d a ys bef ore or se ve n da ys after a pla n ne d 
d osi n g visit is a n acce pta ble wi n d o w wit h c o nti n ue d dail y d osi n g of t he c urre nt d ose le vel.  
St u d y visits f or sc he d ule d bl o o d dra ws or D B P C F C s h o ul d ta ke place wit hi n 2 wee ks of t he 
sc he d ule d visit.  T h ose w h o are u na ble t o c o m pl y wit h t he d osi n g sc he d ule ris k re m o val fr o m t he 
st u d y. 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 3  of 5 7  
* See a p pe n di x 6 . 0 
 
6. 1 1  St u d y Bli n di n g  a n d R a n d o mi z ati o n  P r o c e d u r es  
S u bjects w h o fail t he q ualif yi n g e ntr y D B P C F C t o 1 0 0 0 m g of pea n ut pr otei n will be 
ra n d o mize d i n a 1 : 1 rati o usi n g bl oc k ra n d o mizati o n t o recei ve eit her pea n ut S LI T ( n = 2 5 ) or 
place b o ( n = 2 5 ).  S u bjects , st u d y c o or di nat ors, a n d t he pri mar y i n vesti gat or will re mai n bli n de d  
u ntil s u bjects are u n bli n de d after t he  3 6 m o nt h *  or  3 9 m o nt h *  D B P C F C s de pe n di n g o n c halle n ge 
eli gi bilit y. A ll D B P C F C s will als o be ra n d o mize d .  T he data ma na ge me nt gr o u p f or t he st u d y 
will perf or m all ra n d o mizati o n.  
6. 1 1. 1  R e q ui r e m e nt s f o r U n bli n di n g  
If a cli nicall y si g nifica nt e ve nt occ urs  d uri n g t he st u d y , i m me diate me dical atte nti o n will be 
pr o vi de d irres pecti ve of t he treat me nt assi g n me nt.  Bli n di n g will be br o ke n as dee me d necessar y 
f or t he care of t he s u bject.  A n y pre mat ure u n bli n di n g will re q uire a f ull writte n acc o u nt b y t he 
pri mar y i n vesti gat or  of t he e ve nt(s) t hat necessitate d t he u n bli n di n g of t he st u d y dr u g  f or a n 
i n di vi d ual partici pa nt.  T his acc o u nt will be se nt t o t he s p o ns or/lea d i n vesti gat or, I R B, D S M B , 
a n d F D A. 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 4  of 5 7  
* See a p pe n di x 6 . 0 
 
7.  
S A F E T Y M
O N I T O R I N G  
T his secti o n defi nes t he t y pes of a d verse e ve nts t hat s h o ul d be re p orte d a n d o utli nes t he 
pr oce d ures f or a p pr o priatel y c ollecti n g, gra di n g, rec or di n g a n d re p orti n g t he m.  
7. 1  
P r o c e d u r es a n d M o nit o ri n g  
All u ne x pecte d seri o us a d verse e ve nts relate d t o t he e x peri me ntal pr oce d ures will be re p orte d t o 
t he I R B, D S M B, a n d F D A i n a ma n ner c o nsiste nt wit h 2 1 C F R 3 1 2. 3 2.   All ot her a d verse e ve nts 
relate d t o t he e x peri me ntal pr oce d ures will als o be re p orte d t o t he I R B a n d D S M B i n a n 
e x pe dite d ma n ner if t he y are Gra de 3 a n d a b o ve i n se verit y.   Partici pa nt deat hs are re p orta ble 
wit hi n 2 4 h o urs.  T he e x pe dite d re p ort se nt t o ot her or ga nizati o ns ca n be c o pie d t o t he D S M B.  
T he i n vesti gat or will c o nti n ue t o f oll o w or o btai n d oc u me ntati o n of t he res ol uti o n c o urse of s uc h 
a n e ve nt.  A c o p y of t he a n n ual re p ort of a d verse e ve n ts s u b mitte d t o t he I R B will be c o pie d t o 
t he D S M B.  Reacti o ns t o d osi n g of t he st u d y pr o d uct will be rec or de d o n a d osi n g l o g a n d will 
n ot be re p orte d se paratel y as a d verse e ve nts.  A n y reacti o n t hat meets t he criteria f or a seri o us 
a d verse e ve nt will be re p orte d b ot h o n t he d osi n g l o g a n d o n a n a d verse e ve nt case re p ort f or m. 
7. 2  
D efi niti o ns  
7. 2. 1  A d v e rs e E v e nt ( A E)  o r M e di c al E v e nt  
A n a d verse e ve nt is a ne w, u n desira ble me dical e ve nt or occ urre nce or w orse ni n g of a n e xisti n g 
c o n diti o n (i ncl u di n g a n a b n or mal la b ora t or y fi n di n g) i n a s u bject t hat occ urs d uri n g treat me nt 
a n d t hr o u g h o ut t he st u d y, w het her or n ot it is c o nsi dere d t o be st u d y relate d.  A d verse e ve nts or 
me dical e ve nts a n d t o xicities are treat me nt e mer ge nt si g ns a n d s y m pt o ms.   
T his i ncl u des t he f oll o wi n g : 
•  A Es n ot pre vi o usl y o bser ve d i n t he patie nt t hat e mer ge d uri n g t he pr ot oc ol -s pecifie d A E 
re p orti n g peri o d, i ncl u di n g si g ns or s y m pt o ms ass ociate d wit h pea n ut aller g y t hat were 
n ot prese nt pri or t o t he A E re p orti n g peri o d . 
•  C o m plicati o ns t hat occ ur as a res ult of pr ot oc ol -ma n date d i nter ve nti o ns (e. g.,  i n vasi ve 
pr oce d ures s uc h as bi o psies) . 
•  If a p plica ble, A Es t hat occ ur pri or t o assi g n me nt of st u d y treat me nt ass ociate d wit h 
me dicati o n was h o ut, treat me nt r u n -i n, or ot her pr ot oc ol-ma n date d i nter ve nti o n . 
•  Pree xis ti n g me dical c o n diti o ns ( ot her t ha n t he c o n diti o n bei n g st u die d) j u d ge d b y t he 
i n vesti gat or t o ha ve w orse ne d i n se verit y or fre q ue nc y or c ha n ge d i n c haracter d uri n g t he 
pr ot oc ol -s pecifie d A E re p orti n g peri o d. 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 5  of 5 7  
* See a p pe n di x 6 . 0 
 
P ote ntial a d verse reacti o ns see n i n s u bjects tr eate d wit h pea n ut S LI T a n d s u bjects u n der g oi n g 
D B P C F C i ncl u de t he f oll o wi n g: s ki n ma nifestati o ns s uc h as pr urit us, urticaria, or a n gi oe de ma; 
res pirat or y s y m pt o ms s uc h as w heezi n g, c o u g hi n g, nasal c o n gesti o n/r hi n orr hea, c o u g h a n d 
h oarse ness; a n d gastr oi ntes ti nal s y m pt o ms s uc h as v o miti n g, diarr hea, or a b d o mi nal pai n.  
A na p h yla xis is a p ote ntial ris k i n v ol vi n g a n y of t he a b o ve s y m pt o ms pl us h y p ote nsi o n a n d 
circ ulat or y c olla pse.  
7. 2. 2  S e ri o us A d v e rs e E v e nt ( S A E)  
A seri o us a d verse e ve nt is defi ne d as a n y a d verse t hera p y e x perie nce occ urri n g at a n y d ose t hat 
s u g gests a si g nifica nt hazar d, c o ntrai n dicati o n, si de effect, or preca uti o n will be defi ne d as a n 
S A E.  T his i ncl u des, b ut ma y n ot be li mite d t o a n y of t he f oll o wi n g e ve nts: ( T his ter mi n ol o g y is 
fr o m Secti o n B. 2 o n t he F D A Me d Watc h f or m.  F or a c o p y of t he c urre nt Me d Watc h F or m 3 5 0 0, 
see t he list of P D F f or ms o n t he We b at: 
htt p:// w w w.f da. g o v/ o pac o m/ m orec h oices/f daf or ms/c der. ht ml ) 
1.  Deat h: A deat h occ urri n g d uri n g t he st u d y, or w hic h c o mes t o t he atte nti o n of t he 
i n vesti gat or d uri n g t he pr ot oc ol-defi ne d f oll o w -u p after t he c o m pleti o n of t hera p y 
w het her or n ot c o nsi dere d treat me nt relate d, m ust be re p orte d. 
2.  Life -t hreate ni n g: A n y a d verse t hera p y e x perie nce t hat places t he s u bject or s u bjects, i n 
t he vie w of t he i n vesti gat or, at i m me diate ris k of deat h fr o m t he reacti o n as it occ urre d 
(i.e., it d oes n ot i ncl u de a reacti o n t hat, ha d it occ urre d i n a m ore seri o us f or m, mi g ht 
ha ve ca use d deat h).  
3.  I n-patie nt h os pitalizati o ns or pr ol o n gati o n of e xisti n g h os pitalizati o n.  
4.  Persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
5.  C o n ge nital a n o mal y/ birt h defect.  
6.  A n e ve nt t hat re q uire d i nter ve nti o n t o  pre ve nt per ma ne nt i m pair me nt or da ma ge.  
7. 2. 3  U n e x p e ct e d A d v e rs e E v e nt  
A n a d verse e ve nt is c o nsi dere d “ u ne x pecte d” w he n its nat ure (s pecificit y) or se verit y is n ot 
c o nsiste nt wit h a p plica ble pr o d uct i nf or mati o n, s uc h as safet y i nf or mati o n pr o vi de d i n t he 
pr ot oc ol or c o nse nt.  
7. 3  
T o xi cit y G r a di n g  
T he ter ms “se vere” a n d “seri o us” are n ot s y n o n y m o us.  Se verit y refers t o t he i nte nsit y of a n A E 
(as i n mil d, m o derate, or se vere pai n); t he e ve nt itself ma y be of relati vel y mi n or me dical 
si g nifica nce (s uc h as se vere hea dac he).  “ Seri o us” is a re g ulat or y defi niti o n a n d is base d o n 
patie nt or e ve nt o utc o me or acti o n criteria us uall y ass ociate d wit h e ve nts t hat p ose a t hreat t o a 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 6  of 5 7  
* See a p pe n di x 6 . 0 
 
patie nt’s life or vital f u ncti o ns.  Seri o us ness ( n ot se verit y) ser ves as t he g ui de f or defi ni n g 
re gulat or y re p orti n g o bli gati o ns.   
T o xicit y gra des are assi g ne d b y t he st u d y site t o i n dicate t he se verit y of a d verse e x perie nces a n d 
t o xicities usi n g t he N CI-C T C A E versi o n 4 . 0.  T o xicit y gra di n g f or aller gic reacti o ns i ncl u di n g 
a na p h yla xis is m o difie d fr o m t he N CI-C T C A E s yste m t o be m ore a p pr o priate f or t his st u d y 
p o p ulati o n, a n d is dis pla ye d i n A p pe n di x 2.  T he N CI -C T C A E has bee n re vie we d s pecificall y f or 
t his pr ot oc ol a n d is ot her wise a p pr o priate f or t his st u d y p o p ulati o n.  T he p ur p ose of usi n g t he 
N CI -C T C A E s yste m is t o pr o vi de sta n dar d la n g ua ge t o descri be t o xicities a n d t o facilitate 
ta b ulati o n a n d a nal ysis of t he data a n d assess me nt of t he cli nical si g nifica nce of treat me nt-
relate d t o xicities. 
A d verse e ve nts n ot i ncl u de d i n t he C T C A E listi n g s h o ul d be r ec or de d a n d gra de d 1 -5 acc or di n g 
t o t he Ge neral Gra de Defi niti o n pr o vi de d bel o w: 
Gr a de 1  
Mil d  
Tra nsie nt or mil d disc o mf orts ( < 4 8 h o urs), n o or mi ni mal  
me dical i nter ve nti o n/t hera p y re q uire d, h os pitalizati o n n ot 
necessar y ( n o n -prescri pti o n or si n gle -use pre scri pti o n 
t hera p y ma y be e m pl o ye d t o relie ve s y m pt o ms, e. g., as piri n 
f or si m ple hea dac he, aceta mi n o p he n f or p ost-s ur gical pai n). 
Gr a de 2  
M o der ate  
Mil d t o m o derate li mitati o n i n acti vit y s o me assista nce ma y 
be nee de d; n o or mi ni mal i nter ve nti o n/t hera p y re q uire d, 
h os pitalizati o n p ossi ble.  
Gr a de 3  
Se vere  
Mar ke d li mitati o n i n acti vit y, s o me assista nce us uall y 
re q uire d; me dical i nter ve nti o n/t hera p y re q uire d, 
h os pitalizati o n p ossi ble.  
Gr a de 4  
Life -
t hre ate ni n g 
E xtre me li mitati o n i n acti v it y, si g nifica nt assista nce 
re q uire d; si g nifica nt me dical/t hera p y i nter ve nti o n re q uire d, 
h os pitalizati o n or h os pice care pr o ba ble.  
Gr a de 5  
De at h  
Deat h.  
 
7. 3. 1  R el ati o ns hi p t o P r o c e d u r e D efi niti o ns  
Ass oci ate d:  T here is a reas o na ble p ossi bilit y t hat t he A E ma y ha ve bee n ca use d b y t he test 
pr o d uct a n d/ or pr oce d ure.  T his defi niti o n a p plies t o t h ose a d verse e ve nts t hat are c o nsi dere d 
defi nitel y, pr o ba bl y or p ossi bl y relate d t o t he pr oce d ure.  
1.  Defi nitel y rel ate d:  A n  A E t hat f oll o ws a te m p oral se q ue nce fr o m a d mi nistrati o n of t he 
test pr o d uct a n d/ or pr oce d ure; f oll o ws a k n o w n res p o nse patter n t o t he test article a n d/ or 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 7  of 5 7  
* See a p pe n di x 6 . 0 
 
pr oce d ure; a n d, w he n a p pr o priate t o t he pr ot oc ol, is c o nfir me d b y i m pr o ve me nt after 
st o p pi n g t he test pr o d uct ( p ositi ve rec halle n ge: a n d b y rea p peara nce of t he reacti o n after 
re peat e x p os ure [ p ositi ve rec halle n ge]); a n d ca n n ot be reas o na bl y e x plai ne d b y k n o w n 
c haracteristics of t he s u bject’s cli nical state or b y ot her t hera pies.  
2.  Pr o b a bl y rel ate d:  A n A E t h at f oll o ws a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he test pr o d uct a n d/ or pr oce d ure; f oll o ws a k n o w n res p o nse patter n t o 
t he test pr o d uct a n d/ or pr oce d ure, is c o nfir me d b y i m pr o ve me nt after rec halle n ge; a n d 
ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n c haracteristics of t he partici pa nt’s cli nical 
state or ot her t hera pies. 
3.  P ossi bl y rel ate d:  A n A E t hat f oll o ws a reas o na ble te m p oral; se q ue nce fr o m 
a d mi nistrati o n of t he test pr o d uct a n d/ or pr oce d ure a n d f oll o ws a k n o w n res p o nse patter n 
t o t he test pr o d uct a n d/ or pr oce d ure, b ut c o ul d ha ve bee n pr o d uce d b y t he partici pa nt’s 
cli nical state or b y ot her t hera pies.  
 
N ot ass oci ate d:  A n A E f or w hic h s ufficie nt i nf or mati o n e xists t o i n dicate t hat t he eti ol o g y is n ot 
relate d t o t he test pr o d uct a n d/ or t hera py.  
1.  U nrel ate d : A n A E t hat d oes n ot f oll o w a reas o na ble te m p oral se q ue nce after 
a d mi nistrati o n of t he test pr o d uct a n d/ or pr oce d ure a n d m ost li kel y is e x plai ne d b y t he 
partici pa nt’s cli nical disease state or b y ot her t hera pies.  I n a d diti o n, a ne gati ve 
rec halle n ge t o t he test article a n d/ or pr oce d ure w o ul d s u p p ort a n u nrelate d relati o ns hi p. 
F or a d diti o nal i nf or mati o n a n d a pri nta ble versi o n of t he N CI -C T C A E ma n ual, c o ns ult t he N CI -
C T C A E we bsite, htt p:/ /cte p.ca ncer. g o v/re p orti n g/ctc. ht ml. 
7. 4  
A d v e rs e E v e nts C oll e cti o n P r o c e d u r es  
T he Pri nci pal I n vesti gat or a n d C o -I n vesti gat or are res p o nsi ble f or c ollecti n g a n d rec or di n g all 
cli nical data.  As t hese res ults are c ollecte d, all t o xicities a n d a d verse e ve nts will  be i de ntifie d 
a n d re p orte d t o t he pri nci pal i n vesti gat or.  A d verse e ve nts will be re p orte d as descri be d a b o ve.  
T he Pri nci pal I n vesti gat or will deter mi ne relati o ns hi p of t he e ve nt t o t he st u d y i nter ve nti o n a n d 
deci de c o urse of acti o n f or t he st u d y partici pa nt.  
7. 4. 1  R e c o r di n g a n d R e p o rti n g P r o c e d u r es  
M o nit ori n g of t he pri mar y site ( U N C -C H) will be c o n d ucte d via I nter nal A u dits wit h a Researc h 
Safet y A d v ocate o n t he D S M B.  T he pri mar y site ( U N C -C H) will be res p o nsi ble f or m o nit ori n g 
of t he sec o n dar y site ( U T S W).  Details of t his m o nit ori n g are i n c o nti n ui n g de vel o p me nt.  
M o nit ori n g will occ ur se mi -a n n uall y a n d y earl y re p orts will be ma de t o t he pr o per I nstit uti o nal 
C o m mittee s, as re q uire d.  All a d verse e ve nts will be ke pt i n a file b y n u merical i de ntifier. 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 8  of 5 7  
* See a p pe n di x 6 . 0 
 
7. 4. 2  S A E R e c o r di n g a n d R e p o rti n g  
Seri o us a d verse e ve nts will be rec or de d o n t he a p pr o priate case re p ort f or ms.  
7. 5  
S e ri o us A d v e rs e E v e nt N otifi c ati o n  
T he researc h staff will n otif y  t he s p o ns or/ pri nci pal i n vesti gat or of a n y seri o us a d verse e ve nt 
i m me diatel y u p o n lear ni n g a b o ut t he e ve nt. 
7. 5. 1  N otif yi n g t h e F D A, I R B, a n d D S M B  
T he s p o ns or will pr o vi de t he D S M B  wit h listi n gs of all S A Es o n a n o n g oi n g basis.  F urt her m ore, 
t he s p o ns or will i nfor m t he F D A, I R B, a n d D S M B of e x pe dite d re p orts of S A Es.  
7. 5. 2  R e p o rti n g C rit e ri a  
T he i n vesti gat or will e ns ure t he ti mel y disse mi nati o n of all A E i nf or mati o n, i ncl u di n g e x pe dite d 
re p orts, t o t he I R B i n acc or da nce wit h a p plica ble l ocal re g ulati o ns a n d g ui deli nes. 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 3 9  of 5 7  
* See a p pe n di x 6 . 0 
 
8.  
M
E C H A N I S T I C A S S A Y S  
F ull c o m ple me ntar y st u dies will be perf or me d o n sa m ples fr o m t he U N C -C H site t o meas ure 
cell ular a n d h u m oral i m m u ne res p o nses at baseli ne a n d l o n git u di nall y.   T hese assa ys ha ve bee n 
selecte d base d o n h y p ot hesize d mec ha nis ms of cli nical t olera nce i n d ucti o n.  Mec ha nistic st u dies 
o n sa m ples fr o m t he U T S W site will be li mite d t o s ki n pric k testi n g, bl o o d i m m u n o gl o b uli ns, 
a n d sali var y i m m u n o gl o b uli ns.  T he bl o o d a n d sali var y st u dies will be s hi p pe d t o U N C-C H a n d 
pr ocesse d b y t he B ur ks la b orat or y.  
Earl y data de m o nstrates t hat dese nsitizati o n wit h pea n ut S LI T alters b ot h h u m oral a n d cell ular 
para meters  [1 0 ].  We a ntici pate t hat pea n ut S LI T will i n d uce cli nical dese nsitizati o n a n d 
t olera nce b y eit her ( 1) a c o n versi o n fr o m a TH 2 t o T H 1 i m m u ne res p o nse or ( 2) t he i n d ucti o n of 
T R e gs  or ( 3) a c o m bi nati o n of b ot h.  S u bjects will be f oll o we d f or c ha n ges i n i m m u n ol o gic 
para meters fr o m baseli ne a n d a n n uall y  f or t he d urati o n of t he st u d y.  A fi nal bl o o d dra w will be 
perf or me d at t he ti me of t h e t olera nce D B P C F C after disc o nti n ui n g pea n ut S LI T or place b o 
t hera p y f or 3 m o nt hs.  I m m u n ol o gic assa ys will f oc us o n pea n ut  s pecific para meters i ncl u di n g: 
1) bas o p hil acti vati o n a n d s ki n pric k testi n g; 2) h u m oral st u dies - s pecific I g E, I g G, I g G 4, a n d 
I g A i n bl o o d a n d sali va; a n d 3) cell ular st u dies –  T re g acti vati o n a n d T cell-sti m ulate d c yt o ki ne 
pr o d ucti o n.   
Briefl y, P B M C’s will be is olate d fr o m bl o o d dra w n at yearl y ti me p oi nts a n d c ult ure d wit h cr u de 
pea n ut e xtract ( C P E)  [2 6 ], teta n us t o xi n, a n d C o n A t o assess cell ular pr oliferati o n res p o nses.  A 
c o ntr ol pr oliferati o n assa y usi n g n o nsti m ulate d cells will al s o be perf or me d.  I n a d diti o n, c ult ures 
will be set u p t o assess c yt o ki ne pr o d ucti o n b y P B M C’s after sti m ulati o n wit h C P E, teta n us 
t o xi n, C o n A a n d c o ntr ol.  C ult ure s u per nata nts will be a nal yze d yearl y  f or t he le vels of t he 
f oll o wi n g c yt o ki nes: I F N-g, I L-4 , I L-5, I L -1 0, I L -1 3, T G F -b  a n d T N F-a .  Usi n g fl o w c yt o metr y, 
we will deter mi ne t he prese nce of T R e gs  i n t he bl o o d sa m ple eac h year .  Bas o p hil st u dies will be 
perf or me d a n n uall y t o e xa mi ne acti vati o n mar kers.  Sali var y a n d bl o o d  pea n ut s pecific a nti b o d y 
le vels, i ncl u di n g I g E, I g G, I g G 4, a n d I g A will be assesse d a n n uall y. 
8. 1  
Bl o o d  s p e cifi c I g E, I g G, I g G 4, a n d I g A  
Aller ge n i m m u n ot hera p y has bee n s h o w n t o i n d uce a nti ge n -s pecific h u m oral res p o nses.  T he 
bala nce of is ot y pic res p o nse ma y pla y a r ole i n aller ge n se nsiti vit y (e. g., a n i ncrease of I g G/ 
I g E).  Bl o o d will be c ollecte d  at baseli ne, a n n uall y, a n d at t he t olerance D B P C F C (if nee de d) . 
Pea n ut -s pecific I g E, I g G, I g G 4, a n d I g A le vels will be meas ure d usi n g t he P ha dia I m m u n o C A P 
1 0 0 i nstr u me nt ( U p psala, S we de n) acc or di n g t o t he ma n ufact urer’s i nstr ucti o ns.   


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 0  of 5 7  
* See a p pe n di x 6 . 0 
 
8. 2  
S ali v a r y s p e cifi c I g G , I gA , I g E, a n d S e c r et o r y I g A 
We will u tilize E LI S A assa ys t o e val uate h ost a nti b o d y res p o nses t o Ara h 2 a n d w h ole pea n ut 
e xtract i n sali va sa m ples c ollecte d at t he desi g nate d ti me p oi nts f or bl o o d  c ollecti o n ( baseli ne, 
a n n uall y, a n d at t he t olera nce D B P C F C ).  Ara h 2 is t he maj or aller ge n f o u n d i n pea n ut.  Ot hers 
ha ve use d sali va t o meas ure aller ge n -s pecific S-I g A res p o nses i n aller gic c hil dre n as well as 
a nti ge n-s pecific S-I g A i n d uce d i n res p o nse t o oral i m m u nizati o n wit h K L H ( ke y h ole li m pet 
he m oc ya ni n) or a c h olera vacci ne.  Sali va sa m ples will be teste d at a n i nitial dil uti o n of 1: 4 
f oll o we d b y serial 2-f ol d dil uti o ns u ntil we are a ble t o deter mi ne a n e n d p oi nt titer.  A n e n d p oi nt 
titer will be calc ulate d as t he last sa m ple dil uti o n t hat has a n E LI S A rea di ng (fl u oresce nt relati ve 
li g ht u nits) 3-f ol d great t ha n t he R L U of t he sa me sa m ple teste d a gai nst E LI S A plates t hat are 
n ot c oate d wit h a nti ge n.  O nce t he a nti ge n -s pecific e n d p oi nt titers are calc ulate d, we will 
q ua ntitate t he t otal c o nce ntrati o n ( mc g / ml) of I g G, I gA , I gE , secret or y-I g A i n eac h sali va sa m ple 
a n d re p ort t he a nti ge n -s pecific res p o nses as a “titer/mc g  of t otal a nti b o d y”.  
8. 3  
C yt o ki n e m e as u r e m e nts  
Is olate d P B M Cs  fr o m baseli ne a n d 1 2, 2 4, 3 6, a n d 3 9 m o nt h ti me  p oi nts  will be  c ult ure d i n 
R P MI 1 6 4 0 c o ntai ni n g 1 0 % fetal b o vi ne ser u m, 1 % pe nicilli n/stre pt o m yci n, a n d 1 % gl uta mi ne.  
Cells will be c ult ure d i n 2 4 well plates ( 4 x 1 0 6/ well/ ml) i n t he prese nce or a bse nce of C P E (2 0 0  
mc g / ml), teta n us t o xi n ( 5 mc g / ml), or C o n A (5  mc g / ml).  S u per nata nts will be c ollecte d after 7 2 
hrs of c ult ure a n d ali q u ots will be st ore d at – 8 0 °C u ntil a nal yze d.  I F N -g, I L-4, I L-5, I L -1 3, I L -
1 0, T G F -b , a n d T N F-a  le vels will be deter mi ne d eit her b y E LI S A acc or di n g t o t he 
ma n ufact urer’s i nstr ucti o ns  ( R & D s yste ms, Mi n nea p olis) or b y a C yt o ki ne Bea d Arra y ( B D).  
T he sti m ulate d cells will be c ollecte d t o is olate R N A w hic h will be use d t o meas ure G A T A-3, T -
bet, F o x p 3, a n d TH 2 c yt o ki nes b y q P C R.  
8. 4  
T R e g  ass a y  
Is olate d P B M Cs fr o m baseli ne a n d 1 2, 2 4, 3 6, a n d 3 9  m o nt h  ti me p oi nts will be c ult ure d wit h 
C P E ( 2 0 0 mc g/ ml) or me dia al o ne a n d i nc u bate d f or 7 da ys.  Cells will be s urface stai ne d f or 
C D 4 a n d C D 2 5, t he n i ntracell ularl y stai ne d f or F o x P 3.  T he prese nce of T Re gs  will be assesse d b y 
fl o w c yt o metr y ( C D 2 5 +/ C D 4 +/ F o x p3 +).  
8. 5  
B as o p hil a cti v ati o n ass a y  
W h ole bl o o d fr o m baseli ne a n d 1 2, 2 4, 3 6, a n d 3 9  m o nt h ti me p oi nts will be di vi de d a n d 
sti m ulate d i n t he prese nce of I L-3 wit h se veral dil uti o ns of pea n ut a nti ge n ( 1 0 0 mc g/ ml, 1 0 -1 
mc g/ ml, 1 0 -2 mc g/ ml, 1 0 -3 mc g/ ml), a nti -I g E ( 1 mc g/ ml), a n d me dia al o ne.  After 3 0 mi n utes 
i nc u bati o n, R B Cs will be l yse d a n d le u k oc ytes will be fi xe d a n d st ore d fr oze n f or batc h m A b 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 1  of 5 7  
* See a p pe n di x 6 . 0 
 
stai ni n g a n d fl o w c yt o metric a nal ysis of acti vati o n mar kers.  Bas o p hils will be i de ntifie d as 
C D 1 2 3 +  C D 2 0 3c +  li n- ( CD 3, C D 1 4, C D 1 9, C D 4 1) e ve nts a n d acti vati o n will be assesse d b y 
C D 2 0 3c ( E N P P 3) a n d C D 6 3 ( L A M P -3), w hic h are mar kers f or piece meal a n d classical 
de gra n ulati o n, res pecti vel y.  
8. 6  
St o ol  Ass a y   
St o ol ma y be use d f or micr o bi o me st u dies t o i de ntif y i n di vi d ual strai ns of bacteria f o u n d i n t he 
st o ol.  T hese st u dies c o ul d all o w t he researc hers t o ma ke ass ociati o ns of g ut fl ora t o cli nical 
dese nsitizati o n a n d t olera nce o utc o mes.   A d diti o nall y, st o ol e xtracts ma y be a nal yze d f or I g A, 
I g A 2, secret or y-I g A, or ot her i m m u n o gl o b uli ns.   T hese st u dies c o ul d all o w t he researc hers t o 
i de ntif y c ha n ges d uri n g t he c o urse of t he st u d y t o cli nical o utc o mes, w hic h are n ot p ossi ble fr o m 
peri p heral bl o o d sa m ples . 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 2  of 5 7  
* See a p pe n di x 6 . 0 
 
9.  
S T A T I S T I C A L C O N S I D E R A T I O N S  
9. 1  
St u d y E n d p oi nt Ass ess m e nt  
9. 1. 1  P ri m a r y E n d p oi nt  
T he pri mar y e n d p oi nt is defi ne d i n Secti o n 3. 1. 1 .  Data will be a nal yze d i n a n i nte nti o n -t o-treat 
a p pr oac h.  L o gistic re gressi o n  will be utilize d t o c o m pare t he D B P C F C c halle n ge sc ores  of 
s u bjects o n pea n ut S LI T after 3 6 m o nt hs *  vers us t h e c halle n ge sc ores of s u bjects  o n place b o 
after 3 6 m o nt hs * .  Details of t his a nal ysis are descri be d i n 2 0 1 2 P R A C T A L L c o nse ns us re p ort 
o n sta n dar dizi n g oral f o o d c halle n ges [2 5 ].  I n s h ort, c halle n ge res ults will be sc ore d base d o n 
t he # of d ose wit hi n t he c halle n ge s uccessf ull y i n geste d.  A n e xtre me val ue hazar d f u ncti o n will 
be calc ulate d a n d l o gistic re gressi o n use d t o create a discrete ti me s ur vi val a nal ysis.  
Sa m ple size was calc ulate d f or 9 0 % p o wer of detecti n g a p -val ue of 0. 0 5 c o nsi deri n g 1 : 1 
treat me nt: place b o ra n d o mizati o n a n d esti mati n g an  8 0 % pass rate f or t h ose ra n d o mize d t o pea n ut 
S LI T  vers us a 2 0 % pass rate f or t h ose ra n d o mize d t o place b o .  A dj usti n g f or a n esti mate d 2 0 % 
dr o p o ut rat e res ults i n a mi ni m u m re q uire d sa m ple size of 5 0 s u bjects.  
9. 1. 2  S e c o n d a r y E n d p oi nts  
T he sec o n dar y e n d p oi nts are defi ne d i n Secti o n 3. 1. 2.   C o m paris o n of t he c halle n ge sc ores of 
s u bjects o n pea n ut S LI T vers us o n place b o passi n g t he t olera nce D B P C F C 3  m o nt hs after 
disc o nti n ui n g  treat me nt will be perf or me d usi n g l o gistic re gressi o n i n a si milar fas hi o n as t he 
pri mar y e n d p oi nt .  C o m paris o n of  s ki n pric k testi n g a n d mec ha nistic data (i m m u n o gl o b uli ns, 
bas o p hil reacti vit y, c yt o ki nes, a n d T R e gs ) bet wee n t h ose o n pea n ut S LI T vers us t h ose o n place b o 
will be perf or me d usi n g a t w o-sa m ple t-test ( S A S 9.3 , S A S, C ha pel Hill, N C) wit h a p-val ue < 
0. 0 5 c o nsi dere d si g n ifica nt.  
9. 2  
S u bj e ct a n d D e m o g r a p hi c D at a  
9. 2. 1  B as eli n e C h a r a ct e risti cs a n d D e m o g r a p hi cs  
S u m mar y descri pti ve statistics f or baseli ne a n d de m o gra p hic c haracteristics will be pr o vi de d f or 
all e nr olle d partici pa nts.  De m o gra p hic data will i ncl u de a ge, race, se x, b o d y  wei g ht, a n d hei g ht; 
t hese data will be prese nte d i n t he f oll o wi n g ma n ner: 
•  C o nti n u o us data (i.e., a ge, b o d y wei g ht, a n d hei g ht) will be s u m marize d descri pti vel y b y 
mea n, sta n dar d de viati o n, me dia n, a n d ra n ge.   
•  Cate g orical data (i.e., se x a n d race) will be  prese nte d as e n u merati o ns a n d perce nta ges.   
Statistical prese ntati o n f or baseli ne a n d de m o gra p hic c haracteristics ma y be f urt her s u m marize d 
b y treat me nt gr o u p, baseli ne pea n ut -s pecific I g E, a n d q ualif yi n g e ntr y D B P C F C.  Statistical 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 3  of 5 7  
* See a p pe n di x 6 . 0 
 
c o m paris o n of t he t hes e gr o u ps will be perf or me d b y Fis her’s e xact test ( S A S 9. 3 , S A S, C ha pel 
Hill, N C)  
9. 2. 2  St u d y C o m pl eti o n  
T he perce nt a ge of partici pa nts w h o c o m plete t he st u d y, l osses t o f oll o w -u p, ti mes t o l ost t o 
f oll o w-u p, a n d reas o ns f or disc o nti n uati o n (e. g., a d verse e ve nts) will be prese nte d.  Statistical 
prese ntati o n of st u d y c o m pleti o n will be f urt her prese nte d via a nal ysis of t he sec o n dar y 
e n d p oi nts s u m marize d.  
9. 3  
I nt e ri m A n al ys es t o E ns u r e P ati e nt S af et y  
All e x pe dite d a d verse e ve nt re p orts will be re vie we d b y t he D S M B i n its c o n ve ne d meeti n gs.  
T he a n n ual s u m mar y of all a d verse e ve nts a n d a n y a u dit re p orts will be re vie we d a n n uall y b y t he 
D S M B . 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 4  of 5 7  
* See a p pe n di x 6 . 0 
 
1 0.  
I D E N T I F I C A T I O N A N D A C C E S S T O S O U R C E D A T A  
1 0. 1  D at a M a n a g e m e nt  
All rec or ds ge nerate d d uri n g t he visits will be st ore d b ot h i n a n electr o nic data base t hr o u g h t he 
data ma na ge me nt c o m pa n y a n d t he i n di vi d ual s u bject’s researc h st u d y bi n der.  S pecifics o n t he 
mec ha nis m of data ma na ge me nt a n d m o nit ori n g of t he sec o n dar y site’s ( U T S W) data are i n 
c o nti n ui n g de vel o p me nt.  T he s u bject’s i nf or mati o n will be  accessi ble o nl y t o t he i n vesti gat or or 
his desi g nate d c ollea g ues b y i n di vi d ual pass w or d or direct vie wi n g of t he researc h rec or d . 
1 0. 2  A c c ess t o D at a  
T he s u bject’s i nf or mati o n is accessi ble o nl y t o t he i n vesti gat or or his desi g nate d c ollea g ues b y 
i n di vi d ual pass w or d or direct vie wi n g of t he researc h rec or d.  T he researc h rec or ds will be ke pt 
i n a l oc ke d cl oset i n t he i n vesti gat or’s office s uite.  T he i n vesti gat or is re q uire d b y la w 
( 2 1 C F R 3 1 2. 6 2) t o kee p acc urate case rec or ds u ntil t he y o u n gest s u bject reac hes 2 1 years of a ge 
a n d or f or 6 years after t he i n vesti gati o n is disc o nti n ue d ( w hic he ver is l o n ger) a n d rec or d 
o bser vati o ns t o ass ure t he safe c o n d uct of t he st u d y . 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 5  of 5 7  
* See a p pe n di x 6 . 0 
 
1 1.  
Q U A L I T Y C O N T R O L A N D Q U A L I T Y A S S U R A N C E  
T he s p o ns or/i n vesti gat or is re q uire d t o kee p acc urate rec or ds t o e ns ure t hat t he c o n d uct of t he 
st u d y is f ull y d oc u me nte d.   
T he s p o ns or/i n vesti gat or is res p o nsi ble f or re g ularl y re vie wi n g t he c o n d uct of t he trial, f or 
verif yi n g a d here nce t o t he pr ot oc ol, a n d f or c o nfir mi n g t he c o m plete ness, c o nsiste nc y, a n d 
acc urac y of all d oc u me nte d data.   S pecific o n t he m o nit ori n g of t he sec o n dar y site ( U T S W) are 
i n c o nti n ui n g de vel o p me nt. 
1 1. 1  D at a H a n dli n g  
T he i n vesti gat or is re q uire d t o e ns ure t hat all C R Fs are le gi bl y c o m plete d f or e ver y partici pa nt 
e ntere d i n t he trial.   
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 6  of 5 7  
* See a p pe n di x 6 . 0 
 
1 2.  
E T H I C A L C O N S I D E R A T I O N S A N D C O M P L I A N C E W I T H G O O D 
C L I N I C A L P R A C T I C E  
1 2. 1  St at e m e nt of C o m pli a n c e  
T his st u d y will be c o n d ucte d usi n g g o o d cli nical practice ( G C P), as deli neate d i n G ui d a nce f or 
I n d ustry: E 6 G o od Cli nic al Pr actice C o ns oli d ate d G ui d a nce , a n d acc or di n g t o t he criteria 
s pecifie d i n t his st u d y pr ot oc ol.  Bef ore st u d y i nitiati o n, t he pr ot oc ol a n d t he i nf or me d c o nse nt 
d oc u me nts will be re vie we d a n d a p pr o ve d b y a n a p pr o priate E C or I R B.  A n y a me n d me nts t o t he 
pr ot oc ol or t o t he c o nse nt materials m ust als o be a p pr o ve d bef ore t he y are i m ple me nte d.  
1 2. 2  I nf o r m e d C o ns e nt a n d Ass e nt  
T he i nf or me d c o nse nt f or m is a mea ns of pr o vi di n g i nf or mati o n a b o ut t he st u d y t o a pr os pecti ve 
partici pa nt’s pare nt/ g uar dia n a n d all o ws f or a n i nf or me d decisi o n a b o ut partici pati o n i n t he 
st u d y.  Si nce all s u bjects will be < 1 8 years ol d, pare nts/le gal g uar dia ns will be as ke d t o rea d, 
si g n, a n d date a c o nse nt f or m bef ore e nteri n g t he st u d y, ta ki n g st u d y dr u g, or u n der g oi n g a n y 
st u d y-s pecific pr oce d ures.  C hil dre n will si g n asse nt as a p pr o priate.  C o nse nt materials f or 
s u bjects or pare nts/ g uar dia ns w h o d o n ot s pea k or rea d E n glis h will be tra nslate d i nt o t he 
a p pr o priate la n g ua ge.  T he i nf or me d c o nse nt f or m will be re vise d w he ne ver t he pr ot oc ol is 
a me n de d wit h a st u d y desi g n c ha n ge.  A c o p y of t he i nf or me d c o nse nt will be gi ve n t o a 
pr os pecti ve pare nt/ g uar dia n f or re vie w.  A st u d y  p h ysicia n  or n urse c o or di nat or , i n t he prese nce 
of a wit ness, will re vie w t he c o nse nt a n d a ns wer q uesti o ns.  T he  pr os pecti ve s u bject or 
pare nt/ g uar dia n will be t ol d t hat bei n g i n t he st u d y is v ol u ntar y a n d t hat he or s he ma y wit h dra w 
his/ her c hil d fr o m t he st u d y at a n y ti me, f or a n y reas o n . 
1 2. 3  P ri v a c y a n d C o nfi d e nti alit y  
A partici pa nt’s pri vac y a n d c o nfi de ntialit y will be res pecte d t hr o u g h o ut t he st u d y.  Eac h 
partici pa nt will be assi g ne d a se q ue ntial i de ntificati o n n u m ber a n d t hese n u m bers rat her t ha n 
na mes will be use d t o c ollect, st ore, a n d re p ort partici pa nt i nf or mati o n . 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 7  of 5 7  
* See a p pe n di x 6 . 0 
 
1 3.  
R E S O U R C E S H A R I N G  
S u bject i nf or mati o n will o nl y be s hare d usi n g t he u ni q ue s u bject i de ntificati o n n u m ber.  All 
ot her i de ntifiers of t he s u bject will be re m o ve d pri or t o t he release of t he i nf or mati o n.  If t he 
res ults of t he trial are p u blis he d, t he partici pa nt’s i de ntit y will re main c o nfi de ntial.  St u d y 
rec or ds will be retai ne d u ntil t he s u bject reac hes a ge 2 1.  At t hat p oi nt, a n y data n ot i n t he 
me dical rec or d will be destr o ye d.   
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 8  of 5 7  
* See a p pe n di x 6 . 0 
 
Fi g ure 1 . St u d y Desi g n O ver vie w 
 
 
 
 
 
 
                                                                     
 
 
 
 
 
 
 
 
D B P C F C 
4 4 4 3 m g  
Scree ni n g 
Visit  
Visit -1  
R a n d o mizati o n 
1: 1  
Pea n ut       
n = 2 5  
Place b o 
n = 2 5  
 St u dies : i m m u ne 
st u dies +/- s ki n tests 
 
Assess t olera nce 3 
m o nt hs after 
disc o nti n ui n g 
t hera p y ( 1o o utc o m e)  
Assess 
dese nsitizati o n after 
3 6 m o nt hs of 
t hera p y ( 2o o utc o m e)  
6 m o  
1 2 m o  
1 8 m o  
2 4 m o  
3 0 m o  
* 3 6 m o  
* 3 9 m o  
D B P C F C 
4 4 4 3 m g  
D B P C F C 
1 0 0 0 m g  
* See A p pe n di x 6 re gar di n g c ha n ges i n st u d y visit 
ti me p oi nts d ue t o t he C O VI D -1 9 safet y meas ures  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 4 9  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 1. Sc he d ule of E ve nts  
 
Scr e e ni n g  
Visit  
B as eli n e  
Visit  
I niti al 
D osi n g  
D os e Esc al ati o n  
* D es e nsitiz ati o n 
D B P C F C  
* T ol er a nc e 
D B P C F C  
Visit  #  
-1  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
M o nt h  
-1  
0  
0  
1  
2  
3  
4  
6  
1 2  
1 8  
2 4  
3 0  
3 6  
3 9  
I nf or m e d C o ns e nt  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
X  
R evi e w I ncl usi o n/ Excl usi o n 
Crit eri a  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
R a n d o miz ati o n ( 1 : 1) 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hic I nf or m ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al/ S ur gic al Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Di et a n d All er gy Ass ess m e nt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mit a nt M e dic ati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vit al Si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o m pr e h e nsiv e P hysic al 
Ex a m  
X  
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
Bri ef P h ysic al Ex a m  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
S ki n Pric k T est  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
X  
Bl o o d dr a w f or M ec h a nistic 
St u di es  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
X  
St o ol C oll ecti o n  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
S ali v a c oll ecti o n  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
X  
D B P C F C  
 
X  
 
 
 
 
 
 
 
 
 
 
X  
X  
O bs erv e d SLI T D osi n g  
 
 
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
Dis p e ns e St u d y M e dic ati o n  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Ass ess C o m pli a nc e  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
R ec or d A Es  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
* See A p pe n di x 6 re gar di n g c ha n ges i n st u d y visit ti me p oi nts d ue t o t he C O VI D -1 9 safet y meas ures  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 0  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 2. E v al u ati o n of Ast h m a  
T he e val uati o n of ast h ma se verit y will be assesse d usi n g t he N H L BI classificati o n as descri be d i n t he ta ble bel o w.  
Cl assific ati o n  
S y m pt o ms  
Ni g htti me 
a w a ke ni n gs  
L u n g F u ncti o n  
I nterfere nce wit h 
n or m al acti vit y  
S h ort acti n g bet a -a g o nist 
use  
I nter mitte nt 
( Ste p 1) 
• 
<  2 da ys per wee k  
<  2 x / m o nt h  
•  
N or mal F E V 1 bet wee n 
e xacer bati o ns  
•  
F E V 1> 8 0 % pre dicte d  
•  
F E V 1/ F V C n or mal * 
•  
N o ne  
•  
< 2 x / m o nt h  
Mil d Persiste nt  
( Ste p 2) 
• 
> 2 da ys per wee k b ut 
n ot dail y  
 
3 -4 x / m o nt h  
•  
F E V 1 >  8 0 % pre dicte d  
•  
F E V 1/ F V C n or mal * 
•  
Mi n or 
li mitati o n 
•  
3 -4 x / m o nt h  
M o derate Persiste nt  
( Ste p 3 or 4) 
• 
Dail y  
> 1 x / wee k b ut 
n ot ni g htl y  
•  
F E V 1 > 6 0 % b ut < 8 0 % 
pre dicte d  
•  
F E V 1/ F V C re d uce d 
5 % *  
•  
S o me li mitati o n  
•  
> 1 x / wee k b ut n ot 
ni g htl y  
Se vere Persiste nt  
( Ste p 5 or 6) 
• 
T hr o u g h o ut t he da y  
Ofte n 7 x / wee k 
•  
F E V 1< 6 0 % pre dicte d  
•  
F E V 1/ F V C re d uce d 
> 5 % *  
•  
E xtre mel y 
li mite d 
•  
Ofte n 7 x / wee k  
* N or mal F E V 1/ F V C: 8 -1 9 yr = 8 5 %; 2 0 -3 9 yrs = 8 0 %


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 1  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 3 . Aller gic Re acti o n a n d T o xicit y Gr a di n g 
C urre nt N CI -C T C A E gra di n g s yste m f or aller gic reacti o ns.  
Gra de 1 - Mil d  
Gra de 2 - M o derate  Gra de 3 –  Se vere  
Gra de 4 –  Life -
t hreate ni n g  
Gra de 5 - 
Deat h  
Tra nsie nt fl us hi n g 
or ras h,  
dr u g fe ver < 3 8 
de grees C ( < 1 0 0. 4 
de grees F); 
i nter ve nti o n n ot 
i n dicate d  
I nter ve nti o n or 
i nf usi o n  
i nterr u pti o n 
i n dicate d;  
res p o n ds pr o m ptl y 
t o  
s y m pt o matic 
treat me nt (e. g., 
a nti hista mi nes, 
N S AI D S, 
narc otics); 
pr o p h ylactic 
me dicati o ns 
i n dicate d f or < = 2 4 
h rs  
Pr ol o n ge d (e. g., n ot 
ra pi dl y  
res p o nsi ve t o 
s y m pt o matic  
me dicati o n a n d/ or brief  
i nterr u pti o n of i nf usi o n);  
rec urre nce of s y m pt o ms  
f oll o wi n g i nitial 
i m pr o ve me nt;  
h os pitalizati o n i n dicate d 
f or  
cli nical se q uelae (e. g., 
re nal  
i m pair me nt, p ul m o nar y  
i nfiltrates)  
Life -t hreate ni n g  
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d  
Deat h  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 2  of 5 7  
* See a p pe n di x 6 . 0 
 
T he N CI -C T C A E ta ble will be re place d wit h t he St u d y s pecific gra di n g s yste m f or aller gic reacti o ns as 
dis pla ye d bel o w.   
Gra de 1 - Mil d  
Gra de 2 - M o derate  
Gra de 3 - Se vere  
Gra de 4 - Life 
t hreate ni n g 
Gra de 5 - 
Deat h  
Tra nsie nt or mil d 
disc o mf orts ( < 4 8 
h o urs), n o or 
mi ni mal  me dical 
i nter ve nti o n/t hera p y 
re q uire d. T hese 
s y m pt o ms ma y 
i ncl u de pr urit us, 
s welli n g or ras h, 
a b d o mi nal 
disc o mf ort or ot her 
tra nsie nt s y m pt o ms. 
S y m pt o ms t hat 
pr o d uce mil d t o 
m o derate li mitati o n i n 
acti vit y s o me 
assista nce ma y be 
nee de d; n o or mi ni mal 
i nter ve nti o n/t hera p y is 
re q uire d. 
H os pitalizati o n is 
p ossi ble. T hese 
s y m pt o ms ma y i ncl u de 
persiste nt hi ves, 
w heezi n g wit h o ut 
d ys p nea, a b d o mi nal 
disc o mf ort/ i ncrease d 
v o miti n g or ot her 
s y m pt o ms 
Mar ke d li mitati o n i n 
acti vit y, s o me 
assista nce us uall y 
re q uire d; me dical 
i nter ve nti o n/t hera p y 
re q uire d, 
h os pitalizati o n is 
p ossi ble S y m pt o ms 
ma y i ncl u de 
Br o nc h os pas m wit h 
d ys p nea, se vere 
a b d o mi nal pai n, t hr oat 
ti g ht ness wit h 
h oarse ness, tra nsie nt 
h y p ote nsi o n a m o n g 
ot hers. Pare nteral 
me dicati o n(s) are 
us uall y i n dicate d.  
E xtre me li mitati o n 
i n acti vit y, 
si g nifica nt 
assista nce re q uire d; 
si g nifica nt 
me dical/t hera p y. 
I nter ve nti o n is 
re q uire d; 
h os pita lizati o n is 
pr o ba ble. S y m pt o ms 
ma y i ncl u de 
persiste nt 
h y p ote nsi o n a n d/ or 
h y p o xia wit h 
res ulta nt decrease d 
le vel of 
c o nsci o us ness 
ass ociate d wit h 
c olla pse a n d/ or 
i nc o nti ne nce or 
ot her life t hreate ni n g 
s y m pt o ms. 
Deat h  
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 3  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 4. Criteri a f or deter mi ni n g t he o utc o me of a n Or al F o o d C h alle n ge  
Maj or Criteria  
•  C o nfl ue nt er yt he mat o us pr uritic ras h  
•  Res pirat or y si g ns (at least o ne of t he f oll o wi n g: w heezi n g, i na bilit y t o s pea k, 
stri d or, d ys p h o nia, a p h o nia) 
•  > 3 urticarial lesi o ns  
•  > 1 site of a n gi oe de ma  
•  > 2  disti nct e pis o des of v o miti n g  
•  H y pt ote nsi o n f or a ge n ot ass ociate d wit h vas o va gal e pis o de  
•  E vi de nce of se vere a b d o mi nal pai n t hat persists f or > 5 mi n utes  
Mi n or Criteria  
•  1 -2 urticarial lesi o ns  
•  Si n gle e pis o de of v o miti n g  
•  Diarr hea  
•  N ota ble distresse d beca use of na usea a n d / or a b d o mi nal pai n wit h decrease d 
acti vit y 
•  Dr y hac ki n g c o u g h lasti n g > 3 mi n utes  
•  C o m plai nt of t hr oat ti g ht ness a n d/ or pr uritis pl us > 3 e pis o des of t hr oat cleari n g  
•  Persiste nt r u b bi n g of n ose or e yes t hat lasts f or >  5 mi n utes  
•  Persiste nt r hi n orr hea t hat lasts f or > 5 mi n utes  
•  C o nti n u o us har d scratc hi n g t hat lasts f or >  3 mi n utes  
•  Disti nct c ha n ge i n affect; w hi ni n g, cr yi n g a n d/ or cli n gi n g t o pare nt  
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 4  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 5 . Refere nces 
1.  
Sa m ps o n, H. A., U p d ate o n f o o d aller gy.  J Aller g y Cli n I m m u n ol, 2 0 0 4. 1 1 3 ( 5): p. 8 0 5-1 9; q uiz 
8 2 0.  
2.  
Sic herer, S. H., et al., U S prev ale nce of self -re p orte d pe a n ut, tree n ut, a n d ses a me aller gy: 1 1-
ye ar f oll o w-u p.  J Aller g y Cli n I m m u n ol, 2 0 1 0. 1 2 5 ( 6): p. 1 3 2 2-6.  
3.  
de Sil va, I. L., et al., P ae di atric a n a p hyl axis: a 5 ye ar retr os pective revie w.  Aller g y, 2 0 0 8. 6 3 ( 8): 
p. 1 0 7 1 -6.  
4.  
B oc k, S. A., A. M u n oz -F url o n g, a n d H. A. Sa m ps o n, F urt her f at alities c a use d by a n a p hyl acti c 
re acti o ns t o f o o d, 2 0 0 1-2 0 0 6.  J Aller g y Cli n I m m u n ol, 2 0 0 7. 1 1 9 ( 4): p. 1 0 1 6-8.  
5.  
B oc k, S. A., A. M u n oz -F url o n g, a n d H. A. Sa m ps o n, F at alities d ue t o a n a p hyl actic re acti o ns t o 
f o o ds. J Aller g y Cli n I m m u n ol, 2 0 0 1. 1 0 7 ( 1): p. 1 9 1-3.  
6.  
Nels o n, H. S., et al., Tre at me nt of a n a p hyl actic se nsitivity t o pe a n uts by i m m u n ot her a py wit h 
i njecti o ns of a q ue o us pe a n ut extr act. J Aller g y Cli n I m m u n ol, 1 9 9 7. 9 9 ( 6 Pt 1): p. 7 4 4-5 1.  
7.  
O p pe n hei mer, J.J., et al., Tre at me nt of pe a n ut aller gy wit h r us h i m m u n ot her a py.  J Aller g y Cli n 
I m m u n ol, 1 9 9 2. 9 0 ( 2): p. 2 5 6-6 2.  
8.  
J o nes, S. M., et al., Cli nic al effic acy a n d i m m u ne re g ul ati o n wit h pe a n ut or al i m m u n ot her a py.  
J o ur nal of Aller g y a n d Cli nical I m m u n ol o g y, 2 0 0 9. 1 2 4 ( 2): p. 2 9 2-3 0 0.e 9 7.  
9.  
Vars h ne y, P., et al., A r a n d o mize d c o ntr olle d st u dy of pe a n ut or al i m m u n ot her a py: cli nic al 
dese nsitiz ati o n a n d m o d ul ati o n of t he aller gic res p o nse.  J Aller g y Cli n I m m u n ol, 2 0 1 1. 1 2 7 ( 3): p. 
6 5 4 -6 0.  
1 0.  
Ki m, E. H., et al., S u bli n g u al i m m u n ot her a py f or pe a n ut aller gy: cli nic al a n d i m m u n ol o gic 
evi de nce of dese nsitiz ati o n.  J Aller g y Cli n I m m u n ol, 2 0 1 1. 1 2 7 ( 3): p. 6 4 0-6 e 1.  
1 1.  
Lerc h, E. a n d U. R. M uller, L o n g -ter m pr otecti o n after st o p pi n g ve n o m i m m u n ot her a py: res ults of 
re-sti n gs i n 2 0 0 p atie nts. J Aller g y Cli n I m m u n ol, 1 9 9 8. 1 0 1 ( 5): p. 6 0 6-1 2.  
1 2.  
A k dis, C. A. a n d M. A k dis, Mec h a nis ms of aller ge n -s pecific i m m u n ot her a py. J Aller g y Cli n 
I m m u n ol, 2 0 1 1. 1 2 7 ( 1): p. 1 8-2 7; q uiz 2 8 -9.  
1 3.  
Alla m, J. P., et al., P hl p 5 res or pti o n i n h u m a n or al m uc os a le a ds t o d ose -de pe n de nt a n d ti me -
de pe n de nt aller ge n bi n di n g by or al m uc os al L a n ger h a ns cells, atte n u ates t heir m at ur ati o n, a n d 
e n h a nces t heir mi gr at ory a n d T G F -bet a 1 a n d I L -1 0 -pr o d uci n g pr o perties.  J Aller g y Cli n 
I m m u n ol, 2 0 1 0. 1 2 6 ( 3): p. 6 3 8-4 5 e 1.  
1 4.  
C o x, L. S., et al., S u bli n g u al i m m u n ot her a py: a c o m pre he nsive revie w.  J Aller g y Cli n I m m u n ol, 
2 0 0 6. 1 1 7 ( 5): p. 1 0 2 1-3 5.  
1 5.  
Ki m, E. H., et al., T oler a nce I n d ucti o n i n a n I nteri m A n alysis of Pe a n ut S u bli n g u al 
I m m u n ot her a py. J Aller g y Cli n I m m u n ol, 2 0 1 3. 1 3 1 ( 2): p. A B 1 3 0. 
1 6.  
B ur k, C., et al., C h a n ges i n I g E a n d I g G 4 I n dic ative of Dese nsitiz ati o n Are Ass oci ate d wit h Ar a h 
1 a n d 2, b ut N ot Ar a h 3, 8, a n d 9, i n S u bjects O n S u bli n g u al I m m u n ot her a py f or Pe a n ut Aller gy.  
J Aller g y Cli n I m m u n ol, 2 0 1 3. 1 3 1 ( 2): p. A B 3 3 0. 
1 7.  
K ulis, M. D., et al., Devel o p me nt of T oler a nce F oll o w i n g Pe a n ut I m m u n ot her a py Is Ass oci ate d 
wit h B as o p hil Hy p ores p o nsive ness a n d L o w Pe a n ut -I g E:I g G 4 R ati o. J Aller g y Cli n I m m u n ol, 
2 0 1 3. 1 3 1 ( 2): p. A B 1 3 1. 
1 8.  
Gree n, T. D., et al., Cli nic al c h ar acteristics of pe a n ut -aller gic c hil dre n: rece nt c h a n ges.  
Pe diatrics , 2 0 0 7. 1 2 0 ( 6): p. 1 3 0 4-1 0.  
1 9.  
Os b or ne, N.J., et al., Prev ale nce of c h alle n ge -pr ove n I g E -me di ate d f o o d aller gy usi n g 
p o p ul ati o n -b ase d s a m pli n g a n d pre deter mi ne d c h alle n ge criteri a i n i nf a nts.  J Aller g y Cli n 
I m m u n ol, 2 0 1 1. 1 2 7 ( 3): p. 6 6 8-7 6 e 1 -2.  
2 0.  
Sic herer, S. H., et al., I m m u n ol o gic fe at ures of i nf a nts wit h milk or e g g aller gy e nr olle d i n a n 
o bserv ati o n al st u dy ( C o ns orti u m of F o o d Aller gy Rese arc h) of f o o d aller gy.  J Aller g y Cli n 
I m m u n ol, 2 0 1 0. 1 2 5 ( 5): p. 1 0 7 7-1 0 8 3 e 8.  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 5  of 5 7  
* See a p pe n di x 6 . 0 
 
2 1.  
R o we, J., et al., Pre n at al  vers us p ost n at al se nsitiz ati o n t o e nvir o n me nt al aller ge ns i n a hi g h -risk 
birt h c o h ort.  J Aller g y Cli n I m m u n ol, 2 0 0 7. 1 1 9 ( 5): p. 1 1 6 4-7 3.  
2 2.  
Ne u ma n -S u ns hi ne, D. L., et al., T he n at ur al hist ory of persiste nt pe a n ut aller gy.  A n n Aller g y 
Ast h ma I m m u n ol, 2 0 1 2.  1 0 8 ( 5): p. 3 2 6-3 3 1 e 3.  
2 3.  
Vic ker y, B., et al., E arly i nterve nti o n wit h or al i m m u n ot her a py is a pr o misi n g str ate gy f or t he 
tre at me nt of pe a n ut aller gy. J Aller g y Cli n I m m u n ol, 2 0 1 2. 1 2 9 : p. A B 2 7. 
2 4.  
Vic ker y, B., et al., L o w -d ose or al i m m u n ot her a py as a n e arly i nterve nti o n str ate gy f or pe a n ut 
aller gy.  J Aller g y Cli n I m m u n ol, 2 0 1 3. 1 3 1 : p. A B 1 3 0. 
2 5.  
Sa m ps o n, H. A., et al., St a n d ar dizi n g d o u ble -bli n d, pl ace b o -c o ntr olle d or al f o o d c h alle n ges: 
A meric a n Ac a de my of Aller gy, Ast h m a & I m m u n ol o gy -E ur o pe a n Ac a de my o f Aller gy a n d 
Cli nic al I m m u n ol o gy P R A C T A L L c o nse ns us re p ort.  J Aller g y Cli n I m m u n ol, 2 0 1 2. 1 3 0 ( 6): p. 
1 2 6 0 -7 4.  
 
 
 


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 6  of 5 7  
* See a p pe n di x 6 . 0 
 
A p pe n di x 6. 0  C O VI D -1 9 S afet y Me as ures  
I n Marc h of 2 0 2 0, State a n d Nati o nal e mer ge ncies were declare d o ver t he gl o bal pa n de mic 
c or o na vir us C O VI D -1 9.  U N C -C H  instit ute d  safet y meas ures ( o utli ne d here: 
htt ps:// w w w. u nc.e d u/c or o na vir us/  ) i n a n eff ort t o sl o w t he s prea d of t he vir us a n d hel p ste m t he 
fl o w of patie nts nee di n g access t o the e mer ge nc y res p o nse ser vices a n d t he e mer ge nc y 
de part me nt at U N C H os pitals.  Staff recei ve d g ui da nce f or s ocial dista nci n g a n d re m ote w or ki n g.  
St u de nts were e nc o ura ge d t o re mai n off ca m p us.  Meas ures were create d t o desi g nate esse ntial 
pers o nal as well as halt all n o n -esse ntial a n d i n pers o n visits.  M ost ca m p us b uil di n gs were als o 
s h ut d o w n.  Tele me dici ne meas ures were i m ple me nte d t o scree n patie nts pri or t o i n-pers o n 
treat me nt. C O VI D-1 9 testi n g l ocati o ns were als o create d utilizi n g U N C me dical staff.   
I n li g ht of t he c urre nt sit uati o n, ca m p us researc h als o recei ve d g ui da nce fr o m t he office of Vice 
C ha ncell or of Researc h ( o utli ne d here:  htt ps://researc h. u nc.e d u/c o vi d -1 9/  ) restricti n g all n o n-
esse ntial cli nical researc h acti vities . As a p hase 2 b st u d y, t he c urre nt st u d y has bee n all o we d t o 
c o nti n ue, h o we ver  t he direct or f or t he F o o d Aller g y I nitiati ve ( F AI) at U N C, Dr. E d wi n Ki m, has 
deci de d t o halt all oral f o o d c halle n ges d uri n g t he i m ple me ntati o n of safet y meas ures at U N C -
C H d ue t o t he C O VI D -1 9 pa n de mic .  D B P C F C’s carr y a ris k of a na p h yla xis t hat o n occasi o n 
c o ul d re q uire me dical s u p p ort fr o m t he U N C c o de bl ue e mer ge nc y res p o nse tea m or care wit hi n 
t he U N C e mer ge nc y de part me nt .  Utilizati o n of t hese ser vices as a res ult of cli nical trial 
p ur p oses has bee n dee me d i na p pr o priate d uri n g t he o n g oi n g pa n de mic a n d als o c o ul d p ose a ris k 
of e x p os ure t o t he vir us f or t he st u d y s u bject. As s uc h, a n y  3 6 m o nt h Dese nsitizati o n D B P C F C 
will be p ost p o ne d w hile  t he safet y meas ures s urr o u n di n g C O VI D -1 9 are i n place.  S u bjects w h o 
c h o ose t o re mai n i n t he st u d y will c o nti n ue o n st u d y dr u g at t he mai nte na nce d ose le vel be y o n d 
t he ori gi nall y pla n ne d 3 6 m o nt hs u ntil s uc h ti me t hat t he Dese nsitizati o n D B P C F C is c o n d ucte d.  
. T his will hel p pr otect o ur s u bjects fr o m e x p os ure t o t he C O VI D -1 9 vir us a n d hel p wit h 
meas ures t o re d uce b ur de n o n t he U N C E D.  
S u bjects w h o are sc he d ule d t o u n der g o t he 3 9 m o nt h T olera nce D B P C F C w hile t he C O VI D -1 9 
safet y meas ures are i n place will ha ve t heir D B P C F C ca ncelle d. A d diti o nal ti me off of st u d y 
dr u g t hera p y w o ul d p ote ntiall y i ncrease t he ris k of aller gic reacti o n d uri n g t he D B P C F C a n d 
w o ul d n ot be acce pta ble.  
F or s u bjects w h ose Dese nsitizati o n D B P C F C is p ost p o ne d, a f oll o w -u p visit t o re vie w safet y a n d 
s u bject d osi n g diaries w o ul d be c o n d ucte d. T his visit w o ul d be c o n d ucte d re m otel y b y tele p h o ne. 
A d di ti o nal st u d y dr u g w o ul d be se nt direct-t o-patie nt as necessar y t o c o nti n ue o n mai nte na nce 
d osi n g. La b sa m ple c ollecti o n a n d mec ha nistic st u dies w o ul d be deferre d a n d be c o m plete d at 
t he ti me t hat t he Dese nsitizati o n D B P C F C is c o m plete d. T he T olera nce D B P C FC w o ul d be 
c o m plete d 3 m o nt hs after t he Dese nsitizati o n D B P C F C is c o m plete d as descri be d i n secti o n 6. 5.  


I R B Pr ot oc ol# 1 4 -0 6 4 8  
C O N FI D E N TI A L  
 
F A R E Pea n ut S LI T a n d Earl y T olera nce I n d ucti o n  
 
 
 
V ersi o n 4. 0  
M arc h 1 8, 2 0 2 0  
Pa ge 5 7  of 5 7  
* See a p pe n di x 6 . 0 
 
F or s u bjects w h ose T olera nce D B P C F C is ca ncele d, a n e xit visit w o ul d be c o n d ucte d t o re vie w 
safet y. T he s u bject w o ul d be u n bli n de d t o treat me nt all ocati o n a n d e n d of st u d y i nstr ucti o ns 
w o ul d be re vie we d wit h t he s u bject.  
As t he sit uati o n is c ha n gi n g dail y, we are u na ble t o pr o vi de a ti me fra me f or e xte nsi o n.  We h o pe 
t o li mit t he n u m ber of s u bjects w h o will nee d t o utilize t his o pti o n a n d preser ve t he e nd p oi nt data 
para meters.  Pre vi o us S LI T st u dies ha ve n ot s h o w n a n y a d diti o nal ris k wit h pea n ut S LI T d osi n g 
be y o n d 3 years u p t o a t otal of 5 years of d osi n g.