Validation of a Novel Composite of Skin Biomarkers as a Primary Outcome Measure for Evaluating the Safety of Treatments for Atopic Dermatitis: a Randomized Controlled Trial (Phase 2) Comparing the Effects of Crisaborole 2% Ointment to Betamethasone Valerate 0.1% Cream on Skin Structure and Function in Participants With Atopic Dermatitis.
Phase: PHASE2
Conditions: Atopic Eczema/Dermatitis (Non-Specific)
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 1 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
S ki n bi o M A R kers f or a t o pic ecze m a T her a p y e v al u ati o n
St u d y Title
Vali dati o n of a n o vel c o m p osite of s ki n bi o mar kers as a pri mar y o utc o me meas ure 
f or  e val uati n g  t he  safet y  of  treat me nts  f or  at o pic  der matitis:  a  ra n d o mize d  
c o ntr olle d trial ( p hase 2 ) c o m pari n g t he effects of crisa b or ole 2 % oi nt me nt t o 
bet a met has o ne valerate 0. 1 % crea m o n s ki n str uct ure a n d f u ncti o n i n partici pa nts 
wit h at o pic der matitis.
S h ort Title
S ki n bi o M A R kers f or at o pic ecze ma T hera p y e val uati o n 
Acr o n y m
S M A R T
Date a n d Versi o n
2 7 Ja n 2 0 2 1 , Versi o n 5 . 0
I R A S #
2 6 9 4 1 5
N C T # 
N C T 0 4 1 9 4 8 1 4
E u dra C T #
2 0 1 9- 0 0 2 6 4 3- 2 3
C hief I n vesti gat or
Pr of Mic hael  J.  C or k ,  C o ns ulta nt  Der mat ol o gist &  Hea d  of  Aca de mic  
Der mat ol o g y S heffiel d  Der mat ol o g y  R esearc h,  T he  U ni versit y  of  S heffiel d  
Me dical S c h o ol
Tel: 0 1 1 4 2 1 5 9 5 7 6 , E mail: m.j. c or k @s heffiel d. ac. u k
C o -I n vesti gat ors
Dr Si m o n Da n b y , R esearc h Fell o w ( Trial Ma na ger)
Pr of Ste p he n Matc her , Pr ofess or of Bi o p h ot o nics, 
Miss R osie Ta yl or , Pri nci pal C o ns ulta nt, 
Dr R o b B yers, R esearc h Ass ociate
St u d y Site
T he R o yal Hall ms hire H os pital, Gl oss o p R oa d, S heffiel d S 1 0 2J F
Tel: 0 1 1 4 2 2 6 8 5 1 5
M o bile: 0 7 8 3 4 3 9 2 4 3 9 ( direct n u m ber f or st u d y tea m)
G o ver na nce S p o ns or 
S heffiel d Teac hi n g H os pitals ( S T H) N H S Tr ust
S p o ns or Refere nce
S T H 1 9 9 6 6
Researc h Et hics 
C o m mittee ( R E C)
East Mi dla n ds - Der b y R esearc h Et hics C o m mittee
R E C Refere nce
2 0/ E M/ 0 0 0 6
F u n der
Pfizer, I nc.
F u n der Refere n ce
WI 2 4 2 0 8 3- U K -U ni versit y of S heffiel d -E ucrisa
S h effi el d
D er m at ol o g y
R e s e ar c h

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
D O C U M E N T D E T AI L S  
 
T his pr ot oc ol has r e gar d f or t he H R A g ui da nce  
 
A M E N D M E N T  HI S T O R Y   
A me n d me nt 
N o.  
Pr ot oc ol 
Versi o n 
N o.  
Date 
Iss ue d 
A ut h or(s) 
of 
c ha n ges  
Details of c ha n ges ma de  
1. 0  
2. 0  
1 1 Fe b 2 0  
S D  
T he  f oll o wi n g  c ha n ges  were  i m ple me nte d  i n 
res p o nse t o fee d bac k fr o m t he R E C: 
Secti o n  1  has  bee n  u p dat e d  wit h  a  ne w  la y 
s u m mar y 
Secti o n 3 has bee n m o difie d sli g htl y t o clarif y t he 
pri mar y o bjecti ve of t his st u d y  
N e w  st o p  criteria  ha ve  bee n  a d de d  t o  t he  ne w 
s u b-secti o n 7. 1 1. 1 
Secti o n  1 1. 6  was  u p date d  t o  s pecif y  t he  E D C 
s yste m  
2. 0  
3. 0  
2 5J u n 2 0  
 
 
 
 
 
 
 
 
 
 
 
S D  
Secti o n 9. 3  u p date d t o re m o ve a m bi g uit y o ver t he 
e x pecte d ness  assess me nt,  w hic h  will  o nl y  be 
perf or me d f or A E’s t hat are seri o us.  
Secti o n  1 1. 5  u p date d  t o  refer  t o  t he  data 
ma na ge me nt  
pla n,  
w here  
m ore  
detaile d 
i nf or mati o n  o n  t he  ca pt ure  of  electr o nic  s o urce 
data will be pr o vi de d.  
U p dates  t o  t he  ta pe -stri p  sa m ple  c ollecti o n 
secti o ns ( 7. 8 a n d 1 1. 4) t o re m o ve restricti o ns o n 
w hic h  ta pe -stri ps  will  be  use d  f or  t he  N M F 
meta b olite  a nal ysis.  T he  La b  Ma n ual  pr o vi de 
s pecific i nf or mati o n o n w hic h ta pe-stri ps will be 
a nal yse d  
A p pe n di x B u p date d t o re m o ve t he C R F na mes 
as s o me of t hese na mes ha ve c ha n ge d.  
C ollecti o n of T E W L meas ure me nts d uri n g ta pe -
stri p pi n g as well as after war ds has bee n a d de d i n. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T his  is  t o  e ns ure  t he  data  c ollecte d  ca n  be 
c o m pare d wit h rece ntl y p u bli s he d data. 
T E W L  meas ure me nts  a dj uste d  fr o m  3  t o  2 
re peats  per  test  area t o c o m pe nsate  f or  t he 
a d diti o nal  meas ure me nts  d uri n g  ta pe -stri p pi n g. 
T his still pr o vi des a r o b ust 4 re peats per treat me nt 
area i n t otal. 
F TI R  re peats  re d uce d  t o  a  si n gle  meas ure me nt 
(d o w n fr o m  2) c o m prisi n g  a  greater  n u m ber  of 
sca ns  per  meas ure me nt. T his  will  greatl y 
si m plif y data ma na ge me nt a n d e na ble t he T E W L 
meas ure me nts  i n dicate d  a b o ve  t o  be  c ollecte d . 
N ote  t hat  baseli ne  meas ure me nts  will  still 
i n v ol ve t he c ollecti o n of t w o meas ure me nts fr o m 
t he 2 test areas per treat me nt area. I nter nal data 
de m o nstrates t hat re peats pr o vi de o nl y mar gi nal 
re d ucti o ns  i n  err or  beca use  eac h  meas ure me nt 
c o nsists of m ulti ple (re peat) sca ns a n y wa y.  
3. 0  
4. 0  
2 1 Oct 2 0  
S D  
U p date d t o per mit certai n ele me nts of  t he trial t o 
be c o n d ucte d i n u ns pecifie d cli nical areas wit hi n 
t he R o yal Halla ms hire H os pital, t h ose areas t o be 
a gree d as s uita ble b y t he st u d y s p o ns or . T his als o 
c orrects t he err o ne o us use of t w o versi o ns of t he 
‘ C R F’ a b bre viati o n, wit h it n o w o nl y referri n g t o 
case re p ort f or m. 
4. 0  
5. 0  
2 7Ja n 2 1  
S D  
E x pecte d wei g hts of i n vesti gati o nal pr o d uct use d 
ha ve bee n u p date d t o reflect act ual wei g hts use d , 
w hic h are hi g her t ha n ori gi nall y q u ote d  d ue t o t he 
lar ger n ozzle size of t he beta met has o ne valerate 
dis pe nse d  ( 1 0 0 g t u be wit h 7 m m n ozzle i nstea d of 
5 m m ).  T he  d osa ge (i n fi n gerti p u nits) has  n ot 
bee n  c ha n ge d  a n d  b ot h  pr o d ucts  are still bei n g 
use d i n  li ne  wit h  t heir  res pecti ve  mar keti n g 
a ut h orisati o ns.  
A ne w c o m plia nce visit has bee n a d de d i n, Visit 
6a,  wit h  n o  c ha n ges  t o  t he  o bjecti ves  or 
e n d p oi nts.  T he  a d diti o nal  c o m plia nce  visit  has 
bee n  a d de d  t o  e nc o ura ge  c o ns iste nt t o pical 
pr o d uct usa ge t hr o u g h o ut t he st u d y. T he lar ge 2 -
wee k  ga p  bet wee n  visits  6  a n d  7 has  le d  t o  a 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
gra d ual ta peri n g d o w n of pr o d uct usa ge. T he ne w 
visit  will hel p  e nc o ura ge  g o o d  c o m plia nce 
wit h o ut materiall y c ha n gi n g t he st u d y desi g n.  
Mi n or i nc o nsiste nc y i n t he da ys q u ote d bef or e re-
c o nse nt  is  re q uire d  bet wee n  secti o ns 7. 1  ( 2 8 
da ys) ,  7. 3 ( 2 8  da ys) a n d  7. 4. 3 ( 2 1  da ys) 
c orrecte d . N o w c o nsiste ntl y q u oted as 2 8 da ys . 
  
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
SI G N A T U R E P A G E  
T he u n dersi g ne d c o nfir m t hat t he f oll o wi n g pr ot oc ol has bee n a gree d a n d acce pte d a n d t hat t he C hief 
I n vesti gat or a gr ees t o c o n d uct t he trial i n c o m plia nce wit h t he a p pr o ve d pr ot oc ol a n d will a d here t o 
t he  pri nci ples  o utli ne d  i n  t he  Me dici nes  f or  H u ma n  Use  ( Cli nical  Trials)  Re g ulati o ns  2 0 0 4  ( SI 
2 0 0 4/ 1 0 3 1), a me n de d r e g ulati o ns ( SI 2 0 0 6/ 1 9 2 8) a n d a n y s u bse q ue nt a me n d me nts of t he cli nical trial 
re g ulati o ns,  G C P  g ui deli nes,  t he  S p o ns or’s  (a n d  a n y  ot her  rele va nt)  S O Ps,  a n d  ot her  re g ulat or y 
re q uir e me nts as a me n de d. 
I a gr ee t o e ns ur e t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot be use d f or a n y 
ot her  p ur p ose  ot her  t ha n  t he  e val uati o n  or  c o n d uct  of  t he  cli nical  i n vesti gati o n  wit h o ut  t he  pri or 
writte n c o nse nt  of t he S p o ns or  
I als o c o nfir m t hat I will ma ke t he fi n di n gs of t he trial p u blicl y  a vaila ble t hr o u g h p u blicati o n or ot her 
disse mi nati o n  t o ols  wit h o ut  a n y  u n necessar y  dela y  a n d  t hat  a n  h o nest  acc urate  a n d  tra ns pare nt 
acc o u nt of t he trial will be gi ve n; a n d t hat a n y discre pa ncies a n d seri o us breac hes of G C P fr o m t he 
trial as pla n ne d i n t his pr ot oc ol will be e x plai ne d. 
F or a n d o n be h alf of t he Tri al S p o ns or:  
Si g nat ur e:   
 
… … … … … … … … … … … … … … … … … … … …  Date:  …. …/ …. …/ …. …  
Na me ( please pri nt):  … … … … … … … … … … … … … … … … … … … …  
P ositi o n:  
 
… … … … … … … … … … … … … … … … … … … …  
C hief I n vesti g at or:  
Si g nat ur e:  
 
… … … … … … … … … … … … … … … … … … … …  Date: …. …/ …. …/ …. …  
Na me ( please pri nt):  … … … … … … … … … … … … … … … … … … … …  
P ositi o n:  
 
… … … … … … … … … … … … … … … … … … … …  
 
 
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
K E Y T RI A L C O N T A C T S  
R ole  
T ea m Me m ber  
C HI E F I N V E S TI G A T O R: 
( Me dical E x pert) 
P r of Mic h ael J C or k  
Pr ofess or of Der mat ol o g y at t he U ni versit y of S heffiel d  
C o ns ulta nt Pe diatric Der mat ol o gist at t he S heffiel d 
C hil dre n’s H os pital N H S Tr ust  
C o ns ulta nt Der mat ol o gist at t he S heffiel d T eac hi n g 
H os pitals N H S F o u n dati o n Tr ust  
S heffiel d Der mat ol o g y  R esearc h 
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K 1 2 5), 
Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 7 1 2 9 3 3  
E mail: m.j. c or k @s heffiel d. ac. u k  
 
S U B -I N V E S TI G A T O R S: 
Dr Si m o n G D a n b y  
I n de pe n de nt Researc h Fell o w  
S heffiel d Der mat ol o g y Researc h  
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K 1 2 3), 
Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 1 5 9 5 6 3  
E mail: s. da n b y @s heffiel d. ac. u k 
 
P r of Ste p he n M atc her  
C hair i n Bi o p h ot o nics  
De pt of Electr o nic & Electrical E n gi neeri n g , T he 
U ni versit y of S heffiel d  
T el: 0 1 1 4 2 2 2 5 9 9 4  
E mail: s.j. matc her @s heffiel d. ac. u k 
 
R osie T a yl or  
Pri nci pal C o ns ulta nt  
T he Statistical Ser vices U nit, T he  U ni versit y of S heffiel d, 
S heffiel d  
T el: + 4 4 ( 0) 1 1 4 2 2 2 3 9 0 0  
E mail: r. n.ta yl or @s heffiel d. ac. u k 
 
R o b B yers  
Researc h Ass ociate  
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K 1 2 3), 
Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 1 5 9 5 3 9  
E mail:  r. b yers @s heffiel d. ac. u k 
 
T RI A L M A N A G E R  
Dr Si m o n D a n b y  
S ki n Barrier Researc h Facilit y Ma na ger  
S heffiel d Der mat ol o g y Researc h  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K 1 2 3), 
Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 1 5 9 5 6 3  
E mail: s. da n b y @s heffiel d. ac. u k 
R E S E A R C H C O O R DI N A T O R 
( S P O N S O R):  
( S heffiel d T eac hi n g H os pitals Tr ust) 
 
Ai mee C ar d   
Researc h C o or di nat or  
Cli nical Researc h & I n n o vati o n Office  
S heffiel d T eac hi n g H os pitals N H S F o u n dati o n Tr ust  
D Fl o or, R o yal Halla ms hire H os pital, Gl oss o p R oa d, 
S heffiel d, S 1 0 2J F, U K  
Direct li ne:   + 4 4 ( 0) 1 1 4 2 2 6 5 9 4 5                             
E mail: aimee. car d @ n hs. net  
 
F U N D E R R E P R E S E N T A TI V E S  
A m y C h a  
Sr. Direct or, Gl o bal Me dical Lea d  
Pfizer I nc  
2 3 5 E ast 4 2 n d Street , Ne w Y or k, N Y 1 0 0 1 7  
M o bile: + 1. 9 2 9. 3 1 8. 3 2 5 2  
Office: + 1. 2 1 2. 7 3 3. 1 0 1 6  
E mail: A m y. C ha @ pfizer. c o m  
 
J uli a C ar pe ne d o  
Cli nical a n d Researc h C olla b orati o ns Liais o n  
E xter nal Me dical C o m m u nicati o ns  
Pfizer I nc.  
Office: 2 1 2 7 3 3 9 4 9 0  
M o bile: 3 4 7 4 1 3 1 7 6 9  
E mail: j ulia. car pe ne d o @ pfizer. c o m 
 
S T U D Y A D MI NI S T R A TI O R  
Le s H u nter 
S heffiel d Der mat ol o g y Researc h,  
De part me nt of I nfecti o n & I m m u nit y & Car di o vasc ular 
Disease,  
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K Fl o or),  
Beec h Hill R oa d, S heffiel d.  S 1 0 2 R X  
T el: + 4 4 ( 0) 1 1 4 2 1 5 9 5 6 3  
E mail: l. h u nter @s heffiel d. ac. u k 
 
 
 
 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 8 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
S Y N O P SI S
Title
Vali dati o n of a n o vel c o m p osite of s ki n bi o mar kers as a pri mar y o utc o me 
meas ur e f or e val uati n g t he safet y of treat me nts f or at o pic der matitis: a 
r a n d o mize d c o ntr olle d trial ( p hase 2) c o m pari n g the effects of crisa b or ole 
2 % oi nt me nt t o beta met has o ne valerate 0. 1 % crea m o n s ki n str uct ure a n d 
f u ncti o n i n partici pa nts wit h at o pic der matitis.
Acr o n y m
S M A R T
L o g o
Cli nic al P h ase
P hase 2
O bj ecti ves :
O utc o me me as ures :
P ri m ar y
•
T o deter mi ne w het her t wice 
dail y tr eat me nt wit h crisa b or ole 
( 2 %) oi nt me nt, c o m pare d t o 
beta met has o ne valerate ( 0. 1 %) 
cr ea m, f or u p t o 4 wee ks is a 
ca use of s ki n atr o p h y i n patie nts 
wit h at o pic der matitis.
•
T he differe nce i n t he c ha n ge i n 
e pi der mal t hic k ness ( da y 2 9 –
da y 1), meas ure d b y str uct ural 
O C T, bet wee n t he sites treate d 
wit h crisa b or ole ( 2 %) oi nt me nt 
a n d beta met has o ne valerate 
( 0. 1 %) crea m.
Sec o n d ar y
•
T o i n vesti gate t he ki netics of 
c ha n ges i n e pi der mal t hic k ness 
meas ur e d b y str uct ural O C T 
br o u g ht a b o ut b y treat me nt wit h
crisa b or ole ( 2 %) oi nt me nt a n d 
beta met has o ne valerate ( 0. 1 %) 
cr ea m
•
T o deter mi ne t he t olera bilit y of 
crisa b or ole ( 2 %) oi nt me nt, 
c o m par e d t o beta met has o ne 
valer ate ( 0. 1 %) crea m
•
T he differe nce i n t he c ha n ge i n 
e pi der mal t hic k ness meas ure d 
b y str uct ural O C T d uri n g a n d 
after 2 8 da ys treat me nt. 
•
T he differe nce i n t he c ha n ge i n 
vis ual re d ness/er yt he ma sc ore 
d uri n g a n d after 2 8 da ys 
treat me nt.
•
T he differe nce i n t he c ha n ge i n 
o bjecti ve re d ness a ssess e d wit h 
t he Me xa meter d uri n g a n d after 
2 8 da ys treat me nt.

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  T o deter mi ne t he effect of 
crisa b or ole ( 2 %) oi nt me nt, 
c o m par e d t o beta met h as o ne 
valer ate ( 0. 1 %) crea m, o n s ki n 
barrier f u ncti o n  
 
 
 
 
•  T o deter mi ne t he effect of 
crisa b or ole ( 2 %) oi nt me nt, 
c o m par e d t o beta met has o ne 
valer ate ( 0. 1 %) crea m, o n s ki n 
dr y ness a n d t he le vels of nat ural 
m oist urisi n g f act or ( N M F) i n 
t he s ki n 
 
•  T he differe nce i n t he c ha n ge i n 
Tra ns -E pi der mal Water L oss 
( T E W L) d uri n g a n d after 2 8 
da ys treat me nt.  
 
•  T he differe nce i n s ki n barrier 
i nte grit y ( T E W Lts 2 0) after 2 8 
da ys treat me nt.  
 
•  T he diffe re nce i n t he cha n ge i n 
vis ual s ki n dr y ness  d uri n g a n d 
after  2 8 da ys treat me nt 
 
•  T he differe nce i n Nat ural 
M oist urisi n g Fact or ( N M F, 
fila g gri n brea k d o w n pr o d ucts) 
le vels at t he e n d of treat me nt. 
E x pl or at or y  
•  T o i n vesti gate w het her O C T -
deri ve d bi o mar kers ( ot h er t ha n 
t he esta blis he d str uct ural O C T 
bi o mar ker) e na ble t he acc urate 
q ua ntificati o n of tiss ue c ha n ges 
( vasc ular a n d matri x) ass ociate d 
wit h e pi der mal atr o p h y i n 
r es p o nse t o T C S treat me nt 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  T o i n vesti gate w het her F TI R 
s pectr osc o p y-deri ve d 
bi o mar kers e na ble t he acc urate 
q ua ntificati o n of s ki n barrier 
•  T he differe nce i n t he c ha n ge i n  
s u perficial ple x us de pt h (µ m) 
meas ure d b y a n gi o gra p hic O C T  
 
•  T he differe nce i n t he c ha n ge i n 
mea n bl o o d vessel dia meter 
(µ m) meas ure d b y a n gi o gra p hic 
O C T  
 
•  T he differe nce i n t he c ha n ge i n 
bl o o d vessel de nsit y 
(se g me nts/ m m2) meas ure d b y 
a n gi o gra p hic O C T  
 
•  T he differe nce i n t he c ha n ge i n 
c olla ge n matri x i n de x (a n i n de x 
deri ve d fr o m birefri n ge nce 
i ma ges of c olla ge n de nsit y a n d 
arra n ge me nt) meas ure d b y 
p olarisati o n se nsiti ve ( P S) -O C T  
 
•  T he differe nce i n t he c ha n ge i n 
car b o x ylate le vels (i n direct 
meas ure of nat ural m oist urisi n g 
fact or le vels) i n t he strat u m 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
c o n diti o n a n d f u ncti o n i n 
r es p o nse t o T C S treat me nt 
 
 
 
 
 
 
 
•  T o i n vesti gate t he n u m ber of 
partici pa nts wit h F L G  l oss-of -
f u ncti o n m utati o ns a n d e x pl ore 
if t her e is a n y e vi de nce of a 
r elati o ns hi p t o treatme nt effects  
 
 
 
 
•  T o i de ntif y ( b y c o m pleti n g t he 
o bjecti ves a b o ve) a pa nel of 
bi o mar kers t hat best 
c har acterises e pi der mal atr o p h y. 
T he bi o mar kers i de ntifie d will 
be ta ke n f or war d i nt o t he ne xt 
sta ge of t he r esearc h pr o gra m. 
 
c or ne u m meas ure d b y F TI R 
s pectr osc o p y  
 
•  T he differe nce i n strat u m 
c or ne u m li pi d str uct ure 
meas ure d b y F TI R s pectr osc o p y 
i n c o nj u ncti o n wit h ta pe-
stri p pi n g  
 
•  N u m ber of F L G  l oss-of -
f u ncti o n m utati o n carriers 
 
•  D escri pti ve ta b ulati o ns of 
T E W L a n d e pi der mal t hic k ness 
b y m utati o n stat us, if s ufficie nt 
partici pa nts wit h m utati o n ar e 
detecte d.  
 
•  All of t he a b o ve  
Tri al Desi g n  
A n  o bser ver -bli n d  f orear m -c o ntr olle d  cli nical  trial  i n  3 7  A D  patie nts, 
w her ei n eac h partici pa n t will u n der g o 4 wee ks treat me nt wit h crisa b or ole 
( 2 %) oi nt me nt o n o ne f orear m a n d beta met has o ne valerate ( 0. 1 %) cr ea m 
o n  t he  ot her  (t wice  dail y  a p plicati o n  i n  eac h  case  a n d  ra n d o mise d  site 
all ocati o n). At t he start of t he st u d y t he s ki n of t he test sites (f orear ms) will 
be clear of t he si g ns of A D s o t hat t he i n vesti gati o n f oc uses o n l ocal a d verse 
eff ects o n t he s ki n as o p p ose d t o a nti -i nfla m mat or y effects (f oc us o n l ocal 
a d verse eff ects a n d n ot cli nical efficac y). T he c o n diti o n of t he s ki n will be 
assessed bef or e, d uri n g a n d after treat me nt.  
Tri al P artici p a nts  
Partici pa nts 1 8 -6 5  years ol d  wit h  A D  n ot  c urre ntl y 
u n der g oi n g,  or 
r e q uiri n g, acti ve dr u g treat me nt.  
Pl a n ne d S a m ple 
Size  
A si n gle c o h ort of 3 7 partici pa nts will be recr uite d wit h a tar get of 3 3 f or  
c o m pleti o n ( all o wi n g f or a 1 0 % dr o p o ut rate)  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
Ke y eli gi bilit y 
crit eri a 
I ncl usi o n crit eri a 
1.  V ol u nteers  wit h  A D  defi ne d  acc or di n g  t o  t he  U K  w or ki n g  part y 
dia g n ostic criteria  
2.  Male or f e male a ge d 1 8 -6 5  years ol d  at baseli ne ( Visit 1) 
3.  V ol u nteer u n dersta n ds t he  p ur p ose, m o dalities a n d p ote ntial ris k of 
t he trial  
4.  Partici pa nts  a ble t o rea d a n d u n dersta n d E n glis h  
5.  Partici pa nts  willi n g t o si g n t he i nf or me d c o nse nt  
E xcl usi o n crit eri a  
1.  Partici pa nts  wit h  a  k n o w n aller g y/ h y perse nsiti vit y  t o  a n y  of  t he 
e xci pie nts of t he trial pre parati o ns. 
2.  Partici pa nts  wit h ac ne, s u nta n, birt h mar ks, m ulti ple ne vi, tatt o os, 
ble mis hes or de nse b o d y hair t hat o bstr uct t he test areas.  
3.  I n vesti gat or  assess me nt  of  ecze ma  se verit y  at  t he  treat me nt 
( a nat o mical) sites is al m ost clear  or greater ( sc ore ≥1 ) base d o n t he 
I n vesti gat ors  static gl o bal  assess me nt  scale  at  scree ni n g  a n d 
baseli ne . At t he start of t he st u d y t he s ki n of t he test sites (f orear ms) 
will t her ef ore be clear ( 0) of t he si g ns of ecze ma  
4.  Partici pa nts  wit h a c o n diti o n t hat i n t he o pi n i o n of t he i n vesti gat or 
c o ntr a dicts partici pati o n i n t he st u d y.  
5.  Pr e g na nt  fe male partici pa nts ;  breastfee di n g  fe male partici pa nts ; 
a n d f e male partici pa nts of c hil d beari n g p ote ntial w h o are u n willi n g 
or  u na ble  t o  use  a  hi g hl y  effecti ve  met h o d  of  c o ntrace pti o n  as 
o utli ne d i n t his pr ot oc ol f or t he d urati o n of t he st u d y a n d f or at least 
2 8 da ys after t he last d ose of i n vesti gati o nal pr o d uct.  
6.  Use of a n y t o pical pr o d uct o n t he test areas wit hi n 7 da ys pri or t o 
Baseli ne/ Da y  1,  i ncl u di n g  c os metic  m oist urizers  a n d  s u n scr ee n. 
P artici p a nts usi n g a ny t o pic al pr o d ucts o n t he test are as wit hi n 7 
d ays  at  t he  scree ni n g  visit  will  be  eli gi ble  if  t hey  are  willi n g  a n d 
a ble  t o  w as h -o ut  t hese  pr o d ucts  f or  7  d ays  i n  t ot al  a n d  f or  t he 
d ur ati o n of t he tri al. S uc h p artici p a nts will be  p ote nti ally eli gi ble 
at scree ni n g a n d will be c o nfir me d as eli gi ble if a de q u ate w as h o ut 
is  c o nfir me d  at  visit  1.  Use  of  m oist urizers  a n d/ or  s u nscre e n  is 
per mitte d d uri n g t he st u dy t o m a n a ge dry ski n a n d s u n ex p os ure i n 
are as s urr o u n di n g b ut n ot o n or over l a p pi n g t he test are as. 
7.  Partici pa nts w h o ha ve use d a ta n ni n g be d wit hi n 2 8 da ys of baseli ne 
( visit 1). P artici p a nts w h o h ave use d a s u n be d wit hi n 2 8 d ays at t he 
scree ni n g visit will be eli gi ble if t hey are willi n g a n d a ble t o w as h-
o ut  f or  2 8  d ays  i n  t ot al a n d  f or  t he  d ur ati o n  of  t he  tri al.  S uc h 
p artici p a nts  will  be  p ote nti ally  eli gi ble  at  scree ni n g  a n d  will  be 
c o nfir me d as eli gi ble if a de q u ate w as h o ut is c o nfir me d at visit 1.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8.  Partici pa nts  w h o ha ve use d a n y me dicati o n t hat c o ul d i nterfere wit h 
t he  trial  ai m pri or  t o  t he  start  of  t he  st u d y  ( baseli ne/ visit  1). 
P artici p a nts usi n g  s uc h  me dic ati o n  at  t he  scree ni n g  visit  will  be 
eli gi ble if t hey are willi n g a n d a ble t o w as h -o ut t hese tre at me nts f or 
t he a p plic a ble w as h o ut peri o d as defi ne d by i n secti o n 8. 8 ‘Pri or 
a n d C o nc o mit a nt Me dic ati o n ’ a n d f or t he d ur ati o n of t he tri al. S uc h 
p artici p a nts  will  be  p ote nti ally  eli gi ble  at  scree ni n g  a n d  will  be 
c o nfir me d as eli gi ble if a de q u ate w as h o ut is c o nfir me d at visit 1.  
9.  Partici pa nts  c urre ntl y partici pati n g i n a n ot her i nter ve nti o nal cli nical 
trial.  
1 0.  V ol u nteer is i nca pa ble of gi vi n g f ull y i nf or me d c o nse nt.  
1 1.  Partici pa nts  j u d ge d b y t he PI t o be i na p pr o priate f or t he trial. 
I n vesti g ati o n al 
m e dici n al 
pr o d uct(s)  
•  Crisa b or ole ( 2 %)  oi nt me nt  
•  Beta met has o ne valerate ( 0. 1 %)  crea m 
F or m ul a ti o n, D ose, 
R o ut e of 
A d mi nist r ati o n  
4 wee ks t wice -d ail y self -a d mi nistere d a p plicati o n of 1  fi n ger-ti p u nits of 
eit her crisa b or ole ( 2 %)  oi nt me nt or beta met has o ne valerate ( 0. 1 %) crea m 
t o t he v olar si de of t he f orear m.  
Tre at m e nt d ur ati o n  2 8 da ys  
F oll o w -u p d ur ati o n  
2 8 da ys  
Pl a n ne d Tri al 
P eri o d  
T he d ur ati o n partici pa nts will partici pate i n t his st u d y is a p pr o xi matel y 9  
wee ks, i ncl u di n g t he 1 -wee k r u n -i n peri o d ( n o t o pical pr o d uct use o n test 
sites). 
T he st u d y is e x pecte d t o last 1 2 m o nt hs i n t otal.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
C O N T E N T S  
D O C U M E N T D E T AI L S  ................................................................................................................ 2  
A M E N D M E N T HI S T O R Y  ............................................................................................................. 2  
SI G N A T U R E P A G E  ...................................................................................................................... 5  
K E Y T RI A L C O N T A C T S  .............................................................................................................. 6  
S Y N O P SI S  ..................................................................................................................................... 8  
I ncl usi o n criteria........................................................................................................................ 1 1  
E xcl usi o n criteria  ...................................................................................................................... 1 1  
C O N T E N T S  ................................................................................................................................. 1 3  
i. List of a b br e viati o ns .................................................................................................................. 2 0  
ii. F u n di n g a n d s u p p ort i n ki n d ...................................................................................................... 2 2  
iii. R ole of t he trial s p o ns or a n d f u n der ......................................................................................... 2 2  
i v. R oles a n d res p o nsi bilities of trial ma na geme nt c o m mittees/ gr o u ps a n d i n di vi d uals  .................. 2 2  
v. Pr ot oc ol c o ntri b ut ors  ................................................................................................................. 2 3  
vi. Ke y w or ds ................................................................................................................................ 2 4  
vii. Trial fl o w c hart  ....................................................................................................................... 2 5  
1. L A Y S U M M A R Y  ..................................................................................................................... 2 6  
2. B A C K G R O U N D  ...................................................................................................................... 2 7  
2. 1 S oci oec o n o mic i m pact of At o pic Der matitis/ Ecze ma ( A D)  .................................................. 2 7  
2. 2 T he li mitati o ns of c urr e nt tr eat me nt strate gies ...................................................................... 2 7  
2. 3 Pr eli mi nar y d ata o n t he l ocal a d verse effects of T C S o n t he s ki n  .......................................... 2 9  
2. 4 Pr eli mi nar y data o n ne w n o vel bi o mar kers of T C S -i n d uce d s ki n da ma ge............................. 3 1  
2. 5 Ke y q uesti o ns t o be a ns wer e d  .............................................................................................. 3 3  
2. 6 Selecti o n of t he st u d y T C S  .................................................................................................. 3 4  
2. 7 Crisa b or ole  .......................................................................................................................... 3 5  
2. 8 Assess me nt a n d ma na ge me nt of ris k  .................................................................................... 3 6  
2. 8. 1 P ote ntial et hical iss ues arisi n g fr o m t his st u d y  ............................................................... 3 6  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
2. 8. 2 P ote ntial ris ks a ss ociate d wit h t he I M P .......................................................................... 3 6  
2. 8. 3 P ote ntial ris ks a n d b ur de ns ass ociate d wit h t he s ki n pr oce d ures ..................................... 3 7  
2. 8. 4 P ote ntial ris ks ass ociate d wi t h t he sa m ple c ollecti o n ..................................................... 3 8  
2. 8. 5 P ote ntial b ur de n of ta ki n g part ....................................................................................... 3 8  
2. 8. 6 Data ma na ge me nt iss ues arisi n g fr o m t his st u d y  ............................................................ 3 8  
2. 8. 7 Rete nti o n of sa m ples at t he e n d of t he st u d y  .................................................................. 3 9  
2. 8. 8 Ris k of br eac h of c o nfi de ntialit y .................................................................................... 3 9  
3. R A TI O N A L E  ........................................................................................................................... 4 0  
3. 1 T he nee d f or ne w bi o mar kers t o e val uate t he safet y of treat me nts f or at o pic der matitis  ........ 4 0  
3. 2 Rati o nale f or selecti n g beta met has o ne valerate 0. 1 % crea m  ................................................. 4 1  
3. 3 Rati o nale f or selecti n g Crisa b or ole ( 2 %) oi nt me nt  ............................................................... 4 1  
3. 4 St u d y Ai m  ........................................................................................................................... 4 2  
3. 5 H y p ot hesis  ........................................................................................................................... 4 2  
4. O BJ E C TI V E S A N D O U T C O M E M E A S U R E S/ E N D P OI N T S .................................................. 4 2  
4. 1 Pri mar y  o bjecti ve  ................................................................................................................ 4 2  
4. 2 Sec o n dar y O bjecti ves  .......................................................................................................... 4 2  
4. 3 E x pl or at or y o bjecti ves  ......................................................................................................... 4 3  
4 . 4 Pri mar y e n d p oi nt/ o utc o me ................................................................................................... 4 4  
4. 5 Sec o n dar y e n d p oi nt/ o utc o me  ............................................................................................... 4 4  
4. 6 E x pl or at or y e n d p oi nt/ o utc o me  ............................................................................................. 4 4  
4. 7 T a ble of e n d p oi nts/ o utc o mes  ............................................................................................... 4 5  
5. T RI A L D E SI G N  ....................................................................................................................... 4 8  
5. 1 Trial D ur ati o n  ...................................................................................................................... 4 8  
5. 2 Trial setti n g  ......................................................................................................................... 4 8  
6. P A R TI CI P A N T E LI GI BI LI T Y C RI T E RI A  .............................................................................. 4 9  
6. 1 St u d y P o p ulati o n  ................................................................................................................. 4 9  
6. 2 I ncl usi o n criteria  .................................................................................................................. 4 9  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
6. 3 E xcl usi o n criteria  ................................................................................................................. 4 9  
6. 4 I nstr ucti o ns t o partici pa nts a n d lif est yle c ha n ges .................................................................. 5 0  
6. 5 C o ntr ace pti o n  ...................................................................................................................... 5 0  
6. 6 Scr ee ni n g f ail ur e .................................................................................................................. 5 1  
7. S T U D Y P R O C E D U R E S  ........................................................................................................... 5 2  
7. 1 O ver vie w of pr oce d ur es  ....................................................................................................... 5 2  
7. 2 Recr uit me nt  ......................................................................................................................... 5 6  
7. 2. 1 Pr e -scr ee ni n g ................................................................................................................ 5 7  
7. 3 Scr ee ni n g & I nf or me d C o nse nt  ............................................................................................ 5 7  
7. 3. 1 Assi g n me nt of Fitz patric k s ki n t y pe ( bac k gr o u n d i nf or mati o n f or m)  ............................. 5 8  
7. 3. 2 T he U K W or ki n g Part y Dia g n ostic Criteria f or ecze ma  ................................................. 5 8  
7. 3. 3 Gr a di n g t he se verit y of A D usi n g t he E A SI s yste m  ....................................................... 5 9  
7. 3. 4 T he I n vesti gat ors Static Gl o bal Assess m e nt (I S G A)  ...................................................... 5 9  
7. 4 St u d y visits  .......................................................................................................................... 5 9  
7. 4. 1 Scr ee ni n g & C o nse nt Visit ( a p pr o x. 3 0 -6 0 mi n)  ............................................................ 6 0  
7. 4. 2 Was h -o ut ....................................................................................................................... 6 0  
7. 4. 3 Visit 1, Da y 1 ( a p pr o x. 2. 5 -3 h o urs)  .............................................................................. 6 1  
7. 4. 4 Re mi n ders bet wee n visits  .............................................................................................. 6 1  
7. 4. 5 Visits 2 -5, Da ys 1 t o 1 2 ( a p pr o x. 2 0 mi n eac h)  .............................................................. 6 2  
7. 4. 6 Visit 6, Da y 1 5 +/ - 3 da ys ( a p pr o x. 2. 5 h o urs)  ............................................................... 6 2  
7. 4. 7 Visit 7, Da y 2 9 +/ - 3 da ys ( a p pr o x. 3 h o urs)  .................................................................. 6 3  
7. 4. 8 Visit 8, Da y 5 7 +/ - 4 da ys ( a p pr o x.  2. 5 h o urs)  ............................................................... 6 3  
7. 5 Ra n d o mizati o n & bli n di n g  ................................................................................................... 6 4  
7. 5. 1 Ra n d o mizati o n  .............................................................................................................. 6 4  
7. 5 . 2 Bli n di n g ........................................................................................................................ 6 4  
7. 5. 3 E mer ge nc y u n bli n di n g  .................................................................................................. 6 4  
7. 6 Pr e g na nc y testi n g  ................................................................................................................ 6 5  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7. 7  S ki n assess me nts  ................................................................................................................. 6 5  
7. 7. 1 Accli matizati o n  ............................................................................................................. 6 6  
7. 7. 2 I de ntificati o n a n d de mar cati o n of t he test sites  .............................................................. 6 6  
7. 7. 3 Vis ual sc ori n g of s ki n dr y ness a n d re d ness/er yt he ma ..................................................... 6 8  
7. 7. 4 2 D i ma ge ca pt ur e wit h t he c -c u be ca mera ..................................................................... 6 8  
7. 7. 5 Me xa meter meas ur e me nts of o bjecti ve s ki n re d ness/er yt he ma (t olera bilit y)  .................. 6 9  
7. 7. 6 Str uct ur al & A n gi o gr a p hic O C T sca ns usi n g t he Vi v osi g ht O C T mac hi ne  ..................... 6 9  
7. 7. 7 P olarizati o n se nsiti ve ( P S) -O C T sca n usi n g t he c ust o m P S -O C T mac hi ne  ..................... 7 0  
7. 7. 8 T E W L meas ur e me nts  .................................................................................................... 7 1  
7. 7. 9 F TI R s pectr osc o p y meas ur e me nts of t he s ki n s urface  .................................................... 7 1  
7. 7. 1 0 T a pe -stri p pi n g i n c o nj u ncti o n wit h F TI R a n d T E W L meas ure me nts ............................ 7 2  
7. 8 Sa m ple c ollecti o n  ................................................................................................................ 7 3  
7. 8. 1 S u perficial str at u m c or ne u m sa m ple c ollecti o n  .............................................................. 7 3  
7. 8. 2 Sali va sa m pli n g ( b uccal s wa b) f or F L G ge n ot y pi n g  ...................................................... 7 3  
7. 9 Tr eat me nt a n d c o m plia nce  ................................................................................................... 7 3  
7. 1 0 Partici pa nt c o m pleti o n/ wit h dr a wal  ..................................................................................... 7 4  
7. 1 0. 1 Partici pa nt c o m pleti o n  ................................................................................................. 7 4  
7. 1 0. 2 Partici pa nt wit h dr a wal  ................................................................................................. 7 4  
7. 1 0. 3 Re m u ner ati o n  .............................................................................................................. 7 5  
7. 1 1 Defi niti o n of t he e n d of trial ............................................................................................... 7 5  
7. 1 1. 1 E arl y ter mi nati o n of t he trial  ........................................................................................ 7 5  
8. T RI A L T R E A T M E N T S  ............................................................................................................ 7 6  
8. 1 Na me a n d descri pti o n of i n vesti gati o nal pr o d ucts  ................................................................ 7 6  
8. 2 Re g ulat or y stat us of t he dr u gs  .............................................................................................. 7 6  
8. 2. 1 Beta met has o ne Valer ate ( 0. 1 %) crea m  .......................................................................... 7 6  
8. 2. 2 Crisa b or ole ( 2 %) oi nt me nt  ............................................................................................ 7 7  
8. 3 Pr o d uct c har acteristics  ......................................................................................................... 7 7  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8. 3. 1 Beta met has o ne Valer ate ( 0. 1 %) crea m  .......................................................................... 7 7  
8. 3. 2 Crisa b or ole ( 2 %) oi nt me nt  ............................................................................................ 7 7  
8. 4 Dr u g s u p pl y  ......................................................................................................................... 7 7  
8. 4. 1 Beta met has o ne Valer ate ( 0. 1 %) crea m  .......................................................................... 7 7  
8. 4. 2 Crisa b or ole ( 2 %) oi nt me nt  ............................................................................................ 7 7  
8. 5 Dr u g st or a ge  ........................................................................................................................ 7 7  
8. 6 Pr e par ati o n a n d dis pe nsi n g  .................................................................................................. 7 8  
8. 7 Tr eat me nt r e gi me n ............................................................................................................... 7 8  
8. 8 Pri or a n d c o nc o mita nt me dicati o n  ........................................................................................ 7 9  
8. 8. 1 Pr o hi bite d Me dicati o ns .................................................................................................. 7 9  
8. 9 I n vesti gati o nal pr o d uct acc o u n ta bilit y .................................................................................. 8 0  
8. 1 0 Dis p osal of t he st u d y tr eat me nts  ........................................................................................ 8 1  
8. 1 1 C o m plia nce m o nit ori n g  ..................................................................................................... 8 1  
8. 1 2 Tr eat me nt d osi n g a n d c o m plia nce  ...................................................................................... 8 2  
8. 1 2. 1 I M P a p plicati o n d uri n g t he m or ni n g of st u d y visits ...................................................... 8 3  
8. 1 3 I n vesti gat or ter mi nati o n of partici pa nt i n v ol ve me nt  ........................................................... 8 3  
9. P H A R M A C O VI GI L A N C E  ....................................................................................................... 8 5  
9. 1 Defi niti o ns  ........................................................................................................................... 8 5  
9. 2 Re p orti n g Peri o d .................................................................................................................. 8 6  
9. 3 O per ati o nal defi niti o ns f or ( S) A E’s  ..................................................................................... 8 7  
9. 3. 1 Seri o us ness  ................................................................................................................... 8 7  
9. 3. 2 Ca usalit y  ....................................................................................................................... 8 8  
9. 3. 3 E x pecte d ness ................................................................................................................. 8 9  
9. 4 Re p orti n g ti me -fr a mes ......................................................................................................... 8 9  
9. 5 Res p o nsi bilities  ................................................................................................................... 9 0  
9. 6 Pr e g na nc y r e p orti n g  ............................................................................................................. 9 1  
9. 7 Saf et y u p dates  ..................................................................................................................... 9 1  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 0. S T A TI S TI C S A N D D A T A A N A L Y SI S  ................................................................................. 9 2  
1 0. 1 Sa m ple Size  ....................................................................................................................... 9 2  
1 0. 2 Pla n ne d r ecr uit me nt r ate  .................................................................................................... 9 2  
1 0. 3 A nal ysis p o p ulati o n a n d pr ot oc ol de viati o ns  ...................................................................... 9 2  
1 0. 4 Statistical a nal yses pla n  ..................................................................................................... 9 3  
1 0. 4. 1 S u m mar y of baseli ne data a n d fl o w of patie nts  ............................................................ 9 3  
1 0. 4. 2 Pri mar y o utc o me a nal ysis  ............................................................................................ 9 3  
1 0. 4. 3 Sec o n dar y o utc o me a nal ysis  ........................................................................................ 9 3  
1 0. 4. 4 E x pl or at or y o utc o me a nal ysis  ...................................................................................... 9 4  
1 1. S T U D Y C O N D U C T  ............................................................................................................... 9 5  
1 1. 1 St u d y l ocati o n  .................................................................................................................... 9 5  
1 1. 2 St u d y staff  ......................................................................................................................... 9 5  
1 1. 3 Partici pa nt tr ac ki n g  ............................................................................................................ 9 5  
1 1. 4 Sa m ple tr ac ki n g a n d st or a ge  .............................................................................................. 9 5  
1 1. 5 Data c ollecti o n t o ols a n d s o ur ce d oc u me nt i de ntificati o n  ................................................... 9 6  
1 1. 5. 1 Resear c h n otes  ............................................................................................................ 9 6  
1 1. 6 Data ha n dli n g a n d r ec or d kee pi n g  ...................................................................................... 9 6  
1 1. 7 Data Access  ....................................................................................................................... 9 7  
1 1. 8 Ar c hi vi n g  .......................................................................................................................... 9 7  
1 2. M O NI T O RI N G, A U DI T & I N S P E C TI O N  ............................................................................. 9 7  
1 2. 1 M o nit ori n g  ........................................................................................................................ 9 7  
1 3. E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ........................................................ 9 8  
1 3. 1 Resear c h Et hics C o m mittee ( R E C) re vie w a n d re p orts  ....................................................... 9 8  
1 3. 2 Peer r e vie w  ........................................................................................................................ 9 8  
1 3. 3 P u blic a n d Patie nt I n v ol ve me nt  .......................................................................................... 9 8  
1 3. 4 Re g ulat or y c o m plia nce  ...................................................................................................... 9 8  
1 3. 5 Pr ot oc ol c o m plia nce  .......................................................................................................... 9 9  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 3. 6 N otificati o n of seri o us br eac hes t o G C P a n d/ or t he pr ot oc ol  .............................................. 9 9  
1 3. 7 Data pr otecti o n a n d patie nt c o nfi de ntialit y  ....................................................................... 1 0 0  
1 3. 7. 1 Patie nt C o nfi de ntialit y  ............................................................................................... 1 0 0  
1 3. 7. 2 Data st or a ge  .............................................................................................................. 1 0 0  
1 3. 8 Fi na ncial a n d ot her c o m peti n g i nterests  ........................................................................... 1 0 1  
1 3. 9 I n de m nit y  ........................................................................................................................ 1 0 1  
1 3. 1 0 A me n d me nts .................................................................................................................. 1 0 1  
1 3. 1 1 P ost trial car e  ................................................................................................................. 1 0 2  
1 4. DI S S E MI N A TI O N P O LI C Y  ................................................................................................ 1 0 3  
1 4. 1 Disse mi nati o n p olic y  ....................................................................................................... 1 0 3  
1 4. 2 Fi nal r e p ort  ...................................................................................................................... 1 0 3  
1 4. 3 P u blicati o n  ...................................................................................................................... 1 0 3  
1 5. R E F E R E N C E S  ..................................................................................................................... 1 0 4  
1 6. A P P E N DI X  .......................................................................................................................... 1 0 6  
A p pe n di x A: Ris k assess me nt  .................................................................................................. 1 0 6  
A p pe n di x B: List of s per ate d oc u me nts relati n g t o t his trial  ..................................................... 1 0 6  
A p pe n d i x C: List of I M P i nf or mati o n a vaila ble as se parate d oc u me nts .................................... 1 0 6  
A p pe n di x D: Pfizer saf et y r e p orti n g material a vaila ble as se parate d oc u me nts  ......................... 1 0 6  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
i. List of a b bre vi ati o ns  
A D  
At o pic der matitis  
A E  
A d verse E ve nt  
A R  
A d verse Reacti o n  
A T R  
Atte n uate d t otal r eflecta nce  
C A  
C o m pete nt A ut h orit y  
CI  
C hief I n vesti gat or  
C R F  
Case Re p ort F or m  
C R O  
C o ntr act Resear c h Or ga nisati o n  
C T A  
Cli nical Trial A ut h orisati o n  
C TI M P  
Cli nical Trial of I n vesti gati o nal Me dici nal Pr o d uct   
C T U  
Cli nical Trials U nit  
 
D M C  
Data M o nit ori n g C o m mittee  
D S U R  
De vel o p me nt Saf et y U p date Re p ort  
E A SI  
E cze ma Ar ea a n d Se verit y I n de x   
E C  
E ur o pea n C o m missi o n  
e C R F  
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
E M E A  
E ur o pea n Me dici nes A ge nc y  
E U  
E ur o pea n U ni o n  
E U C T D  
E ur o pea n Cli nical Trials Directi ve  
E u dr a C T  
E ur o pea n Cli nical Trials Data base  
E u dr a VI GI L A N C E  E ur o pea n data base f or P har mac o vi gila nce  
F TI R  
F o urier Tr a nsf or m I nfrare d  
G C P  
G o o d Cli nical Pr actice  
G M P  
G o o d Ma n u f act uri n g Practice  
H P L C  
Hi g h Perf or ma nce Li q ui d C hr o mat o gra p h y  
I B 
I n vesti gat or Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nf ere nce o n Har m o nisati o n of tec h nical re q uire me nts f or 
r e gistr ati o n of p har mace uticals f or h u ma n use. 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
I M P D 
I n vesti gati o nal Me dici nal Pr o d uct D ossier 
I S F 
I n vesti gat or Site File ( T his f or ms part of t he T M F) 
I S R C T N 
I nter nati o nal Sta n dar d Ra n d o mise d C o ntr olle d Trials N u m ber 
M A  
Mar keti n g A ut h orisati o n  
M H R A  
Me dici nes a n d Healt hcare pr o d ucts R e g ulat or y A ge nc y  
M S  
Me m ber State  
N H S R & D  
Nati o nal Healt h Ser vice Researc h & De vel o p me nt   
NI M P  
N o n -I n vesti gati o nal Me dici nal Pr o d uct 
N M F  
Nat ur al m oist urizi n g fact or  
O C T  
O ptical C o her e nce T o m o gra p h y  
PI  
Pri nci pal I n vesti gat or  
PI C  
Partici pa nt I de ntificati o n C e ntre 
PI L  
Partici pa nt i nf or mati o n leaflet  
PI S  
Partici pa nt I nf or mati o n S heet  
P S -O C T  
P olarizati o n se nsiti ve O C T  
Q A  
Q ualit y Ass ur a nce  
Q C  
Q ualit y C o ntr ol  
Q P  
Q ualifie d Pers o n  
R C T  
Ra n d o mise d C o ntr ol Trial  
R E C  
Resear c h Et hics C o m mittee  
S A E  
Seri o us A d verse E ve nt  
S A R  
Seri o us A d verse Reacti o n  
S D V  
S o ur ce Data Verificati o n  
S O P  
Sta n dar d O per ati n g Pr oce d ure  
S m P C  
S u m mar y of Pr o d uct C haracteristics  
S R S D  
S i n gle r ef er e nce safet y d oc u me nt 
S SI  
Site S pecific I nf or mati o n  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T C I 
T o pical calci ne uri n i n hi bit or  
T C S  
T o pical c ortic oster oi d  
T E W L  
Tr a ns -E pi der mal Water L oss  
T M F  
Trial Master File  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T M G  
Trial Ma na ge me nt Gr o u p  
T S C  
Trial Steeri n g C o m mittee  
U S PI  
U nite d States pr escri bi n g i nf or mati o n  
 
 
ii. F u n di n g a n d s u p p ort i n ki n d  
F u n der(s)  
( N a mes a n d c o nt act det ails of A L L or g a nis ati o ns pr ovi di n g f u n di n g a n d/ or s u p p ort i n ki n d f or t his 
tri al) 
Pfizer I nc.  
 
J ulia Car pe ne d o 
Cli nical a n d Resear c h C olla b or ati o ns Liais o n  
E xter nal Me dical C o m m u nicati o ns  
Pfizer I nc.  
Office: 2 1 2 7 3 3 9 4 9 0  
M o bile: 3 4 7  4 1 3 1 7 6 9  
E mail: j ulia. car pe ne d o @ pfizer. c o m 
 
 
iii. R ole of t he t ri al s p o ns or a n d f u n der  
T he s p o ns or, S heffiel d T eac hi n g H os pitals Tr ust, ass u mes o verall res p o nsi bilit y f or t he i nitiati o n a n d 
ma na ge me nt of t he trial. 
T he i n vesti gati ve tea m, i n t he e m pl o y of t he U ni versit y of S heffiel d, ass u mes res p o nsi bilit y f or trial 
desi g n, c o n d uct, data a nal ysis a n d i nter pr etati o n, ma n uscri pt writi n g, a n d disse mi nati o n of res ults.  
T he f u n der, Pfizer, ass u mes t he r ole of c olla b orat or, b y re vie wi n g t he st u d y desi g n, s u p pl yi n g t he 
st u d y me dicati o n, s u p p orti n g t he st u d y set-u p a n d hel pi n g e ns ure t he st u d y is c o n d ucte d safel y  b y 
c o m m u nicati n g a n y perti ne nt saf et y u p dates relati n g t o crisa b or ole ( 2 % oi nt me nt t o t he PI .  
iv . R ole s a n d res p o nsi bilities of t ri al m a n a ge me nt c o m mittees/ gr o u ps a n d i n di vi d u als 
A  Trial Ma na ge me nt Gr o u p  will m o nit or all as pects of t he c o n d uct a n d pr o gress of t he trial, e ns ure 
t hat t he pr ot oc ol is a d her e d t o a n d ta ke a p pr o priate acti o n t o safe g uar d participa nts a n d t he q ualit y of 
t he trial itself. 
T he gr o u p will c o m prise t he C hief  I n vesti gat or, c o-i n vesti gat ors, trial ma na ger, st u d y c o-or di nat or 
a n d statisticia n. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T he gr o u p will c o n ve ne at r e g ular i nter vals d uri n g t he c o urse of t he st u d y.  F urt her t o t he o ver all r ole 
of t he gr o u p as a w h ole t he f oll o wi n g i n di vi d uals will u n derta ke s pecific res p o nsi bilities:  
•  T he st u d y c o or di nat or will be r es p o nsi ble f or pr o vi di n g recr uit me nt metrics  
•  T he statisticia n will be r es p o nsi ble f or pr o vi di n g bli n de d safet y data  
•  T he trial ma na ger will be r es p o nsi ble f or u p dat es o n t he c o m plete ness, i nte grit y a n d sec urit y 
of r esear c h data  a n d u p dates o n safet y re p orti n g . 
D ue t o t he l o w le vel of assesse d ris k, t he si n gle ce ntre nat ure of t he trial a n d t he strai g ht -f or war d 
desi g n a Data M o ni t ori n g C o m mittee a n d Trial Steeri n g C o m mittee  are n ot c o nsi dere d t o be re q uire d. 
T he T M G will t her ef or e ass u me t he r oles of b ot h t he D M C a n d T S C.  
v . P r ot oc ol c o nt ri b ut ors  
R ole  
T ea m Me m ber  
C HI E F 
I N V E S TI G A T O R: 
( Me dical E x pert) 
P r of Mic h ael J C or k  
Pr of ess or  of Der mat ol o g y at t he U ni versit y of S heffiel d  
C o ns ulta nt Pe diatric Der mat ol o gist at t he S heffiel d C hil dre n’s H os pital 
N H S Tr ust  
C o ns ulta nt Der mat ol o gist at t he S heffiel d T eac hi n g H os pitals N H S 
F o u n dati o n Tr ust  
S heffiel d Der mat ol o g y  Researc h  
T he U ni versit y  of S heffiel d Me dical Sc h o ol ( K 1 2 5), Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 7 1 2 9 3 3  
E mail: m.j. c or k @s heffiel d. ac. u k  
 
S U B -
I N V E S TI G A T O R S: 
Dr Si m o n G D a n b y  
I n de pe n de nt Researc h Fell o w  
S heffiel d Der mat o l o g y Researc h 
T he U ni versit y of S heffiel d Me dical Sc h o ol ( K 1 2 3), Beec h Hill R oa d,  
S heffiel d S 1 0 2 R X  
T el: 0 1 1 4 2 1 5 9 5 6 3  
E mail: s. da n b y @s heffiel d. ac. u k 
 
P r of St e p he n M atc her  
C hair i n Bi o p h ot o nics  
De pt of Electr o nic & Electrical E n gi neeri n g , T he U ni versit y of 
S heffiel d  
T el: 0 1 1 4 2 2 2 5 9 9 4  
E mail: s.j. matc her @s heffiel d. ac. u k 
 
R osie T a yl or  
Pri nci pal C o ns ulta nt  
T he Statistical Ser vices U nit, T he U ni versit y of S heffie l d, S heffiel d 
T el: + 4 4 ( 0) 1 1 4 2 2 2 3 9 0 0  
E mail: r. n.ta yl or @s heffiel d. ac. u k 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
vi. Ke y w or ds  
At o pic Der matitis  
C ortic oster oi d  
P D E 4 I n hi bit or  
S ki n Barrier  
E pi der mal Atr o p h y  
T o pical  
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
vii.  Tri al fl o w c h art  
  
 
 
 
 
P h o n e c all
Pr e -scr e e ni n g
Visit 1 – D a y 1
B as eli n e s ki n ass ess m e nts
Visit 6 – D a y 1 5
2 -w e e k s ki n ass ess m e nts
Visit 7 – D a y 2 9
4 -w e e k s ki n ass ess m e nts
Visit 8 – D a y 5 7
Fi n al s ki n ass ess m e nts
2 -w e e ks s elf 
tr e at m e nt
2 -w e e ks s elf 
tr e at m e nt
Scr e e ni n g & C o ns e nt visit
P artici p a nt p at h w ay
Visits 2 t o 5
D a ys 1 t o 1 2 
Tr e at m e nt c h ec ks
4 -w e e ks 
f oll o w-u p
Visit 6 a
D a y 2 2 ± 3
Tr e at m e nt c h ec k

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1. L A Y S U M M A R Y  
T he first -c h oice dr u g tr eat me nt f or mil d -m o derate ecze ma is c urre ntl y a t o pical c ortic oster oi d. B y 
t o pical,  we  mea n  t he  tr eat me nt  is  i nte n de d  f or  a p plicati o n  directl y  t o  t he  s ki n.  W hilst  t o pical 
c ortic oster oi ds ar e eff ecti ve at tr eati n g  ecze ma, t he y ha ve bee n f o u n d t o ca use u n wa nte d s ki n c ha n ges, 
s uc h  as  s ki n  t hi n ni n g,  if  use d  i na p pr o priatel y  o ver  l o n g  peri o ds  of  ti me.  E xactl y  h o w  m uc h 
u n warr a nte d t hi n ni n g is ca use d b y diff er e nt treat me nt r o uti nes is u nclear, s o we wa nt t o use s o me 
ne w n o n -i n vasi ve wa ys t o meas ur e s ki n t hi n ni n g t o better u n dersta n d t he pr o ble m. O ne of t hese wa ys 
is t o ta ke a 3 D i ma ge of t he s ki n usi n g a tec h ni q ue calle d O C T, w hic h is si milar t o ultras o u n d. Beca use 
t he met h o ds ar e s o se nsiti ve, t he si g ns of s ki n t hi n ni n g ca n be see n bef ore t he s ki n bec o mes visi bl y 
da ma ge d.  
Crisa b or ole oi nt me nt is a ne w n o n -ster oi dal dr u g treat me nt f or ecze ma t hat a p pears t o be as effecti ve 
as s o me t o pical c ortic oster oi ds, a n d is n ot e x pecte d t o ca use a b n or mal s ki n t hi n ni n g. Beta met has o ne 
v aler ate cr ea m is o ne of t he m ost c o m m o nl y prescri be d t o pical c ortic oster oi ds f or ecze ma i n t he U K. 
T her ef or e, t he ai m of t his st u d y is t o c o n d uct a trial i n ecze ma patie nts i n v ol vi n g treat me nt of se parate 
ar eas of t heir s ki n wit h eit her crisa b or ole oi nt me n t or beta met has o ne valerate crea m. T he effects of 
t he tr eat me nts will be assess e d usi n g t he n o n-i n vasi ve s ki n i ma gi n g tec h ni q ues. 
B ot h tr eat me nts ha ve alr ea d y bee n teste d i n cli nical trials f or cli nical efficac y, a n d s o efficac y will 
n ot  be  assesse d  a gai n her e.  T his  st u d y  will  c o nfir m  w het her  or  n ot  crisa b or ole  ca uses  t he  sa me 
u n warr a nte d s ki n t hi n ni n g ca use d b y beta met has o ne valerate i n a direct c o m paris o n. Ha vi n g a better 
u n dersta n di n g of t he u n wa nte d eff ects of t hese treat me nts will be i nf or mati ve f or pr escri bers/ d oct ors 
a n d patie nts. T he fi n di n gs will als o hel p i de ntif y i m p orta nt wa ys of meas uri n g s ki n t hi n ni n g f or use 
i n f ut ur e cli nical trials. 
 
 
 
 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 2 7 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
2. B A C K G R O U N D
2 . 1 S oci oec o n o mic i m p act of At o pic Der m atitis/ Ecze m a ( A D) 
A D is a c hr o nic, r ela psi n g, i nfl a m mat or y disease of t he s ki n. Its pre vale nce c o nti n ues t o i ncrease 
t hr o u g h o ut t he w orl d, aff ecti n g 1 5– 3 0 % of c hil dre n a n d 2 – 1 0 % of a d ults 1. I n t he U K A D acc o u nts 
f or t he hi g hest n u m ber of c o ns ultati o ns wit h a Ge neral Practiti o ner ( G P) f or a s ki n c o m plai nt2.
T he pri mar y e ve nt i n t he de vel o p me nt of A D is brea k d o w n of t he ‘s ki n barrier’, f or me d b y t he i ntact 
str at u m c or ne u m ( Fi g ur e 2. 1). 3 A d ysf u ncti o nal s ki n barrier per mits t he pe netrati o n of irrita nts a n d 
aller ge ns, w hic h s u bse q ue ntl y tri g ger i m m u ne s yst e m h y per reacti vit y. A D is t he first ste p al o n g t he 
at o pic mar c h lea di n g t o t he de vel o p me nt of f o o d aller g y, ast h ma, a n d aller gic r hi nitis. 4 T o get her t hese 
ar e t he m ost c o m m o n c hr o nic diseases of c hil d h o o d a n d a maj or fi na ncial b ur de n t o healt h ser vices: 
i n t he U K al o ne t he dir ect c osts t o t he Nati o nal Healt h Ser vice ( N H S) are esti mate d at o ver £ 1 billi o n 
per a n n u m 5. 
Fi g 2. 1: T he de vel o p me nt a n d pr o gressi o n of A D
2. 2 T he li mit ati o ns of c urre nt t re at m e nt str ate gies
T he mai nsta y of tr eat me nt f or flar es of A D 6 is t he use of t o pical c ortic oster oi ds ( T C S). It is well 
esta blis he d t hat i nte nsi ve tr eat me nt ( o nce or t wice dail y) wit h T C S is effecti ve at s u pressi n g cli nicall y 
visi ble s ki n i nfla m mati o n ( Fi g ur e 2. 2). H o we ver, t he o ver use, or i na p pr o priate use, of T C S ca uses 
atr o p h y of t he s ki n tiss ue, c har acterise d b y w h ole s ki n t hi n ni n g a n d da ma ge t o t he s ki n barrier (s u b -
cli nical a d verse eff ects). T he atr o p hic c ha n ges ass o ciate d wit h T C S use are pr o gressi ve, starti n g wit h 
t hi n ni n g of t he e pi der mal a n d der mal la yers a n d lea di n g t o tela n giesctasia, he mat o mas, a n d e ve nt uall y 
s ki n lacer ati o ns/fiss ur es, l oss of s ki n barrier f u ncti o n a n d dela ye d heali n g (cli nical a d verse effects). 
T his pr ocess, w her e b y t he s ki n is er o de d a wa y u ntil it l oses f u ncti o nal ca pacit y is s o meti mes referre d 
t o as der mat o p or osis. E ve n a defecti ve/s u b-o pti mal s ki n barrier ca n n ot pr o vi de pr o per pr otecti o n fr o m 
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S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 2 8 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
har mf ul e x o ge n o us a ge nts s uc h as irrita nts a n d aller ge ns 7, a n d pre dis p oses t he s ki n t o f urt her flares3. 
T he a d verse effects of c hr o nic T C S use t heref ore a p pear t o c o ntri b ute t o t he c hr o nicit y of A D.
I n r ec o g niti o n of t hese a d verse eff ects of T C S o n t he s ki n, c urre nt g ui da nce6 s u g gests li miti n g 
i nte nsi ve T C S tr eat me nt t o ‘s h ort-c o urses’, f or w hic h t here is n o clear defi niti o n. T his creates a 
cli nical dile m ma: o n o ne ha n d T C S tr eat me nt s h o ul d be li mite d t o a v oi d a d verse effects, b ut o n t he 
ot her ha n d T C S tr eat me nt s h o ul d be c o nti n ue d l o n g e n o u g h t o f ull y s u p pr ess i nfla m mati o n (i ncl u di n g 
s u b-cli nical i nfla m mati o n) a n d mai ntai n re missi o n. I n cli nical practice, t he mai n pr o ble m wit h T C S 
is its u n der use d ue t o i na p pr o priate f ear of si de effects, yet clear g ui da nce base d o n e vi de nce f or 
e xactl y h o w l o n g T C S s h o ul d be use d a n d i n w hat wa y is lac ki n g. Rece nt e vi de nce 8 s u g gests t hat t he 
peri o d of r e missi o n (flar e fr ee peri o d) ca n be pr ol o n ge d, b y gai ni n g c o ntr ol of cli nical a n d s u b -cli nical 
i nfla m mati o n earl y o n ( Fi g ur e 2. 3). H owe ver, t he relati o ns hi p bet wee n t he d urati o n of treat me nt of 
s u b-cli nical i nfla m mati o n (i n d ucti o n of r e missi o n), t he de vel o p me nt of l ocal/s ki n a d verse effects, a n d 
t he l o n g-ter m c o ntr ol of A D (t he fr e q ue nc y of flares) has n ot bee n f ull y esta blis he d.
Fi g 2. 2: P ositi ve a n d ne gati ve eff ects of T C S tre at me nt o n t he s ki n ( bl ue a n d re d li nes, res pecti vel y). 
I nitiall y T C S e xert p ositi ve effe cts b y effe cti vel y r e d uci n g cli nic al/ visi ble i nfla m mati o n ( T 1). Cli nicall y 
visi ble a d verse effects (s ki n t hi n ni n g) arise wi t h pr ol o n ge d, or i na p pr o priate, use of T C S ( T 4). S u b-cli nic al 
( n o n-visi ble)  i nfla m mati o n  persists  i n  t he  s ki n  f oll o wi n g  r es ol uti o n  of  cli nic al  i nfla m mati o n,  a n d  is  
s u p pr esse d u p o n c o nti n ue d i nte nsi ve tr eat me nt ( T 3). It is n ot k n o w n w he n s u b-cli nical a d verse effe cts arise 
( T 2) i n A D patie nts u n der g oi n g treat me nt, or w hat t he o pti m u m tr a de-off is ( X).
Fi g 2. 3: T he eff ect of s u b- cli nical i nfla m mati o n o n t he c o ntr ol of A D. T he peri o d of r e missi o n (flare -fre e) 
c a n be pr ol o n ge d, b y pr ol o n ge d use of T C S t o c o ntr ol cli nic al a n d s u b -cli nical i nfla m mati o n e arl y o n.
` 
` 
P o siti v e 
A nti-i nfl a m m at or y  
eff e ct 
N e g ati v e 
A d v er s e eff e ct 
Tr e at m e nt d ur ati o n 
Eff e ct si z e 
T 4 
T 3 
T 2 
T 1 
X 
P o siti v e 
N e g ati v e 
T 4 
T 3 
T 2 
T 1 
X 
` 
` 
P o siti v e 
A nti-i nfl a m m at or y  
A nti-i nfl a m m at or y  
A nti-i nfl a m m at or y  
eff e ct 
eff e ct 
N e g ati v e 
A d v er s e eff e ct 
A d v er s e eff e ct 
T 4 
T 4 
T 3 
T 3 
T 2 
T 2 
T 1 
T 1 
X X 
Cli ni c al 
S u b- cli ni c al 
N o eff e ct 
I nfl a m m ati o n 
S u b- cli ni c al i nfl a m m ati o n 
N o i nfl a m m ati o n 
Cli ni c al i nfl a m m ati o n 
Ti m e 
( a) C urr e nt i nt e n si v e tr e at m e nt 
( b) O pti m u m i nt e n si v e tr e at m e nt ? 
T C S 
T C S 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 2 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T o pical  a nti -i nfla m mat or y  tr eat me nts  wit h o ut  l ocal  a d verse  effects,  or  treat me nt  a p pr oac hes  t hat 
mi ni mise t hese eff ects, ha ve t he p ote ntial t o c ha n ge t he c urre nt treat me nt para di g m f or mil d -m o derate 
A D. T o pical calci ne uri n i n hi bit ors ( T CI), wit h c o m para ble efficac y t o mil d a n d m o deratel y p ote nt 
T C S, d o n ot a p pear t o ca use l ocal a d verse effects o n t he s ki n barrier or e pi der mal atr o p h y. T he use 
of T CI is li mite d , h o we ver , d ue t o t he b ur ni n g/sti n gi n g se nsati o n t he y i n d uce u p o n a p plicati o n i n A D 
patie nts a n d t he war ni n g r elati n g t o a n u nc o nfir me d ca ncer ris k. I n b ot h cases t here is a nee d t o f urt her 
esta blis h  t he  l ocal  a d verse  eff ects  of  differe nt  treat me nt  a p pr oac hes  t o  pr o vi de  better  g ui da nce  o n 
t heir o pti m u m saf e use. 
2. 3 P reli mi n ar y d at a o n t he l oc al a d verse effects of T C S o n t he s ki n  
We ha ve pr e vi o usl y i n vesti gate d t he c o m parati ve effects of t he T C S beta met has o ne valerate ( 0. 1 %) 
cr ea m  a n d  e q ui vale nt  p ote nc y  T CI  tacr oli m us  ( 0. 1 %)  oi nt me nt  o n  t he  s ki n  barrie r  a n d  e pi der mal 
t hic k ness  (see  attac he d  p u blicati o ns).  I n  s h ort  beta met has o ne  valerate  ( 0. 1 %)  crea m,  b ut  n ot 
tacr oli m us  ( 0. 1 %)  oi nt me nt:  decr eases  s ki n  barrier  f u ncti o n (i ncrease d  Tra nse pi der mal  water l oss, 
T E W L) ( Fi g 2. 4); decr eases s ki n barrier i nte grit y  a n d i nter -c or ne oc yte c o hesi o n ( Fi g 2. 5); s u p presses 
nat ur al m oist urisi n g f act or  ( N M F) c o nstit ue nt  ( 2 -p yrr oli d o ne -5 -car b o x ylic  aci d a n d  ur oca nic  aci d) 
le vels  ( Fi g  2. 6);  a n d  i n d uce d  e pi der mal  atr o p h y  meas ure d  usi n g  str uct ural  o ptical  c o here nce 
t o m o gr a p h y ( OC T) ( Fi g 2. 7).  
 
Fi g  2. 4:  T he eff ect  of  beta met has o ne  valer ate  ( 0. 1 %) cre a m  ( B M Vc)  a n d  Ta cr oli m us  ( 0. 1 %)  oi nt me nt 
( T A C o) o n s ki n barrier f u ncti o n i n patie nts wit h q uiesc e nt A D. T E W L was si g nifica ntl y diff er e nt p ost-
tr e at me nt, ac c o u nti n g f or baseli ne me as ure me nts ( n = 2 5, o ne-wa y A N C O V A, p = 0. 0 3 8). T he das he d li ne 
i n dic ates mea n T E W L bef ore tre at me nt.  
B M V c 
T A C o
6
8
1 0
1 2
1 4
1 6
Tr e at m e nt
T E W L ( g/ m 2 / h)
* p  = 0. 0 3 8 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
 
Fi g  2. 5:  T he eff ect  of  beta met has o ne  valer ate  ( 0. 1 %) cre a m  ( B M Vc)  a n d  Ta cr oli m us  ( 0. 1 %)  oi nt me nt 
( T A C o) o n s ki n barrier i nte grit y a n d c o hesi o n. (a) T E W L me as ur e d i n c o nj u ncti o n wit h ta pe -stri p pi n g was 
si g nific a ntl y hi g her f oll o wi n g tr eat me nt wit h B M Vc c o m pare d wit h T A C o ( n = 2 5, p  = 0. 0 0 2 4). ( b) T he 
c u m ulati ve a m o u nt of pr otei n re m o ve d b y t he ta pe -stri ps was si g nifica ntl y hi g her f oll o wi n g treat me nt wit h 
B M V c  c o m par e d  wit h  T A C o  ( n  =  2 5, p  < 0. 0 0 0 1).  Asteris ks  i n dic ate  t he  r es ults  of  a  T u ke y  p ost -test 
c o m pari n g B M Vc a n d T A C o tr eate d sites ( * p < 0. 0 5, * * * p < 0. 0 0 1).  
 
Fi g  2. 6: T he eff ect  of  beta met has o ne  valer ate  ( 0. 1 %) cre a m  ( B M Vc)  a n d  Ta cr oli m us  ( 0. 1 %)  oi nt me nt 
(T A C o) o n t he water h ol di n g ca pa cit y of t he S C. (a) S C h y dr ati o n me as ur e d usi n g t he ca pacita nc e met h o d. 
A o ne -wa y A N C O V A r e veale d a si g nifica nt diff er e nce bet wee n t he t w o tre at me nts ( n = 2 5, p = 0. 0 2 0). 
T he  das he d  li ne  i n dicates  me a n  ca pa cita nce  bef or e  tr ea t me nt.  ( b) T he  le vel  of N M F  c o m p o ne nts 2 -
p yrr oli d o ne -5 -car b o x ylic aci d ( P C A) a n d ( c) ur oc a nic a ci d ( U C A) dete cta ble i n t he S C, as meas ure d ex 
viv o b y H P L C ( n = 2 5). B M Vc si g nific a ntl y l o wer e d P C A ( * * * * p  < 0. 0 0 0 1) a n d  U C A ( * p  < 0. 0 5) le vels 
c o m par e d t o u ntre a te d s ki n. F or cli nical rele va nce b ot h P C A a n d U C A were q ua ntifie d i n F L G m utati o n 
c arriers ( n = 6) wit h a cti ve A D at n o n -lesi o nal sites ( N L-A D). + All gr o u ps wer e si g nifica ntl y differe nt fr o m 
N L -A D ( * p  < 0. 0 5).  
5
1 0
1 5
2 0
0
2 0
4 0
6 0
T a p e- stri p n u m b er
T E W L ( g/ m 2 / h)
Pr e- B M V c
P o st- B M V c
P o st- T A C o
Pr e- T A C o
***
***
***
*
5
1 0
1 5
2 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T a p e- stri p n u m b er
C u m ul ati v e Pr ot ei n ( µ g/ c m 2 )
Pr e- B M V c
P o st- B M V c
P o st- T A C o
Pr e- T A C o
***
***
***
***
a
b
B M V c 
T A C o
2 0
2 5
3 0
3 5
4 0
4 5
5 0
C a p a cit a n c e ( A U)
* p = 0. 0 2 0
0
2 0 0
4 0 0
6 0 0
8 0 0
P C A ( µ m ol  g- 1  Pr ot ei n)
U ntr e at e d 
B M V c 
T A C o
N L- A D +
**** p < 0. 0 0 0 1
* p < 0. 0 5
0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
U C A ( µ m ol  g- 1  Pr ot ei n)
U ntr e at e d 
B M V c 
T A C o
N L- A D +
* p < 0. 0 5
** p < 0. 0 1
a
b
c

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 3 1 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
Fi g 2. 7: ( Left) Re prese ntati ve r a w B sca n o f e pi der mis ( hi g hli g hte d) deter mi ne d b y str uct ural O C T. 
( Ri g ht) C ha n ge  i n  e pi der mal  t hic k ness  f oll o wi n g  a  4 -we e k,  t wic e -dail y  tre at me nt  r e gi me n  usi n g  
beta met has o ne valer ate ( 0. 1 %) cr ea m ( B M V) a n d Ta cr oli m us ( 0. 1 %) oi nt me nt ( T A C). 
T he s u p pr essi o n of N M F is i m p orta nt f or 2 reas o ns: ( 1) N M F pla ys a n i m p orta nt r ole i n s ki n barrier 
h o me ostasis ( p H r e g ulati o n) a n d m oist urizati o n a n d ( 2) N M F is a d o w nstrea m pr o d uct of Fila g gri n 
cata b olis m a n d s o its r e d ucti o n s u g gests a decrease i n fila g gri n le vels/ F L G ge ne (e n c o di n g fila g gri n) 
e x pr essi o n. Re d uce d fila g gri n le vels/F L G ge ne e x pressi o n is a ke y c a use of s ki n barrier d ysf u ncti o n, 
a n d patie nts e x hi biti n g a deficit of f u ncti o nal fila g gri n are pre dis p ose d t o m ore se vere, persiste nt, 
A D , de pe n di n g o n t he e xte nt of t he deficit . W hat is n ot clear fr o m t he literat ure is w het her fila g gri n 
f u ncti on itself is i m p orta nt, or its r ole i n pr o vi di n g t he material f or N M F or a c o m bi nati o n of b ot h
(t he latter bei n g m ost li kel y) d ue t o t he pi v otal f u ncti o ns of b ot h fila g gri n a n d N M F.
T o get her t he data clearl y e vi de nces t he ne gati ve l oc al a d verse effects of t o pical c ortic oster oi ds, w hic h 
ca n w orse n A D after t he a nt -i nfla m mat or y effects ha ve wa ne d f oll o wi n g T C S disc o nti n uati o n, a n d 
hel ps esta blis h a set of be nc h mar ks u p o n w hic h t o c o m par e alter nati ve t o pical a nt -i nfla m mat or y 
tr eat me nts.
2. 4 P reli mi n ar y d at a o n ne w n o vel bi o m ar kers of T C S -i n d uce d s ki n d a m a ge
W hilst str uct ur al O C T a nal ysis of e pi der mal t hic k ness pr o vi des a usef ul meas ure of T C S -i n d uce d 
s ki n atr o p h y ( Fi g 2. 7), its a p plicati o n i n A D patie nts is li mite d d ue t o a l oss of defi niti o n i n t he 
b o u n dar y bet wee n t he e pi der mis a n d der mis i n i nfla me d s ki n. T hr o u g h a d diti o nal i ma ge a nal ysis 
usi n g s oft war e de vel o pe d i n -h o use str uct ural O C T i ma ges ac q uire d usi n g t he Vi v o Si g ht cli nical O C T 
syste m ca n r e veal detaile d a n gi o gr a p hs of t he s ki n. We ha ve s h o w n t hat vasc ular c ha n ges ca n be 
ass ociate d  wit h  str uct ur al  s ki n  c ha n ges,  i ncl u di n g  e pi der mal  t hic k ness,  a n d  t hat  t he  vasc ular  
ar c hitect ur e of t he s ki n c ha n ges a p pr ecia bl y i n patie nts wit h A D (e v e n i n t he a bse nce of cli nical 
i nfla m mati o n). I m p orta ntl y t he a bilit y t o vis ualise a n d a nal yse t he vasc ul ar arc hitect ure of t he s ki n is 
n ot aff ecte d b y disease se verit y, ma ki n g it a m ore r o b ust a nal ytical a p pr oac h c o m pare d t o str uct ural 
meas ur e me nts. Fi g ur e 2. 8 ill ustr ates t he a nal ysis of t he O C T i ma ges. I n a d diti o n, a n gi o gra p hic O C T 
ma y  off er  a d diti o nal  earl y  bi o mar kers  relati n g  t o  t he  later  cli nical  a d verse  effects  of  T C S  
(tela n giectasia  a n d  he mat o mas  f or  e xa m ple).  We  t heref ore  pr o p ose  t hat  a n gi o gra p hic  O CT 
meas ur e me nts will off er m or e r o b ust a n d i nf or mati ve bi o mar kers of T C S -i n d uce d a d verse effects.
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- 3 0
- 2 0
- 1 0
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1 0
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B M V
T A C

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
A  varia nt  of  O C T,  r ef err e d  t o  p olarisati o n  se nsiti ve  ( P S) -O C T  ca n  be  use d  t o  meas ure  s ki n 
bir efri n ge nce, w hic h r elates t o t he de nsit y a n d directi o nalit y of c o lla ge n fi bres. T he u n d ue i n hi biti o n 
of c olla ge n s y nt hesis is a n a d v erse eff ect ass ociat e d wit h e pi der mal atr o p h y t hat occ urs f oll o wi n g 
pr ol o n ge d,  or  i na p pr o priate,  use  of  T C S.  We  pr o p ose  usi n g  a  c ust o m -b uilt  P S -O C T  t o  meas ure 
bir efri n ge nce bef or e a n d after  tr eat me nt t o e x pl ore w het her t his m o dalit y ca n pr o vi de a ne w n o vel 
bi o mar ker f or t he a d verse eff ects of T C Ss.  
 
Fi g 2. 8: A n gi o gra p hic a nal ysis of O C T i ma ges  
We ha ve als o use d F o urier -Tr a nsf or m I R s pectr osc o p y t o q ua ntif y t he m olec ular str uct ure of t he s ki n, 
i ncl u di n g t he le vels of car b o x ylate gr o u ps ( w hic h relate t o nat ural m oist urisi n g fact or [ N M F] le vels 
a n d  fila g gri n  ge ne  e x pr essi o n),  t he  arr a n ge me nt  of  la mellar  li pi ds  ( w hic h  als o  relates  t o  s ki n 
per mea bilit y  barrier  f u ncti o n,  T E W L),  a n d  t he  water  c o nte nt  of  t he  s ki n  a m o n g  ot her  str uct ural 
par a meters  ( Fi g ur es 2. 9  a n d 2. 1 0).  Tr eat me nt  wit h  T C S  has  bee n  s h o w n  t o  i n hi bit  e pi der mal 
diff er e ntiati o n  a n d  ne gati vel y  aff ect  li pi d  meta b olis m  i n  t he  s ki n.  T hese  c ha n ges  u n der pi n  t he 
ne gati ve eff ects of T C S o n s ki n b arrier f u ncti o n. We ha ve alrea d y de m o nstrate d t hat T C S -treat me nt 
lea ds t o t he s u p pr essi o n of N M F le vels i n strat u m c or ne u m sa m ples usi n g a H P L C-base d tec h ni q ue. 
T he a p plicati o n of F TI R t o t he assess me nt of T C S -i n d uce d s ki n c ha n g es c o ul d t heref ore i ntr o d uce a 
ne w pa nel of earl y bi o mar kers f or s ki n barrier str uct ural defects.  
A n gi o gr a p hic O C T, P S -O C T, tr a nse pi der mal water l oss a n d F TI R s ki n str uct ure meas ure me nts all 
ha ve t he p ote ntial t o pr o vi de earl y bi o mar kers relati n g t o t he a d verse effects of T C S w hic h r e q uire 
f urt her  de vel o p me nt  a n d  vali dati o n  i n  or der t o  defi ne  a n  o pti m u m  li mite d  pa nel  f or  f ut ure  use  as 
saf et y bi o mar kers i n f ut ur e cli nical trials. 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 3 3 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
Fi g 2. 9: T o p: Me a n A T R -F TI R a bs or ba nce s pectra c ollecte d at t he c u bital f ossa f or healt h y partici pa nts 
(bl ue li ne), all A D patie nts (r e d li ne), a n d se vere A D patie nts wit h cli nic al si g ns at t he test sites ( gre y li ne). 
B ott o m: Diff er e nce s pectra ( Healt h y – all A D).
Fi g 2. 1 0: C orrelati o n  bet wee n  str at u m c or ne u m N M F le vels  a n d  li pi d  str uct ur e. Li pi d  str uct ur e
was 
deter mi ne d ac c or di n g t o a pr e vi o usl y p u blis he d pr ot oc ol. F W H M, f ull wi dt h at half ma xi m u m – a s pe ctr al 
f eat ure ass ociate d wit h li pi d me m bra ne later al c hai n pac ki n g. A hi g hl y or der e d ort h or h o m bic state (t o war d 
F W H M of 1 2) is ass ociate d wit h o pti m u m per me a bilit y barrier f u ncti o n ( T E W L).
2 . 5 Ke y q uesti o ns t o be a ns were d 
I n s u m mar y t he o ver use, or i na p pr o priate use, of T C S c a uses l oc al a dverse effects t h at e x acer b ate 
t he u n derlyi n g s ki n b arrier d ef ect i n p atie nts wit h A D lea di n g t o p o or c o ntr ol of t he c o nditi o n. I n 
ac k n o wle d ge me nt of t his f act, c o u ple d wit h t he lac k of first-li ne alter nati ve treat me nt o pti o ns ( be y o n d 
T CI’s, c urr e ntl y r eser ve d as a sec o n d -li ne treat me nt wit h p o or u pta ke), a ke y q uesti o n of healt hcare 
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A mi d e II 
Li pi d 
e st er s 
N or m ali z e d t o A mi d e II 
C ar b o x yl at e 
C o n si st e nt wit h t h e d e pl eti o n of c er a mi d e s & N M F 
C H 2  s ci s s ori n g 
4 
6 
8
1 0 
1 2
0
2 0 0 0
4 0 0 0
6 0 0 0
Li pi d Str u ct ur e F W H M 1 4 6 5 c m - 1
N M F ( n m ol m g pr ot ei n)
Mil d A D
M o d er at e A D
S e v er e A D
F L G-
H e alt h y

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
pr actiti o ners a n d patie nts ali ke is “ h o w  l o n g c a n we use T C S bef ore t hey i n d uce cli nic ally relev a nt 
s ki n b arrier d a m a ge a n d s ki n t hi n ni n g” 9. 
Wit h  t he  i ntr o d ucti o n  of  ne w  tr eat me nt  o pti o ns  t he  pressi n g  q uesti o n  will  bec o me:  “ d oes t he  ne w 
tr eat me nt ca use l ocal a d verse eff ects, a n d t heref ore d oes it alter t he c urre nt treat me nt para di g m”. 
A barrier t o a d dr essi n g t hese q uesti o ns is t he a vail a bilit y of vali date d n o n -i n vasi ve earl y bi o mar kers 
f or the assess me nt of T C S -i n d uce d a d verse effects. We ai m t o t ac kle t his b arrier by ev al u ati n g t w o 
ne w  n o n -i nv asive  tec h n ol o gies  f or  assessi n g  s ki n  pr o perties t o  i de ntify  a n d  v ali d ate  a  p a nel  of 
s af ety bi o m ar kers. 
2 . 6 Selecti o n of t he st u d y  T C S  
T her e ar e a n u m b er of T C S pr e par ati o ns a vaila ble, a n d t o c o n d uct a r o b ust c o ntr olle d c o m paris o n a 
si n gle c o m par at or is r e q uir e d t o r e pr ese nt T C S’s as a class. A brea k d o w n of t he 1 0 m ost c o m m o nl y 
pr escri be d  t o pical  c ortic oster oi d  pr e parati o ns  (e xcl u di n g  pre parati o ns  wit h  a d diti o nal  acti ve 
i n gr e die nts, s uc h as a nti-f u n gal a n d a nti bi otic a ge nts) b y t he Nati o nal Healt h Ser vice i n E n gla n d f or 
2 0 1 6 is pr o vi de d i n t he ta ble bel o w.  I n ter ms of ris k, mil d T C S’s s uc h as h y dr oc ortis o ne crea m 1 %, 
e x hi bit  t he  least  ris k  of  l ocal  a d ver se  effects,  a n d  s o  were  eli mi nate d  fr o m  o ur  selecti o n. 
Beta met has o ne valer ate cr ea m is t her ef or e t he m ost wi del y prescri be d T C S i n t he U K a n d a p pr o priate 
f or o ur st u d y p o p ulati o n, ma ki n g it o ur c h ose n re prese ntati ve T C S f or t his st u d y i n b ot h p ote nt ( 0. 1 %) 
a n d m o der atel y p ote nt ( 0. 2 5 %) cr ea m f or ms.  
T a ble 2. 1:  T C S r a n ke d b y pr escri pti o ns  
Ra n k  Na me (acti ve c o m p o u n d)  
P ote nc y  
( 2 0 0 7  
NI C E 
g ui deli nes)  
N u m ber  of  Ite ms 
iss ue d 
1  
H y dr oc ortis o ne crea m 1 %  
Mil d  
1, 5 0 4, 5 6 9  
2  
B eta met has o ne Valerate crea m 0. 1 %  
P ote nt  
1, 0 5 3, 9 9 9  
3  
B eta met has o ne Valerate oi nt me nt 0. 1 %  P ote nt  
6 1 9, 2 1 4  
4  
Cl o betas o ne b ut yrate 0. 0 5 % crea m  
M o deratel y p ote nt  
6 0 8, 5 8 6  
5  
Cl o betas o ne b ut yrate 0. 0 5 % oi nt me nt  
M o deratel y p ote nt  
5 2 1, 2 5 8  
6  
H y dr oc ortis o ne oi nt me nt 1 %  
Mil d  
4 7 1, 7 6 8  
7  
M o metas o ne F ur oate o i nt me nt 0. 1 % 
P ote nt  
4 3 6, 6 1 8  
8  
Cl o betas o ne Pr o pri o nate oi nt. 0. 0 5 %  
Ver y p ote nt  
3 8 9, 2 9 2  
9  
Cl o betas o ne Pr o pri o nate 0. 0 5 % crea m  
Ver y p ote nt  
3 5 2, 0 7 8  
1 0  
M o metas o ne F ur oate crea m 0. 1 %  
P ote nt  
3 4 4, 3 0 2  
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
2. 7 Cris a b or ole  
Crisa b or ole  is a l o w  m olec ular  wei g ht n o nster oi dal be nz o xa b or ole  p h os p h o diesterase  4  (P D E -4 ) 
i n hi bit or. T he r o ute of a d mi nistr ati o n is t o pical i n a 2 % oi nt me nt pre parati o n. P D E -4 i n hi biti o n res ults 
i n  i ncr ease d  i ntr acell ular  c yclic  a de n osi ne  m o n o p h os p hate  (c A M P)  le vels.  W hile  t he  s pecific 
mec ha nis m(s)  b y  w hic h  crisa b or ole  e xerts  its  t hera pe utic  acti o n  is  n ot  well  defi ne d,  crisa b or ole 
re d uces t he pr o d ucti o n of se ver al i nfla m mat or y c yt o ki nes i m plicate d i n t he pat h o p h ysi ol o g y of A D 
a n d ot her i nfla m mat or y s ki n diseases, i ncl u di n g T N F -a , I F N-γ, I L-2,  I L-5, I L -6, I L -1 0, I L -1 2, a n d 
I L-2 3 . Crisa b or ole a p plie d t o h u ma n s ki n ex viv o or o n A D  lesi o ns of patie nts re d uces e x pressi o n of 
ke y  dri vers  of A D  i ncl u di n g  T-cell  deri ve d  c yt o ki nes  i nterle u ki n  (I L) -1 3,  I L -3 1,  a n d  i nterfer o n 
ga m ma (I F N -γ) as well as i n nate mar kers of i nfla m mati o n s uc h as matri x-metall o pr otei nase ( M M P) -
1 2. T he cli nical efficac y a n d saf et y of crisa b or ole ha ve bee n de m o nstrate d i n 2 P hase 3 ra n d o mise d 
c o ntr olle d trials a n d 1 P hase 3 o pe n la bel e xte nsi o n st u d y. Crisa b or ole 2 % oi nt me nt , a p plied t wice 
per da y t o aff ecte d s ki n,  r ece ntl y de m o nstrate d cli nical efficac y i n t he treat me nt of mil d-m o derate 
A D.  
T he  t w o  P hase  3,  m ultice nter,  r a n d o mize d,  d o u ble -bli n d,  ve hicle -c o ntr olle d  st u dies  e val uate d  t he 
efficac y a n d saf et y of crisa b or ole i n patie nts  ≥ 2 years of a ge wit h mil d t o m o derate A D affecti n g at 
least 5 % b o d y s urf ace ar ea ( B S A). A statisticall y si g nifica ntl y hi g her perce nta ge of patie nts i n t he 
crisa b or ole gr o u p met criteria f or s uccess as meas ure d b y t he I n vesti gat or’s Static Gl o bal Assess me nt 
(I S G A) scale (sc or e of 0 or 1 a n d ≥ 2-p oi nt i m pr o ve me nt fr o m baseli ne) c o m pare d wit h t h ose gi ve n 
ve hicle  at  Da y  2 9  (st u d y  A D -3 0 1:  p = 0. 0 3 8  a n d  st u d y  A D -3 0 2:  p < 0. 0 0 1). C risa b or ole  treat me nt 
res ulte d i n a statisticall y si g nifica ntl y hi g her perce nta ge of patie nts wit h A D rate d as clear or al m ost 
clear (sc or e of 0 or 1 o n I S G A) at Da y 2 9 t ha n ve hicle treat me nt (st u d y A D -3 0 1: p = 0. 0 0 5 a n d st u d y 
A D -3 0 2: p < 0. 0 0 1). A pr e -defi ne d s u p p orti ve efficac y e n d p oi nt of Ti me t o I m pr o ve me nt i n Pr urit us 
was defi ne d as a pr uri t us sc or e of N o ne [ 0] or Mil d [ 1] wit h at least a 1-gra de i m pr o ve me nt fr o m 
baseli ne ( o n a scale of 0 [ n o ne], 1 [ mi l d], 2 [ m o derate], 3 [se vere]). T he crisa b or ole gr o u p ac hie ve d 
I m pr o ve me nt i n Pr urit us earlier t ha n ve hicle ( p o ole d data, 1. 3 7 da ys vs 1. 7 0 days, p = 0. 0 0 1).  
T he maj orit y of a d verse e ve nts ( A Es) wit h crisa b or ole were mil d i n se verit y; t here were n o treat me nt -
relate d seri o us a d verse e ve nts ( S A Es) r e p orte d wit h crisa b or ole. T here were n o cli nicall y rele va nt 
diff er e nces b y a ge gr o u p i n t he i nci de nce , t y pes, or se verit y of A Es, relati o ns hi p of A Es t o st u d y dr u g, 
or t he i nci de nce of A Es lea di n g t o pr e mat ure wit h dra wal fr o m t he st u dies. T he l o n g -ter m saf et y of 
crisa b or ole was f urt her e val uate d i n patie nts w h o c o nti n ue d i nt o t he o pe n -la bel e xte nsi o n st u dy.  
T he  P hase  3,  o pe n -la bel,  si n gle-ar m  e xte nsi o n  st u d y  c o nfir me d  t he  t olera bilit y  of  crisa b or ole  f or 
tr eat me nt of mil d-t o-m o der ate A D u p t o 4 8 wee ks. T his st u d y i ncl u de d c hil dre n ( 2 -1 1 years of a ge), 
a d olesce nts ( 1 2 -1 7 years of a ge) a n d a d ults ( ≥1 8 years of a ge). T he maj orit y of A Es were mil d or 
m o der ate i n se verit y. T her e was n o cli nicall y si g nifica nt differe nce bet wee n a ge gr o u ps i n t he e xte nt 
of e x p os ur e t o crisa b or ole or t he i nci de nce of A Es.  
T her e was n o e vi de nce of si g nifica nt or l o n g -ter m c uta ne o us a d verse reacti o ns at t he  a p plicati o n site 
s uc h as atr o p h y, tela n giectasia, or h y p o pi g me ntati o n d uri n g s h ort-ter m or l o n g-ter m i nter mitte nt use 
of crisa b or ole.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
Base d u p o n t he efficac y a n d saf et y of crisa b or ole 2 % oi nt me nt (tra de na me E U C RI S A) de m o nstrate d 
i n t hese st u dies, t he dr u g was a p pr o ve d  f or t he treat me nt of mil d t o m o derate A D i n patie nts 2 years 
a n d ol der b y t he U nite d States ( U S ) F o o d a n d Dr u g A d mi nistrati o n  ( F D A) o n 1 4 Dece m ber 2 0 1 6. 
Crisa b or ole ( 2 %) oi nt me nt is c urr e ntl y a n a p pr o ve d t hera p y i n t he U nite d States ( U S) a n d Ca na da 
( E U C RI S A® ), a n d Isr ael a n d A ustr alia ( S T A Q UI S® ) as a t o pical treat me nt i n patie nts 2 years of a ge 
a n d ol der wit h mil d t o m o der ate A D.  It is c urre ntl y bei n g de vel o pe d w orl d wi de as a t o pical t hera p y 
f or patie nts wit h mil d t o m o der ate A D. F urt her details o n crisa b or ole ca n be f o u n d i n  t he crisa b or ole 
I n vesti gat or’s Br oc h ur e (I B). 
2. 8  Assess m e nt a n d m a n a ge m e nt of ris k  
2. 8. 1  P ote nti al et hic al iss ues arisi n g fr o m t his st u dy  
I n or der t o deter mi ne a set of saf et y bi o mar kers it is necessar y t o c haracterise a n u nsafe treat me nt 
sce nari o, w hic h r aises i m p orta nt et hical q uesti o ns a b o ut as ki n g partici pa nts/ patie nts t o u n derta ke a 
tr eat me nt t hat ma y ca use t he m har m. It is i m p orta nt t o hi g hli g ht t hat t his st u d y f oc uses o n ‘earl y’ 
‘tr a nsie nt’ si g ns  of ‘s ki n  atr o p h y’,  a n d  s o t here  is  n o  i nte nti o n  t o  i n d uce  cli nical  ( visi ble)  a d verse 
eff ects.  We  ha ve  alr ea d y  esta blis he d  t hat  4  wee ks  of  treat me nt  wit h  beta met has o ne  valerate  0. 1 % 
i n d uces  s u b-cli nical  s ki n  barrier  disr u pti o n  a n d  e pi der mal  s ki n  t hi n ni n g  wit h o ut  i n d uci n g  cli nical 
a d verse eff ects. P u blis he d liter at ur e f urt her de m o nstrates t hat e pi der mal s ki n t hi n ni n g i n d uce d d uri n g 
s h ort  c o urses  of  t o pical  c ortic oster oi d  treat me nt  is  tra nsie nt,  wit h  s ki n  ret ur ni n g  t o  pre-treat me nt 
t hic k ness wit hi n a matter of wee ks f oll o wi n g cessati o n of treat me nt.  
M or e o ver, it is i m p orta nt t o r ec o g nise t hat t he treat me nt re gi me n pr o p ose d c o nf or ms t o t he c urre nt 
mar keti n g  lice nce  f or  Bet n o vate  cr ea m  a n d  is  i n  li ne  wit h  sta n dar d  treat me nt  practice  f or  at o pic 
der matitis ,  wit h  beta met has o ne  valer ate  crea ms  bei n g  wi del y  prescri be d  (1, 0 5 3, 9 9 9  prescri pti o n 
ite ms i n 2 0 1 6). T her e is t her ef or e a str o n g et hical ar g u me nt t o i de ntif y a n y p ote ntial har m usi n g t his 
pr o d uct ma y ha ve.   
I n s h ort, we d o n ot e x pect t o c o m pr o mise t he safe t y of partici pa nts as a res ult of t heir ta ki n g part. 
Ne vert heless,  we will m o nit or a n d r e p ort a n y a d verse e ve nts, a n d cease treat me nt i n a n y partici pa nt 
s h o wi n g cli nical si g ns of s ki n atr o p h y, a d di n g a le vel of safet y a b o ve t hat of sta n dar d care. 
T he  st u d y  is  n ot  e x pecte d  t o  r aise  a n y  ot her  si g nifica nt  et hical  iss ues  a b o ve  a n d  be y o n d  t h ose 
ass ociate d wit h c o n d ucti n g cli nical r esearc h.  
2. 8. 2 P ote nti al risks ass oci ate d wit h t he  I M P 
T he st u d y i n v ol ves t w o t o picall y a d mi nistere d I M P’s: crisa b or ole ( 2 %) oi nt me nt  a n d beta met has o ne 
valer ate ( 0. 1 %) cr ea m. B ot h I M P’s will be pr o vi de d t o eac h partici pa nt f or c o nc urre nt use o n differe nt 
s ki n sites ( o ne o n eac h f or ear m).  
•  Beta met has o ne valer ate ( 0. 1 2 2 %) cr ea m is a t o pical pre parati o n of 0. 1 2 2 % ( w/ w) beta met has o ne 
valer a te i n a petr olat u m base c o ntai ni n g t he f oll o wi n g e xci pie nts: C hl or ocres ol B P, Cet o macr o g ol 
1 0 0 0  B P,  Cet ostear yl  Alc o h ol  B P,  W hite  S oft  Paraffi n  B P,  Li q ui d  Paraffi n  B P,  S o di u m  Aci d 
P h os p hate B P, P h os p h oric Aci d B P, S o di u m H y dr o xi de B P P urifie d Water B P . with a M A i n t he 
U K  ( P L  1 0 9 4 9/ 0 0 1 4)  u n der  t he  br a n d  na me  Bet n o vate  crea m.  Classifie d  as  a  p ote nt  t o pical 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
c ortic oster oi d, t he Bet n o vate cr ea m will be use d i n acc or da nce wit h t his M A. T he M A H is Gla x o 
Wellc o me U K Lt d. A c o p y of t he S m P C is i ncl u de d i n t he a p pli cati o n. 
•  Crisa b or ole  ( 2 %) 
oi nt me nt  is  a  t o pical  pre parati o n  of  2 %  ( w/ w)  crisa b or ole 
(p h os p h o diester ase  4  i n hi bit or)  i n  a  petr olat u m  base  c o ntai ni n g  t he  f oll o wi n g  e xci pie nts: 
w hite 
p etr olat u m , pr o p yle ne  gl yc ol,  m o n o - a n d  di-gl yceri des,  paraffi n,  b ut ylate d 
h y dr o x yt ol ue ne, a n d e detate calci u m dis o di u m.  W hilst n ot c urre ntl y lice nce d i n t he U K or 
wi der E U, crisa b or ole ( 2 %) oi nt me nt  has a U S PI i n t he U S (si nce Dece m ber 2 0 1 6), u n der t he 
br a n d na me E ucrisa, f or tr eat me nt of mil d t o m o derate at o pic der matitis i n pati e nts 2 years of 
a ge a n d ol der. I n t his st u d y crisa b or ole ( 2 %) oi nt me nt  will be use d i n acc or da nce wit h t his 
mar ket a ut h orizati o n. T he M A H is Pfizer.  A c o p y of t he U S PI  is i ncl u de d i n t his a p plicati o n. 
Si nce t he I M P d oes n ot ha ve mar keti n g a ut h orizati o n f or  t he U K a n I n vesti gat or Br oc h ure is 
als o i ncl u de d i n t he a p plicati o n a n d t he trial will re q uire a ut h orizati o n b y M H R A, rat her t ha n 
n otificati o n t o M H R A.  
T we nt y -fi ve ( 25 ) cli nical trials of t o pical f or m ulati o ns of crisa b or ole ha ve bee n c o m plete d t o date, 
w it h a t otal of 2 2 2 7  partici pa nt s e x p ose d t o o ne or m ore crisa b or ole f or m ulati o ns. Crisa b or ole  has 
bee n well t oler ate d acr oss c o m plete d cli nical st u dies. N o cli nicall y i m p orta nt s yste mic safet y si g nals 
ha ve bee n i de ntifie d. M ost a d verse e ve nts ( A Es) ha ve be e n mil d, a n d m ost c o nsi dere d u nrelate d or 
u nli kel y t o be r elate d t o st u d y dr u g. T he m ost c o m m o n dr u g -relate d A Es ha ve bee n a p plicati o n site 
reacti o ns. T he F D A s u m marize d t hat at t his ti me t he safet y pr ofile of crisa b or ole oi nt me nt a p pears 
m or e f a v o ur a ble t ha n t o pical c ortic oster oi ds or calci ne uri n i n hi bit ors b ut less fa v o ura ble t ha n de vice 
cr ea ms.  
Gi ve n t hat t he use of t o pical c ortic oster oi ds, i ncl u di n g beta met has o ne valerate crea m, a n d calci ne uri n 
i n hi bit ors  ar e  sta n dar d  me dical  car e  f or  at o pic  der matitis patie nts  i n  t he  U K,  a n d  t hat  crisa b or ole 
oi nt me nt  is pr ese ntl y mar kete d f or t his c o n diti o n i n t he U S a n d Ca na da b ut n ot yet mar kete d i n t he 
U K , t he ris ks ass ociate d wit h t his st u d y ha ve bee n classifie d as ris k cate g or y B; s o me w hat hi g her 
t ha n t he ris k of sta n dar d me dical car e. A f ull st u d y -s pecific ris k assess me nt is attac he d (see a p pe n di x).  
M or e detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y e x pe cte d 
a d verse  e ve nts  ( A Es)  of  crisa b or ole  ma y  be  f o u n d  i n t he I B,  w hic h  is t he  si n gle  refere nce  safet y 
d oc u me nt ( S R S D) f or t his st u d y.  
O n t he basis t hat t his ris k assess me nt, patie nt safet y will be m o nit ore d l ocall y b y t he PI a n d wi der 
trial ma na ge me nt gr o u p. A data m o nit ori n g c o m mittee will n ot be i m ple me nte d, base d u p o n t he level 
of ris k i de ntifie d a b o ve, t he i ncl usi o n of a si n gle site o nl y a n d t he s h ort d urati o n of treat me nt. Safet y 
data  ( A E  r e p orti n g)  will  be  c ollecte d  i n  a n  o n g oi n g  ma n ner  a n d  re vie we d  b y  t he  st u d y  m o nit or 
a p p oi nte d b y t he S p o ns or. Saf et y will be re vie we d re g ularl y at Trial Ma na ge me nt Gr o u p meeti n gs . 
2. 8. 3  P ote nti al risks a n d b ur de ns ass oci ate d wit h t he  ski n pr oce d ures 
T his st u d y i n v ol ves a series of n o n -i n vasi ve pr oce d ures t o test t he bi o p h ysical pr o perties of t he s ki n. 
T hese pr oce d ures ha ve all bee n use d saf el y i n pre vi o us cli nical st u dies, a n d s o t he ris ks of har m are 
mi ni mal. T he O C T a n d P S -O C T e q ui p me nt c o m prises a class 1 M laser a n d C lass 3 laser atte n uate d 
d o w n t o class 1 A E L r es pecti vel y, ma ki n g t he m safe f or t he pr o p o se d testi n g u n der n or mal o perati n g 
c o n diti o ns. A r e g ular mai nte na nce pla n  a n d ris k assess me nt  has bee n de vel o pe d t o miti gate t he ris ks 
of partici pa nts bec o mi n g e x p ose d t o t he u natte n uate d Class 3 laser.  T he s ki n sites f or assess me nt are 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
all l ocate d o n t he v olar si de of t he f or ear m, a n d s o p artici pa nts will o nl y be re q uire d t o r oll u p t heir 
slee ves f or t he tests t o be perf or me d.  
T he  f oll o wi n g  ste ps  will  be  ta ke n  t o  a v oi d  a n y  ris k  of  p h ysical  a n d/ or  ps yc h ol o gical  har m  t o 
partici pa nts:  
•  Partici pa nts will be n otifie d i n a d va nce of t he a nat o mical  l ocati o ns we are i ntereste d i n (f orear ms 
o nl y) a n d e nc o ur a ge d t o wear a p pr o priate cl ot hi n g.  
•  E x perie nce d me m bers of staff w h o ha ve recei ve d a p pr o priate trai ni n g will c o n d uct all of t he test 
pr oce d ur es. T his i ncl u de s laser safet y trai ni n g i n or der t o o perate t he O C T a n d P S -O C T de vices.  
•  T he  e q ui p me nt  r e g ularl y  u n der g oes  mai nte na nce,  perf or ma nce  verificati o n  a n d  bi o me dical 
e n gi neeri n g  testi n g  f or  acc ur ac y  a n d  safet y.  T his  i ncl u des  assess me nt  of  laser  safet y  b y  t he 
S p o ns or bi o me dical e n gi neeri n g de part me nt.  
•  I n di vi d ual pr oce d ur es will o nl y be perf or me d wit h partici pa nt asse nt (i n a d diti o n t o c o nse nt), a n d 
w her e partici pa nts f eel disc o mf ort we will cease t he pr oce d ures a n d offer a brea k –  we w o ul d 
t he n o nl y c o nti n ue wit h asse nt. 
2. 8. 4  P ote nti al risks ass oci ate d wi t h t he sa m ple c ollecti o n  
T w o  t y pes  of  sa m ples  will  be  c ollecte d  i n  a  n o n /mi ni mall y -i n vasi ve  wa y:  ( 1)  s u perficial  strat u m 
c or ne u m (s ki n) sa m ples b y ta pe -stri p pi n g a n d ( 2) sali va sa m ples b y b uccal s wa b bi n g. T a pe stri p pi n g 
is a pai nless pr oce d ur e, t hat r e m o ves t he dea d cells ( de n ucleate d c or ne oc ytes) fr o m t he s urface of t he 
s ki n t hat will e ve nt uall y be l ost/s he d as a r es ult of n or mal des q ua mati o n. It ca n ca use s o me disc o mf ort 
a n d r e d ness, b ut a n y r e d ness us uall y dissi pates i n a matter of h o urs/ da ys. N o dressi n gs are re q uire d. 
T a pe -stri p pi n g will n ot be perf or me d o n br o ke n s ki n. T he pr oce d ure is n o w r o uti nel y use d i n cli nical 
trials i n partici pa nt s of all a ges fr o m birt h u p war ds. T he strat u m c or ne u m re ge nerates f ull y e ver y 2 
wee ks a n d s o t he 2 8 -da y f oll o w -u p is s ufficie nt t o e ns ure ta pe-stri p pe d sites are f ull y heale d. 
2. 8. 5  P ote nti al  b ur de n of t aki n g p art  
D ue t o t he n u m ber of site visits a n d t he fr e q ue nc y of c o m plia nce c hec ks t here is a si g nifica nt b ur de n 
o n partici pa nts ti me. T his b ur de n will be lesse ne d b y pr o vi di n g ta xi tra ns p ort t o a n d fr o m t he test 
ce ntr e. Partici pa nts  will  als o  be  r e m u ner ate d f or  t he  b ur de n t he y  e n d ure,  w hic h  ma y  i n v ol ve  ti me 
ta ke n o ut of w or k f or e xa m ple ( wit h r e m u nerati o n bei n g c o m me ns urate wit h t he le vel of i n v ol ve me nt 
f or t h ose n ot c o m pleti n g t he f ull st u d y).  
2. 8. 6  D at a m a n a ge me nt  iss ues arisi n g fr o m t his st u dy 
T he st u d y i n v ol ves t he c ollecti o n of a n u m ber of i nstr u me ntal s ki n meas ure me nts (rea di n gs ta ki n g 
fr o m  s ki n  dia g n ostic  de vices)  a n d  s ki n  i ma ges  a n d  s pectra  (as  ra w  data  files).  T o e ns ure  s ki n 
meas ur e me nts ar e acc ur atel y d oc u me nte d t he y will be directl y e ntere d i nt o a n electr o nic case rec or d 
f or m ( e C R F) de vel o pe d b y E pi ge nesis at t he ti me of ca pt ure ( n o pa per s o urce f or s ki n meas ure me nts). 
T he  s yste m  will  utilise  data  fiel d  e ntr y  li mits  t o  i m me diatel y  fla g  u p  t o  t he  researc her  a n y  val ue 
e nter e d t hat d oes n ot c o nf or m t o e x pecte d p h ysi ol o gical ra n ges a d di n g i n a la yer of data i nte grit y 
c hec ki n g n ot p ossi ble wit h pa per r ec or ds. T o e ns ure t he vali dit y of t hese rec or ds as tracea ble s o urce  
d oc u me nts,  electr o nic  f or ms  will  be  pri nte d  o n  t he  da y  of  ca pt ure  a n d  si g ne d  b y  t he  researc her 
c ollecti n g  t he  data.  Access  t o  t he  e C R F  will  be  user  c o ntr olle d,  wit h  all  e ntries  a n d  s u bse q ue nt 
c ha n ges tr ac ke d t o pr e ve nt data ma ni p ulati o n. T he data base will  be ma n ge d b y E pi ge nesis.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 3 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T o pr eser ve t he i nte grit y of s ki n i ma ges a n d s pectra, t he files will be directl y tra nsferre d via i ntra net 
c o n necti o n t o t he sec ur e st u d y ser ver ma na ge d b y t he U ni versit y of S heffiel d. All files will be date 
sta m pe d a n d c ollecti o n will be tr ac ke d i n t he ass ociate d e C R F.  
Access t o t he e C R F a n d st u d y ser ver will be restricte d t o o nl y t he s yste m a d mi nistrat ors a n d t he direct 
st u d y tea m as per dele gati o n i n t he st u d y dele gati o n l o g. 
2. 8. 7  R ete nti o n of s a m ples at t he e n d of t he st u dy  
N o  materials r ele va nt u n der t he H u ma n Tiss ue Act will be ke pt be y o n d t he e n d of t his st u d y.  
T he  ta pe -stri p  sa m ples  ar e  n ot  c o nsi der e d  rele va nt  material  u n der  t he  H u ma n  Tiss ue  Act  as  o nl y 
e n ucleate d n o n -via ble c or ne oc ytes ar e c ollecte d. It is p ossi ble t hat via ble cells are c ollecte d as ta pe-
stri p pi n g nears c o m plete r e m o val of t he strat u m c or ne u m s ki n la yer (t o war ds t he 2 0 t h c o nsec uti ve 
ta pe-stri p). T o miti gate a n y s mall ris k of o btai ni n g t hese cells, ta pe-stri ps 1 1-2 0 will be st ore d o nl y 
after l ysis i n R L T b u ff er. S pecific c o nse nt will be o btai ne d fr o m partici pa nts t o st ore  t heir s u perficial 
s ki n sa m ples be y o n d t he e n d of t his st u d y f or use i n f ut ure pr ojects. 
T he  sali va  sa m ples c ollecte d will  be  pr ocesse d  d uri n g  t he  c o urse  of  t his  st u d y  t o  is olate  ge n o mic 
D N A . S pecific c o nse nt will be o btai ne d fr o m partici pa nts t o st ore t his ge n o mic D N A be y o n d t he e n d 
of t his st u d y.  
2. 8. 8  Risk of bre ac h of c o nfi de nti ality  
We will ta ke ste ps t o pr eser ve t he c o nfi de ntialit y of partici pa nts. T he partici pa nts i n t his st u d y will 
be  a d vise d t hat t heir st u d y data will be hel d sec urel y, i de ntifie d o nl y b y a u ni q ue st u d y n u m ber, a n d 
t hat all pers o nal i nf or mati o n will be ke pt strictl y c o nfi de ntial. I de ntif yi n g pers o nal details will o nl y 
be ke pt o n t he st u d y r e gistr ati o n f or m a n d t he P art ici p a nt Scree ni n g, E nr ol me nt & C o m pleti o n L o g . 
T hese  d oc u me nts  pr o vi de  t he  o nl y  li n k  bet wee n  pers o nal  i de ntifia ble  i nf or mati o n  a n d  t he  st u d y  
partici pa nt  n u m ber,  a n d  will  be  ke pt  se paratel y  fr o m  st u d y  data,  a n d  st ore d  sec urel y  i n  t he  st u d y 
office.  T he i nf or mati o n i n t he st u d y r e gistrati o n f or m is als o st ore d se paratel y i n t he S D R v ol u nteer 
data base w her e s pe cific c o nse nt is pr o vi de d i n t he c o nse nt f or m f or a peri o d li mite d t o n o m ore t ha n 
5 years.  
 
 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 4 0 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
3. R A TI O N A L E
3. 1 T he nee d f or ne w bi o m ar kers t o e v al u ate t he s afet y of tre at me nts f or at o pic der m atitis
T he first -li ne dr u g tr eat me nt f or mil d-m o derate A D is c urre ntl y a t o pical c ortic oster oi d ( T C S). T C S 
ar e cli nicall y efficaci o us, h o we ver t heir pr ol o n ge d, or i na p pr o priate use, ca n lea d t o l ocal a d verse 
eff ects. T hese  eff ects  i ncl u de  e pi der mal  atr o p h y,  s u p pressi o n  of  s ki n  barrier  h o me ostasis  (i. e.  
decr ease d e x pr essi o n of fila g gri n a n d its d o w nstrea m meta b olites), a n d re d uce d per mea bilit y barrier 
f u ncti o n. F or t he p ote nt T C S beta met has o ne valerate ( 0. 1 %) crea m t hese effects a p pear wit hi n 4 
wee ks of tr eat me nt w he n a p plie d t o cli nicall y clear s ki n. T hese a d verse effects li mit t he cli nical utilit y 
of T C S, a n d u n der pi n t he cli nical nee d f or alter nati ve treat me nt a p pr oac hes a n d alter nati ve t o pical 
a nti-i nfla m mat or y tr eatme nts f or A D. A barrier t o assessi n g t he safet y (l ocal a d verse effects) of ne w 
tr eat me nts a n d tr eat me nt a p pr oac hes is t he a bilit y t o n o n-i n vasi vel y m o nit or earl y s ki n (s u bcli nical)
c ha n ges ass ociate d wit h t he l ocal cli nical a d verse effects of T C S.
T her e is a nee d t o f urt her de vel o p a n d vali date ne w n o n -i n vasi ve tec h n ol o gies f or t he assess me nt of 
earl y s u b-cli nical s ki n c ha n ges ass ociate d wit h T C S a d verse effects a n d t o deri ve a n o pti m u m pa nel 
of saf et y bi o mar kers f or use i n f ut ur e cli nical trials of t o pical a nti-i nfla m mat or y treat me nts.
•
Rese arc h Q uesti o n 1:
D o O C T -deri ve d bi o mar kers e na ble t he acc urate q ua ntificati o n of 
e pi der mal atr o p h y i n r es p o nse t o T C S treat me nt
•
Rese arc h  Q uesti o n  2:
D o  F TI R  s pectr osc o p y -deri ve d  bi o mar kers  e na ble  t he  acc urate  
q ua ntificati o n of s ki n barrier c o n diti o n a n d f u ncti o n i n res p o nse t o T C S treat me nt
I n or der t o a ns wer t he r esear c h q uesti o ns raise d a b o ve a pr o gra m of researc h has bee n de vel o pe d as 
o utli ne d i n Fi g 3. 1. 
Fi g ure 3. 1: O ver vie w of t he r esearc h pr o gra m me
Ste p 1 i n v ol ves t he c ollecti o n of data o n t he earl y s u b -cli nical s ki n c ha n ges ass ociate d wit h T C S 
tr eat me nt usi n g t he n o n -i n vasi ve tec h n ol o gies; O C T a n d F TI R s pectr osc o p y. T his pr ot oc ol details 
t he cli nical st u d y desi g ne d t o meet t he ne e ds of  t his first ste p . T he safet y of t w o t o pical a nti -
i nfla m mat or y tr eat me nts f or A D will be c o m pare d, wit h a f oc us o n earl y s u b-cli nical si g ns. 
T h e data fr o m t his st u d y will t he n be use d t o i de ntif y a n d refi ne bi o p h ysical bi o mar kers of s ki n 
atr o p h y a n d s ki n barrier disr u pti o n i n ste ps 2 a n d 3. I n a sec o n d cli nical st u d y t he vali dit y of t he ne wl y 
i de ntifie d bi o mar kers will be de m o nstr ate d ( o utsi de t he sc o pe of t his pr ot oc ol).
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S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
3. 2 R ati o n ale f or selecti n g b et a m et h as o ne v aler ate 0. 1 % cre a m  
T he  T C S  beta met has o ne  valer ate  is  t he  c h ose n  c o m pa rat or  base d  u p o n  U K  prescri bi n g  data  (see 
secti o n 1. 5), a n d beca use we ha ve esta blis he d t hat t his p ote nc y of T C S i n d uces earl y ‘s u b-cli nical’ 
s ki n c ha n ges i n t he test s yste m. 
C o m pari n g a gai nst t he cr ea m pr e par ati o n of beta met has o ne valerate kee ps para meter s c o nsiste nt wit h 
o ur pr e vi o usl y teste d m o del. Beta met has o ne valerate 0. 1 % crea m is t he m ost fre q ue ntl y prescri be d 
pr e par ati o n of T C S i n t he U K ( e xcl u di n g t he mil d T C S h y dr oc ortis o ne), ma ki n g it t he pra g matic first 
c h oice.  
3. 3 R ati o n ale f or selecti n g Cris a b or ole ( 2 %) oi nt me nt  
I n t w o p hase-3 cli nical st u dies, t wice dail y treat me nt wit h crisa b or ole ( 2 %) oi nt me nt  f or 4 wee ks was 
f o u n d t o be a n efficaci o us a n d well-t oler ate d treat me nt f or mil d-m o derate at o pic der matitis/ecze ma 
( A D)  w he n  c o m par e d  t o  n o  tr eat me nt.  T o  ai d  cli nical  decisi o n-ma ki n g  i n  t he  treat me nt  of  mil d -
m o der ate A D a c o m paris o n bet wee n t he l ocal effects of crisa b or ole ( 2 %) oi nt me nt  a n d a p ote nt T C S 
o n t he s ki n is r e q uir e d. As a ne w t o pical a nti -i nfla m mat or y a n d n o nster oi dal treat me nt f or A D, wit h 
n o  r e p orte d T C S -li ke l ocal  a d verse  eff ects,  crisa b or ole  is  t he  i deal  c o m parat or  f or  T C S  i n  t he 
de vel o p me nt of ne w saf et y bi o mar kers.  
Ai m  of t his st u d y : T o deter mi ne t he r elati ve l ocal s ki n effects of crisa b or ole ( 2 %) oi nt me nt  c o m pare d 
t o a p ote nt a n d m o deratel y p ote nt T C S i n partici pa nts wit h A D. T he f oc us is o n ‘earl y bi o mar kers’ 
of ‘l ocal s ki n c ha n ges’, a n d n ot cli nical efficac y, w hic h has bee n esta blis he d i n pre vi o us trials.  
•  Rese arc h  Q uesti o n  3:  D oes crisa b or ole ( 2 %) oi nt me nt ,  ca use  s ki n  barrier  da ma ge  an d 
e pi der mal atr o p h y , a n d if s o h o w d oes it c o m pare wit h a p ote nt a n d m o deratel y p ote nt T C S?  
Crisa b or ole ( 2 %) oi nt me nt  will be c o m par e d t o t he p ote nt T C S, Beta met has o ne valerate 0. 1 % cr ea m , 
i n t his st u d y a n d t o t he m o der atel y p ote nt T C S Beta met has o ne valerate 0. 0 2 5 % crea m i n a s u bse q ue nt 
st u d y. 
T her e is t he p ote ntial t hat i n t he a bse nce of atr o p hic effects crisa b or ole ( 2 %) oi nt me nt  will e xert a 
p ositi ve  a d diti o nal  be nefit  o n  t he  s ki n  ( pr o m otes healt h y  s ki n  barrier)  ass ociate d  wit h  t he  s pecific 
t o pical  f or m ulati o n  bei n g  teste d.  T he  base ( ve hicle) c o ntai ns  i n gre die nts  ot her  t ha n  t he  acti ve, 
i ncl u di n g b ut n ot li mite d t o petr olat u m  a n d b ut ylate d h y dr o x yt ol ue ne ( B H T ), t hat ha ve t he p ote ntial 
t o i n de pe n de ntl y (fr o m t he acti ve) pr o m ote a healt h y s ki n barrier. As s uc h a n y effect re p orte d c o ul d 
o nl y be ass ociate d wit h t he c o m plete pr e parati o n u n der i n vesti gati o n (i. e. acti ve c o m bi ne d wit h base) 
a n d c o ul d n ot be ge ner alize d t o a n y ot her t o pical pre parati o n c o ntai ni n g crisa b or ole. T he bi o mar kers 
of s ki n barrier str uct ur e ( F TI R-base d) ma y t heref ore pr o vi de a d diti o nal i nf or mati o n o n A D relate d 
p ositi ve  tr eat me nt  eff ects,  i n  a d diti o n  t o t he  prese nce  or a bse nce  of ne gati ve  effects,  t hat  ca n  be 
e x pl or e d wit hi n t he r e mit of t his st u d y ( as part of researc h q uesti o n 2).  
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
3. 4  S t u d y Ai m 
•  T o dir ectl y c o m par e t he eff ects of crisa b or ole ( 2 %) oi nt me nt  t o t he p ote nt T C S beta met has o ne 
valer ate ( 0. 1 %) cr ea m o n t he pr o perties of t he s ki n usi n g a n esta blis he d m o del f or q ua ntif yi n g t he 
l ocal a d verse eff ects of T C S.  
B y ac hie vi n g t his ai m, w e will pr o vi de t he data ne e de d t o i de ntif y t he m ost i nf or mati ve bi o mar kers 
of e pi der mal atr o p h y/l ocal a d verse eff ects of T C S treat me nt usi n g m ulti variate a nal ysis tec h ni q ues 
a n d de vel o p a pr eli mi nar y pa nel f or f urt her vali dati o n i n a s u bse q ue nt st u d y.  
3. 5  H y p ot hesis  
•  Tr eat me nt  wit h  a  p ote nt  T C S  i n d uces  atr o p hic  c ha n ges  (re d uce d  e pi der mal  t hic k ness 
deter mi ne d  b y  str uct ur al  O C T)  n ot  o bser ve d  wit h  c o m para ble crisa b or ole ( 2 %) oi nt me nt  
tr eat me nt.  
•  A n gi o gr a p hic  O C T  meas ur e me nts  pr o vi de  a  r o b ust  a n d  acc urate  bi o mar ker  of  e pi der mal 
t hic k ness/atr o p h y. 
•  F TI R  s pectr a  of  t he  s ki n  pr o vi de  a  bi o mar ker  of  s ki n  barrier  str uct ure  t hat  relates  t o  s ki n 
barrier f u ncti o n a n d d ysf u ncti o n, ma ki n g it s uita ble f or assessi n g b ot h t he ne gati ve effects of 
T C S a n d t he p ositi ve eff ects of tr eat me nt bases/e m ollie nts. 
 
4. O B J E C TI V E S A N D O U T C O M E M E A S U R E S/ E N D P OI N T S  
4. 1 P ri m ar y o bj ecti ve  
T o  deter mi ne  w het her  t wice  dail y  tr eat me nt  wit h crisa b or ole ( 2 %) oi nt me nt ,  c o m pare d  t o 
beta met has o ne valer ate ( 0. 1 %) cr ea m, f or u p t o 4 wee ks is a ca use of s ki n  atr o p h y i n patie nts wit h 
at o pic der matitis.  T his o bjecti ve r elates t o  researc h q uesti o n 3. 
•  H 1: Tr eat me nt wit h crisa b or ole ( 2 %) oi nt me nt  t wice dail y f or 2 8 da ys res ults i n less ( b y ≥8 0 %)  
pat h ol o gic e pi der mal t hi n ni n g t ha n t he e q ui vale nt treat me nt re gi me n w it h beta met has o ne valerate 
( 0. 1 %) cr ea m. 
•  H 0:  Tr eat me nt  wit h crisa b or ole ( 2 %) oi nt me nt  t wice  dail y  f or  2 8  da ys  d oes  n ot  res ult  i n  less 
pat h ol o gic e pi der mal t hi n ni n g t ha n t he e q ui vale nt treat me nt re gi me n wit h beta met has o ne valerate 
( 0. 1 %) cr ea m. 
4. 2 Sec o n d ar y O bj ecti ves  
T he f oll o wi n g sec o n dar y o bjecti ves r elate t o researc h q uesti o n 3: 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  T o i n vesti gate t he ki netics of c ha n ges i n e pi der mal t hic k ness meas ure d b y str uct ural O C T 
br o u g ht a b o ut b y tr eat me nt wit h crisa b or ole ( 2 %) oi nt me nt a n d beta met has o ne valerate ( 0.1 %) 
cr ea m  
•  T o deter mi ne t he t oler a bilit y of crisa b or ole ( 2 %) oi nt me nt, c o m pare d t o beta met has o ne valerate 
( 0. 1 %) cr ea m 
•  T o deter mi ne t he eff ect of crisa b or ole ( 2 %) oi nt me nt, c o m pare d t o beta met has o ne valerate 
( 0. 1 %) cr ea m, o n s ki n barrier f u ncti o n 
•  T o deter mi ne t he eff ect of crisa b or ole ( 2 %) oi nt me nt, c o m pare d t o beta met has o ne valerate 
( 0. 1 %) cr ea m, o n s ki n dr y ness a n d t he le vels of nat ural m oist urisi n g fact or i n t he s ki n 
4. 3 E x pl or at or y o bj ecti ves  
T he f oll o wi n g e x pl or at or y o bjecti ves r elate t o researc h q uesti o ns 1 a n d 2:  
•  T o  i n vesti gate  w het her  O C T -deri ve d  bi o mar kers  ( ot her  t ha n  t he  esta blis he d  str uct ural  O C T 
bi o mar ker) e na ble t he acc ur ate q ua ntificati o n of tiss ue c ha n ges ( vasc ular a n d matri x) ass ociate d 
wit h e pi der mal atr o p h y i n r es p o nse t o T C S treat me nt . Bi o m ar ker m eas ure me nts fr o m t he i ma ges 
will i ncl u de:  
o  S u perficial ple x us de pt h ( µ m)  fr o m a n gi o gra p hic O C T i ma ges1 0   
o  Mea n vess el dia meter ( µ m)  fr o m a n gi o gra p hic O C T i ma ges1 0 
o  Vessel de nsit y (se g me nts/ m m 2) fr o m a n gi o gra p hic O C T i ma ges1 0 
o  C olla ge n matri x i n de x ( a n i n dex deri ve d fr o m birefri n ge nce i ma ges of c olla ge n de nsit y 
a n d arr a n ge me nt)  fr o m p olarisati o n se nsiti ve O C T i ma ges1 1, 1 2 
•  T o i n vesti gate w het her F TI R s pectr osc o p y -deri ve d bi o mar kers e na ble t he acc urate q ua ntificati o n 
of  s ki n barrier c o n diti o n a n d f u ncti o n i n res p o nse t o T C S treat me nt. Bi o mar ker m eas ure me nts 
fr o m t he s pectr a will i ncl u de: 
o  N M F le vels i n t he s ki n 1 3, 1 4 
o  Li pi d Str uct ur e 1 5, 1 6 
•  T o  i n vesti gate t he n u m ber of partici pa nts wit h F L G  l oss-of -f u ncti o n m utati o ns a n d e x pl ore if 
t her e is a n y e vi de nce of a r elati o ns hi p t o treat me nt effects 
•  T o i de ntif y ( b y c o m pleti n g t he o bjecti ves a b o ve) a pa nel of bi o mar kers t hat best c haracterises 
e pi der mal  atr o p h y. T he bi o mar kers i de ntifie d will be ta ke n f or war d i nt o t he ne xt sta ge of t he 
r esear c h pr o gr a m. 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
4. 4  P ri m ar y e n d p oi nt / o ut c o m e 
•  T he diff er e nce i n t he c ha n ge i n e pi der mal t hic k ness  ( da y 2 9  –  da y 1 ), meas ure d b y str uct ural 
O C T, bet wee n t he sites tr eated wit h crisa b or ole ( 2 %) oi nt me nt a n d beta met has o ne valerate 
( 0. 1 %) cr ea m. 
4. 5  Sec o n d ar y e n d p oi nt/ o ut c o m e  
•  T he diff er e nce i n t he c ha n ge i n e pi der mal t hic k ness meas ure d b y str uct ural O C T d uri n g a n d after 
2 8 da ys tr eat me nt. O C T i ma ges of e pi der mal t hic k ness take n o n  da y 1 , da y 1 5 , da y 2 9  a n d da y 
5 7 .  
•  T he diff er e nce i n t he c ha n ge i n s ki n r e d ness/er ythe ma  (relati n g t o t olera bilit y) d uri n g a n d after 
2 8 da ys tr eat me nt  deter mi ne d b y:  
o  V is ual r e d ness/er yt he ma sc or e deter mi ne d o n da y 1, da y 1 5 , da y 2 9 a n d da y 5 7  
o  O bject i ve r e d ness ass ess e d wit h t he Me xa meter meas ure d o n da y 1, da y 1 5 , da y 2 9 a n d 
da y 5 7  
•  T he diff er e nce i n t he c ha n ge i n Tr a ns -E pi der mal Water L oss ( T E W L, relates t o s ki n barrier 
f u ncti o n) d uri n g a n d after tr eat me nt. 1 7, 1 8 T E W L meas ure me nts o n da y 1, da y 1 5, da y 2 9 a n d da y 
5 7 . 
•  T he diff er e nce i n s ki n barrier i nte grit y ( T E W Lts 2 0) after 2 8 da ys treat me nt. T E W L meas ure me nts 
after ta pe-stri p pi n g ( T E W Lts 2 0) o n da y 2 9 
•  T he diff er e nce i n t he c ha n ge i n vis ual s ki n dr y ness  d uri n g a n d after treat me nt . Vis ual s ki n 
dr y ness  sc or e d o n da y 1, da y 1 5, da y 2 9 a n d da y 5 7  
•  T he diff er e nce i n Nat ur al M oist urisi n g Fact or ( N M F, fila g gri n brea k d o w n pr o d ucts) le vels at 
t he e n d of tr eat me nt1 9 N M F will be q ua n tifie d fr o m s u perficial strat u m c or ne u m sa m ples 
c ollecte d o n da y 2 9 usi n g  H P L C.  
4. 6  E x pl or at or y e n d p oi nt/ o ut c o m e  
Details pertai ni n g t o t he e x pl or at or y e n d p oi nts/ o utc o me meas ures ca n be f o u n d i n secti o n 4. 7. 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
4. 7  T a ble of e n d p oi nts/ o ut c o m es  
E ac h st u d y e n d p oi nt/ o utc o me is liste d i n t he f oll o wi n g ta ble b y st u d y o bjecti ve.  
O bjecti ves  
O utc o me Meas ures  
Ti me p oi nt(s) of e val uati o n  
Pri m ar y O bjecti ve : 
T o deter mi ne w het her t wice dail y 
treat me nt wit h crisa b or ole ( 2 %) 
oi nt me nt, c o m pare d t o beta met has o ne 
valerate ( 0. 1 % ) crea m, f or u p t o 4 
wee ks is a ca use of s ki n atr o p h y i n 
patie nts wit h at o pic der matitis.  
Pri m ar y O utc o m es:  
T he differe nce i n t he c ha n ge i n 
e pi der mal t hic k ness ( da y 2 9 –  
da y 1), meas ure d b y str uct ural 
O C T, bet wee n t he sites treate d 
wit h crisa b or ole ( 2 %) oi nt me nt 
a n d beta met has o ne valerate 
( 0. 1 %) crea m. 
 
 
Str uct ural O C T i ma ges of 
e pi der mal t hic k ness ta ke n o n 
da y 1  a n d da y 2 9   
 
 
S ec o n d ar y O bjecti ves : 
T o i n vesti gate t he ki netics of c ha n ges 
i n e pi der mal t hic k ness meas ure d b y 
str uct ural O C T br o u g ht a b o ut b y 
treat me nt wit h crisa b or ole ( 2 %) 
oi nt me nt a n d beta met has o ne valerate 
( 0. 1 %) crea m 
 
T o deter mi ne t he t olera bilit y of 
crisa b or ole ( 2 %) oi nt me nt, c o m pare d 
t o beta met has o ne valerate ( 0. 1 %) 
crea m  
 
 
 
 
 
 
T o deter mi ne t he effect of crisa b or ole 
( 2 %) oi nt me nt, c o m pare d t o 
beta met has o ne valerate ( 0. 1 %) crea m, 
o n s ki n barrier f u ncti o n  
 
 
 
 
 
T o deter mi ne t he effect of crisa b or ole 
( 2 %) oi nt me nt, c o m pare d t o 
beta met has o ne valerate ( 0. 1 %) crea m, 
o n  s ki n dr y ness a n d t he le vels of 
nat ural m oist urisi n g fact or ( N M F) i n 
t he s ki n 
 
S ec o n d ar y  O utc o m es:  
T he differe nce i n t he c ha n ge i n 
e pi der mal t hic k ness meas ure d 
b y str uct ural O C T d uri n g a n d 
after 2 8 da ys treat me nt.  
 
 
 
T he differe nce i n t he c ha n ge i n 
vis ual re d ness/er yt he ma  sc ore 
d uri n g a n d after 2 8 da ys 
treat me nt. 
 
T he differe nce i n t he cha n ge i n 
o bjecti ve re d ness assesse d wit h 
t he Me xa meter d uri n g a n d after 
2 8 da ys treat me nt.  
 
T he differe nce i n t he c ha n ge i n 
Tra ns -E pi der mal Water L oss 
( T E W L) d uri n g a n d after 2 8 
da ys treat me nt.  
 
T he differe nce i n s ki n barrier 
i nte grit y ( T E W Lts 2 0) after 2 8 
da ys treat me nt.  
 
T he differe nce i n t he c ha n ge i n 
vis ual s ki n dr y ness  d uri n g a n d 
after 2 8 da ys treat me nt . 
 
 
T he differe nce i n Nat ural 
M oist urisi n g Fact or ( N M F, 
 
Str uct ural O C T i ma ges of 
epi der mal t hic k ness ta ke n o n 
da y 1, da y 1 5, da y 2 9 a n d da y 
5 7 .  
 
 
 
Vis ual re d ness/er yt he ma 
sc ore deter mi ne d o n da y 1, 
da y 1 5, da y 2 9 a n d da y 5 7  
 
 
O bjecti ve re d ness assesse d 
wit h t he Me xa meter 
meas ure d o n da y 1, da y 1 5, 
da y 2 9 a n d da y 5 7  
 
T E W L meas ure me nts o n da y 
1, da y 1 5 , da y 2 9 a n d da y 5 7 . 
 
 
 
T E W L meas ure me nts after 
ta pe-stri p pi n g ( T E W L ts 2 0) o n 
da y 2 9  
 
Vis ual s ki n dr y ness  sc ore d o n 
da y 1, da y 1 5 , da y 2 9 a n d da y 
5 7  
 
 
N M F will be q ua ntifie d fr o m 
s u perficial strat u m c or ne u m 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
 
 
fila g gri n brea k d o w n pr o d ucts) 
le vels at t he e n d of treat me nt  
 
sa m ples c ollecte d o n da y 2 9 
usi n g  H P L C.  
E x pl or at or y o bjecti ves:  
T o i n vesti gate w het her O C T -deri ve d 
bi o mar kers ( ot her t ha n t he esta blis he d 
str uct ural O C T bi o mar ker) e na ble t he 
acc ur ate q ua ntificati o n of tiss ue 
c ha n ges ( vasc ular a n d matri x) 
ass ociate d wit h e pi der mal atr o p h y i n 
res p o nse t o T CS treat me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T o i n vesti gate w het her F TI R 
s pectr osc o p y-deri ve d bi o mar kers 
e na ble t he acc urate q ua ntificati o n of 
s ki n barrier c o n diti o n a n d f u ncti o n i n 
res p o nse t o T C S treat me nt 
 
 
 
 
 
 
 
 
 
 
T o i n vesti gate t he n u m ber of 
partici pa nts wit h F L G  l oss-o f-f u ncti o n 
m utati o ns a n d e x pl ore if t here is a n y 
e vi de nce of a relati o ns hi p t o treat me nt 
effe cts  
 
 
 
E x pl or at or y o utc o m es:  
T he differe nce i n t he c ha n ge i n 
s u perficial ple x us de pt h (µ m) 
meas ure d b y a n gi o gra p hic O C T  
 
T he differe nce i n t he c ha n ge i n 
mea n bl o o d vessel dia meter 
(µ m) meas ure d b y a n gi o gra p hic 
O C T  
 
T he differe nce i n t he c ha n ge i n 
bl o o d vessel de nsit y 
(se g me nts/ m m2) meas ure d b y 
a n gi o gra p hic O C T  
 
T he differe nce i n t he c ha n ge i n 
colla ge n  matri x  i n de x (a n i n de x 
deri ve d fr o m birefri n ge nce 
i ma ges of c olla ge n de nsit y a n d 
arra n ge me nt) meas ure d b y 
p ola risati o n se nsiti ve ( P S)-O C T  
 
T he differe nce i n t he c ha n ge i n 
car b o x ylate le vels (i n direct 
meas ure of N M F  le vels, n ot t o 
be c o nf use d wit h direct 
q ua ntificati o n fr o m strat u m 
c or ne u m sa m ples b y H P L C ) i n 
t he strat u m c or ne u m meas ure d 
b y F TI R s pectr osc o p y  
 
T he  differe nce i n strat u m 
c or ne u m li pi d str uct ure 
meas ure d b y F TI R s pectr osc o p y  
i n c o nj u ncti o n wit h ta pe-
stri p pi n g  
 
N u m ber of F L G  l oss-of -
f u ncti o n m utati o n carriers 
 
Descri pti ve ta b ulati o ns of 
T E W L a n d e pi der mal t hic k ness 
b y m utati o n stat us, if s ufficie nt 
pa rtici pa nts wit h m utati o n are 
detecte d.  
 
A n gi o gra p hic O C T i ma ges 
ta ke n o n da y 1, da y 1 5 , da y 
2 9 a n d da y 5 7  
 
 
 
 
 
 
 
 
 
 
 
P olarisati o n se nsiti ve ( P S)-
O C T i ma ges ta ke n o n da y 1  
a n d da y 2 9 . 
 
 
 
 
F TI R s pectr u m of t he s ki n 
s urface ta ke n o n da y 1 da y 
1 5 , da y 2 9 a n d da y 5 7  
 
 
 
 
 
 
F TI R s pectra ta ke n t hr o u g h 
t he strat u m c or ne u m ( d uri n g 
ta pe-stri p pi n g) o n da y 2 9 
 
 
 
S ali va sa m ple at visit 1  f or 
F L G  ge n ot y pi n g  
 
T E W L a n d str uct ural O C T 
deri ve d e pi der mal t hic k ness 
meas ure d at da y 1 , da y 1 5 
a n d da y 2 9   
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T o i de ntif y ( b y c o m pleti n g t he 
o bjecti ves a b o ve) a pa nel of 
bi o mar kers t hat best c haracterises 
e pi der mal atr o p h y. T he bi o mar kers 
i de ntifie d will be ta ke n f or war d i nt o 
t he ne xt sta ge of t he researc h pr o gra m. 
 
All t he a b o ve  
N ot a p plic a ble 
 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 4 8 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
5 . T RI A L D E SI G N
A n o bser ver - bli n d r a n d o mize d wit hi n-s u bject c o ntr olle d cli nical trial i n 3 3 A D patie nts is pr o p ose d, 
w her ei n eac h partici pa nt will u n der g o 4 wee ks treat me nt wit h crisa b or ole ( 2 %) oi nt me nt o n o ne 
f or ear m a n d beta met has o ne valer ate ( 0. 1 %) crea m o n t he ot her (t wice dail y a p plicati o n i n eac h case 
a n d r a n d o mise d site all ocati o n) . At t he start of t he st u d y t he s ki n of t he test sites (f orear ms) will be 
clear of t he si g ns of A D s o t hat t he i n vesti gati o n f oc uses o n l ocal a d verse effects o n t h e s ki n as 
o p p ose d t o a nti -i nfla m mat or y eff ects (f oc us o n l ocal a d verse effects a n d n ot cli nical efficac y). T he 
c o n diti o n of t he s ki n will be assess e d bef ore, d uri n g a n d after treat me nt. A n o ver vie w of t he desi g n 
is  pr o vi de d  bel o w  ( Fi g ur e  4. 1).  A  p ost- treatme nt was h o ut  peri o d  of  4 wee ks  p ost -treat me nt  is  
i ncl u de d t o esta blis h h o w q uic kl y s ki n c ha n ges re-a dj ust t o baseli ne.
Fi g 4. 1: st u d y desi g n
5. 1 Tri al D ur ati o n
T he d ur ati o n partici pa nts will partici pate i n t his st u d y is a p pr o xi matel y 1 0 wee ks , i ncl u di n g t he 1-
wee k r u n -i n peri o d ( n o t o pical pr o d uct use o n test sites ).
T he st u d y is e x pecte d t o last 1 2 m o nt hs i n t otal, wit h recr uit me nt ta ki n g 6 m o nt hs .
5. 2 Tri al setti n g
T his si n gle -ce ntr e cl nical trial will ta ke place at:
S heffiel d T eac hi n g H os pitals N H S F o u n dati o n Tr ust
T he R o yal Halla ms hir e H os pital,
S heffiel d, S 1 0 2J F
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S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 4 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
6 . P A R TI CI P A N T E LI GI BI LI T Y C RI T E RI A   
6 . 1 St u d y P o p ul ati o n  
Partici pa nts wit h A D n ot c urr e ntl y u n der g oi n g, or re q uiri n g, acti ve dr u g treat me nt  at baseli ne ( visit 
1) .  
6 .2  I ncl usi o n crit eri a 
1.  V ol u nteers wit h A D  defi ne d acc or di n g t o t he U K w or ki n g part y dia g n ostic criteria  
2.  Male or f e male  age d  1 8 -6 5  years  ol d  at baseli ne ( Visit 1) 
3.  V ol u nteer u n dersta n ds t he p ur p ose, m o dalities a n d p ote ntial ris k of t he trial  
4.  Partici pa nts  a ble t o r ea d a n d u n dersta n d E n glis h  
5.  Partici pa nts  willi n g t o si g n t he i nf or me d c o nse nt  
6 .3  E xcl usi o n crit eri a  
1.  Partici pa nts  wit h  a  k n o w n aller g y/ h y perse nsiti vit y  t o  a n y  of  t he  e xci pie nts  of  t he  trial 
pr e par ati o ns.  
2.  Partici pa nts  wit h ac ne, s u nta n, birt h mar ks, m ulti ple ne vi, tatt o os,  ble mis hes or de nse b o d y 
hair t hat o bstr uct t he test ar eas. 
3.  I n vesti gat or assess me nt of ecze ma se verit y at t he treat me nt (a nat o mical) sites is al m ost clear  
or gr eater (sc or e ≥1 ) base d o n t he I n vesti gat ors static gl o bal assess me nt scale  at s cree ni n g a n d 
base li ne. At t he start of t he st u d y t he s ki n of t he test sites (f orear ms) will t heref ore be clear 
( 0) of t he si g ns of ecze ma 
4.  Partici pa nts  wit h a c o n diti o n t hat i n t he o pi ni o n of t he i n vesti gat or c o ntra dicts partici pati o n i n 
t he st u d y. 
5.  Pr e g na nt  f e male partici pa nts ;  br eastfee di n g  fe male partici pa nts ;  a n d  fe male partici pa nts of 
c hil d beari n g  p ote ntial  w h o  ar e  u n willi n g  or  u na ble  t o  use  a  hi g hl y  effecti ve  met h o d  of 
c o ntr ace pti o n as o utli ne d i n t his pr ot oc ol f or t he d urati o n of t he st u d y a n d f or at least 2 8 da ys 
after t he last d ose of i n vesti gati o nal pr o d uct. 
6.  Use of a n y t o pical pr o d uct o n t he test areas wit hi n 7 da ys pri or t o Baseli ne/ Da y 1, i ncl u di n g 
c os metic m oist urizers a n d s u ns cr ee n. P artici p a nts usi n g a ny t o pic al pr o d ucts o n t he test are as 
wit hi n 7 d ays at t he sc ree ni n g visit will be eli gi ble if t hey are willi n g a n d a ble t o w as h-o ut 
t hese pr o d ucts f or 7 d ays i n t ot al a n d f or t he d ur ati o n of t he tri al. S uc h p artici p a nts will be 
p ote nti ally  eli gi ble  at  scree ni n g  a n d  will  be  c o nfir me d  as  eli gi ble  if  a de q u ate  w as h o ut is 
c o nfir me d at visit 1. Use of m oist urizers a n d/ or s u nscree n is per mitte d d uri n g t he st u dy t o 
m a n a ge dry ski n a n d s u n ex p os ure i n are as s urr o u n di n g b ut n ot o n or overl a p pi n g t he test 
are as.  
7.  Partici pa nts w h o ha ve use d a ta n ni n g be d wit hi n 2 8 da ys of baseli ne ( visit 1).  P artici p a nts 
w h o h ave use d a s u n be d wit hi n 2 8 d ays at t he scree ni n g visit will be eli gi ble if t hey are willi n g 
a n d a ble t o w as h -o ut f or 2 8  d ays i n t ot al a n d f or t he d ur ati o n of t he tri al. S uc h p artici p a nts 
will be p ote nti ally eli gi ble at scre e ni n g a n d will be c o nfir me d as eli gi ble if a de q u ate w as h o ut 
is c o nfir me d at visit 1. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8.  Partici pa nts  w h o ha ve use d a n y me dicati o n t hat c o ul d i nterfere wit h t he trial ai m pri or t o t he 
start of t he st u d y ( baseli ne/ visit 1). P artici p a nts usi n g s uc h me dic ati o n  at  t he scree ni n g visit 
will be eli gi ble if t hey are willi n g a n d a ble t o w as h -o ut t hese tre at me nts f or t he a p plic a ble 
w as h o ut peri o d as defi ne d by i n se cti o n 8. 8 ‘ Pri or a n d C o nc o mit a nt Me dic ati o n ’ a n d f or t he 
d ur ati o n of t he tri al. S uc h p artici p a nts will be p ote nti ally eli gi ble at scree ni n g a n d will be 
c o nfir me d as eli gi ble if a de q u ate w as h o ut is c o nfir me d at visit 1.  
9.  Partici pa nts  c urr e ntl y partici pati n g i n a n ot her  i nter ve nti o nal cli nical trial.  
1 0.  V ol u nteer is i nca pa ble of gi vi n g f ull y i nf or me d c o nse nt.  
1 1.  Partic i pa nts j u d ge d b y t he PI t o be i na p pr o priate f or t he trial.  
6 .4  I nst r ucti o ns t o p artici p a nts a n d lif est yle c h a n ges  
P artici pa nts will be as ke d n ot t o a p pl y a n y t o pical lea ve -o n pr o d ucts t o t he s ki n sites of i nterest f or 1 
wee k pri or t o atte n di n g Visit 1/ bas eli ne a n d t hr o u g h o ut t he st u d y .  
T he  use  of  t heir  n or mal  was h  pr o d ucts  is  per mitte d  t hr o u g h o ut  t he  trial . Partici pa nts  s h o ul d  pla n 
was hes  s uc h  t hat  t he  i n vesti gati o nal  pr o d ucts  are  a p plie d  after  (rat her  t ha n  bef ore)  was hi n g. 
Partici pa nts s h o ul d n ot s wi m, b at he or was h t he treat me nt areas f or at least 4 h o urs after a p plicati o n 
of i n vesti gati o nal pr o d ucts.  
W he n a p pl yi n g i n vesti gati o nal pr o d uct, t he partici pa nts will ge nerall y n ot be re q uire d t o wear gl o ves. 
H o we ver, t he y m ust be i nstr ucte d t o was h t heir ha n ds  wit h mil d s oa p a n d water bef ore a n d after eac h 
a p plicati o n.  
Partici pa nts m ust n ot a p pl y t he test pr o d ucts i n t he m or ni n g bef ore st u d y visits . 
T he f oll o wi n g lif e -st yle r estricti o ns a p pl y: 
•  T a n ni n g be d use 2 8 Da ys Pri or t o Baseli ne/ Da y  1 a n d t hr o u g h o ut t he st u d y.  
•  Use of m oist urisers , lea ve-o n c os metics  or s u nscre e n o n t he test are as , wit hi n 7 da ys pri or t o 
Baseli ne/ Da y 1  a n d t hr o u g h o ut t he st u d y . Use of m oist urizers  a n d/ or s u nscree n is per mitte d 
d uri n g  t he  st u d y  t o  ma na ge  dr y  s ki n  a n d  s u n  e x p os ure  i n  areas s urr o u n di n g  b ut  n ot  o n  or 
o verla p pi n g t he test ar eas.  
W her e t hese e xce pti o ns ar e met t he PI will deter mi ne w het her t he partici pa nt s h o ul d be wit h dra w n. 
I n all cases a pr ot oc ol de viati o n will be l o g ge d. 
6 . 5 C o nt r ace pti o n  
All f ertile f e male partici pa nt s w h o ar e of c hil d beari n g p ote ntial as a p plica ble t o t he st u d y w h o are, i n 
t he o pi ni o n of t he i n vesti gat or, se x uall y acti ve a n d at ris k f or pre g na nc y wit h t heir part ner(s) m ust 
a gr ee t o use a hi g hl y eff ecti ve met h o d of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y f o r t he scree ni n g 
peri o d,  t he  d ur ati o n  of  t he  acti ve  tr eat me nt  peri o d  a n d  f or  at  least  2 8 da ys  after  t he  last  d ose  of 
i n vesti gati o nal pr o d uct.  T he i n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he partici pa nt , 
will c o nfir m t hat t he partici pa nt  h as selecte d a n a p pr o priate met h o d of c o ntrace pti o n f or t he i n di vi d ual 
partici pa nt  fr o m t he per mitte d list of c o ntrace pti o n met h o ds (see bel o w) a n d will c o nfir m t hat t he 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
partici pa nt  has  bee n  i nstr ucte d  i n  its  c o nsiste nt  a n d  c orrect  use.  At  ti me  p oi nts  i n dic ate d  i n  t he 
Sc he d ule of E ve nts , t he in vesti gat or or his/ her  desi g nee will i nf or m t he partici pa nt  of t he nee d t o use 
hi g hl y  eff ecti ve  c o ntr ace pti o n  c o nsiste ntl y  a n d  c orrectl y  a n d  d oc u me nt  t he  c o n versati o n  a n d  t he 
partici pa nt ’s  affir mati o n  i n  t he partici pa nt ’s n otes  (partici pa nt  nee ds  t o  affir m  t heir  c o nsiste nt  a n d 
c orr ect use of at least  1 of t he selecte d met h o ds of c o ntrace pti o n).  I n a d diti o n, t he in vesti gat or or 
his/ her  desi g nee will i nstr uct t he partici pa nt  t o call i m me diatel y if t he selecte d c o ntrace ptio n met h o d 
is disc o nti n ue d or if pr e g na nc y is k n o w n or s us pecte d i n t he partici pa nt .  
Hi g hl y eff ecti ve met h o ds of c o ntr ace pti o n are t h ose t hat, al o ne or i n c o m bi nati o n, res ult i n a fail ure 
rate of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y (ie, perfect use) a n d i ncl u de t he 
f oll o wi n g: 
1.  Esta blis he d use of h or m o n al met h o ds of c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
( e g, or al, i nserte d, i njecte d, i m pla nte d, tra ns der mal) pr o vi de d t he partici pa nt  pla ns t o re mai n 
o n  t he  sa me  tr eat me nt  t hr o u g h o ut  t he  e ntire  st u d y  a n d  has  bee n  usi n g  t hat  h or m o nal 
c o ntr ace pti ve f or a n a de q uate peri o d of ti me t o e ns ure effecti ve ness.  
2.  C orr ectl y place d c o p per -c o ntai ni n g i ntra uteri ne de vice (I U D).  
3.  Male c o n d o m or f e male c o n d o m use d WI T H a s per mici de pr o d uct (i e, f oa m, gel, fil m, crea m, 
or s u p p osit or y).   
4.  Male sterilizati o n wit h a bse nce of s per m i n t he p ost  vasect o m y ejac ulate.  
5.  Bilater al  t u bal  li gati o n/ bilater al  sal pi n gect o m y  or  bilateral  t u bal  occl usi ve  pr oce d ure 
( pr o vi de d t hat occl usi o n has bee n c o nfir me d i n acc or da nce wit h t he de vice’s la bel).  
N O T E:  Se x ual  a bsti ne nce,  defi ne d  as  c o m pletel y a n d  persiste ntl y refrai ni n g  fr o m  all  heter ose x ual 
i nter c o urse  (i ncl u di n g  d uri n g  t he  e ntir e  peri o d  of  ris k  ass ociate d  wit h  t he  st u d y  treat me nts)  ma y 
o b viate t he nee d f or c o nt r ace pti o n O N L Y if t his is t he preferre d a n d us ual lifest yle of t he partici pa nt .   
 
6 .6  Scree ni n g f ail ure  
All i n di vi d uals w h o si g n t he c o nse nt f or m a n d eit her ( 1) wit h dra w t heir partici pati o n bef ore t he first 
assess me nt, ( 2) f ail t o meet all of t he eli gi bil it y criteria a n d/ or ( 3) f or tec h nical or l o gistical reas o ns 
d o n ot partici pate i n t he first assess me nt sessi o n / visit will be c o nsi dere d a “scree ni n g fail ure. ”  
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7 . S T U D Y P R O C E D U R E S  
7 . 1 O ver vie w of pr oce d ures 
A n o ver vie w of t he st u d y pr oce d ur es is pr o vi de d i n t he T a ble bel o w , wit h f urt her details pr o vi de d i n t he s u b-se cti o ns bel o w. 
T a ble 7 . 1: Sc he d ule of e ve nts  
St u d y Pr oce d ures:  a 
C o nse nt & 
scree ni n g 
B aseli ne  
C o m pli a nce m o nit ori n g b 
F oll o w -u p  
W as h -
o ut  
Visit:  
C o nse nt & 
scree ni n g  
V isit 1  
Visit 2  
Visit 3  
Vis it 4  
Visit 5  
Visit 6  
Visit 6a  
Visit 7  
Visit 8  
St u d y Wee k:  
-3  t o 1 
1  
1  
1  
1  
1  
2  
3  
4  
8  
St u d y Da y (i ncl. wi n d o w):  
-2 8  t o 1 
1  
2 + 4  
3 + 5  
4 + 6  
5 + 7  
1 5 ± 3  
2 2 ± 3  
2 9 ± 3  
5 7 + 4 s 
D ur ati o n ( mi n utes) - 2 0 h t ot al:  
2 0 - 6 0 mi n  
2. 5 -3  h  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 . 5 h 
2 0 mi n  
3  h  
2 . 5 h 
Scree ni n g, c o nse nt a n d e nr ol me nt  i n a cli ni c al are a desi g n at e d f or 
u n bli n de d assess m e nts  
 
 
 
 
 
 
 
 
 
 
1  
Recei ve v ol u nt eer referr als c 
X  
 
 
 
 
 
 
 
 
 
2  
Sc he d ule t he st u d y visits  acc or di n g t o t his sc he d ul e 
X  
 
 
 
 
 
 
 
 
 
3  
I nf or m e d C o nse nt (I nf or me d C o nse nt s heet) d 
X  
 
 
 
 
 
 
 
 
 
4  
Re -c o nfir m c o nse nt ver ball y  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
5  
C o nfir m s uita bilit y a n d c o m pl et e A d missi o n F or m  (i ncl u des 
coll ect i o n of de m o gr a p h y  & m e di cal hist or y ) e 
X  
 
 
 
 
 
 
 
 
 
6  
C o m pl et e a f oll o w -u p A d missi o n F or m I F e nr ol me nt  was s u bj ect t o a 
was h o ut peri o d or m ore t ha n 2 8 da ys has l a pse d si nce scr ee ni n g e 
 
( X) 
 
 
 
 
 
 
 
 
7  
Ca pt ur e of A E a n d c o nc o mit a nt m e di cati o n  usi n g t he A E F or m a n d 
C o n Me d F or m  f 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
8  
Carr y o ut E A SI a n d I S G A assess m e nt of ecze m a se verit y  
X  
( X)q 
 
 
 
 
 
 
 
 
9  
C o n d uct a uri ne pr e g na nc y test (fe male parti ci pa nts o nl y) g , h 
X  
X  
 
 
 
 
 
 
X  
 
1 0  
C hec k t hat a n a p pr o priate met h o d of c o ntr ace pti o n is i n use g , i 
X  
X  
 
 
 
 
X  
 
X  
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
St u d y Pr oce d ures:  a 
C o nse nt & 
scree ni n g 
B aseli ne  
C o m pli a nce m o nit ori n g b 
F oll o w -u p  
W as h -
o ut  
Visit:  
C o nse nt & 
scree ni n g  
V isit 1  
Visit 2  
Visit 3  
Vis it 4  
Visit 5  
Visit 6  
Visit 6a  
Visit 7  
Visit 8  
St u d y Wee k:  
-3  t o 1 
1  
1  
1  
1  
1  
2  
3  
4  
8  
St u d y Da y (i ncl. wi n d o w):  
-2 8  t o 1 
1  
2 + 4  
3 + 5  
4 + 6  
5 + 7  
1 5 ± 3  
2 2 ± 3  
2 9 ± 3  
5 7 + 4 s 
D ur ati o n ( mi n utes) - 2 0 h t ot al:  
2 0 - 6 0 mi n  
2. 5 -3  h  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 . 5 h 
2 0 mi n  
3  h  
2 . 5 h 
1 1  
C o m pl eti o n of Scr ee ni n g, E nr ol m e nt & C o m pl eti o n L o g  as 
a p pr o pri at e 
X  
X  
 
 
 
 
 
 
 
 
1 2  
Iss ue of a Ra n d o mizati o n  n u m ber  
 
X  
 
 
 
 
 
 
 
 
1 3  
Re mi n d partici pa nts n ot t o a p pl y pr o d ucts i n t he m or ni n g bef ore 
st u d y visits. Re mi n ders s h o ul d be se nt o ut t he da y bef or e t he 
a p p oi nt me nt is d ue. r 
 
 
X  
X  
X  
X  
X r 
X  
X r 
 
1 4  
C hec k c o m pli a nce wit h d osi n g c o n d iti o ns o n t he st u d y da ys 
i n v ol vi n g s ki n assess me nts n 
 
 
X  
X  
X  
X  
X r 
X  
X r 
 
1 5  
Access a n d u p dat e patie nt n otes wit h st u d y details. If t he partici pa nt 
has n o S T H n ot es alr ea d y, a ne w set of n ot es s h o ul d be pr e par e d. p 
X  
 
 
 
 
 
 
 
 
 
1 6  
Tr a nsfer parti ci pa nt t o s ki n barri er s uit e  
 
X  
 
 
 
 
X  
 
X  
X  
S ki n assess m e nts  a n d s a m pl e c oll ecti o n at t he s ki n b arrier s uite j 
 
 
 
 
 
 
 
 
 
 
1 7  
Accli m atise test sit es f or 2 0 mi n ut es  
 
X  
 
 
 
 
X  
 
X  
X  
1 8  
I de ntif y a n d de m ar cat e t he test sit es 
 
X  
 
 
 
 
X  
 
X  
X  
1 9  
Vis ual l y sc ore s ki n dr y ness a n d re d ness/ er yt he m a at eac h tr eat m e nt 
ar ea 
 
X  
 
 
 
 
X  
 
X  
X  
2 0  
Ca pt ur e t he 2 D s ki n i m a ge s 
 
X  
 
 
 
 
X  
 
X  
X  
2 1  
Perf or m Me xa meter m eas ure m e nt s at eac h sit e (s ki n r e d ness, 4 
r e peats per sit e) 
 
X  
 
 
 
 
X  
 
X  
X  
2 2  
Ta ke  O C T (str uct ural & a n gi o gr a p hic) i ma ges/sca ns wit h the 
Vi v osi g ht  at eac h t est site (i n tri plicat e)  
 
X  
 
 
 
 
X  
 
X  
X  
2 3  
Ta ke P S -O C T i m a ge s/sca ns wit h t he P S-O C T m ac hi ne a t eac h t ests 
sit e (i n tri pli cat e) 
 
X  
 
 
 
 
 
 
X  
 
2 4  
Meas ur e T E W L at eac h test sit e (i n tri pli cat e) 
 
X  
 
 
 
 
X  
 
X  
X  
2 5  
C ollect F TI R s pectr a at eac h test sit e  
 
X  
 
 
 
 
X  
 
X  
X  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
St u d y Pr oce d ures:  a 
C o nse nt & 
scree ni n g 
B aseli ne  
C o m pli a nce m o nit ori n g b 
F oll o w -u p  
W as h -
o ut  
Visit:  
C o nse nt & 
scree ni n g  
V isit 1  
Visit 2  
Visit 3  
Vis it 4  
Visit 5  
Visit 6  
Visit 6a  
Visit 7  
Visit 8  
St u d y Wee k:  
-3  t o 1 
1  
1  
1  
1  
1  
2  
3  
4  
8  
St u d y Da y (i ncl. wi n d o w):  
-2 8  t o 1 
1  
2 + 4  
3 + 5  
4 + 6  
5 + 7  
1 5 ± 3  
2 2 ± 3  
2 9 ± 3  
5 7 + 4 s 
D ur ati o n ( mi n utes) - 2 0 h t ot al:  
2 0 - 6 0 mi n  
2. 5 -3  h  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 0 mi n  
2 . 5 h 
2 0 mi n  
3  h  
2 . 5 h 
2 6  
Perf or m t a pe-stri ppi n g i n c o nj u ncti o n wit h T E W L a n d F TI R 
assess me nts 
 
 
 
 
 
 
 
 
X  
 
2 7  
C ollect t a pe -stri p sa m pl es (i ncl u di n g N M F sa m pl e c ollecti o n ) 
 
 
 
 
 
 
 
 
X  
 
2 8  
C ollect b uccal s wa b sa m pl e f or F L G  ge n ot y pi n g  m  
 
X  
 
 
 
 
 
 
 
 
2 9  
Tr a nsfer parti ci pa nt t o C R F  
 
X  
 
 
 
 
X  
 
X  
X  
Tre at me nt a n d c o m pli a nce  k 
 
 
 
 
 
 
 
 
 
 
3 0  
Iss ue IM P ’s ( wei g he d) a n d pr o vi de de m o nstr ati o n of d osi n g b y 
fi n gerti p u nit 
 
X  
 
 
 
 
 
 
 
 
3 1  
Iss ue tr eat m e nt diar y, c o m pl et e t he rele va nt secti o ns, a n d pr o vi de 
tr ai ni n g o n its c o m pl eti o n 
 
X  
 
 
 
 
 
 
 
 
3 2  
Wei g h I M P’s, r ec or d wei g hts i n t he C R F a n d tr eat m e nt diar y, a n d 
i nf or m parti ci pa nts of t heir usa ge i n t he c o nt e xt of e x pect e d usa ge.l 
 
 
X  
X  
X  
X  
X  
X  
X  
 
3 3  
C hec k all di ar y e ntri es f or missi n g a p plicati o ns a n d a d verse e ve nts 
(s ki n reacti o ns re p orte d at t he ti m e of a p plicati o n). 
 
 
X  
X  
X  
X  
X  
X  
X  
 
3 4  
S u per vise d pr o d uct a p pli cati o n ( aft er meas ure m e nts) . 
 
X  
X  
X  
X  
X  
X  
X  
 
 
3 5  
Pr o vi de r e -trai ni n g/ g ui da nce t o i m pr o ve o n a p pli cati o n t ec h ni q ue 
a n d/ or d osi n g ‘ as r e q uir e d’ 
 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
 
 
3 6  
Retri e ve diar y a n d I M P’s  
 
 
 
 
 
 
 
 
X  
 
3 7  
Arr a n ge ta xi tra nsf er f or ne xt sessi o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
3 8  
C o m pl et e cl ai m f or m f or re m u ner ati o n  
 
 
 
 
 
 
 
 
 
X  
3 9  
St u d y c o m pleti o n ( Scr ee ni n g, E nr ol me nt & C o m pl eti o n L o g)  
 
 
 
 
 
 
 
 
 
X  
a , A descri pti o n o f t he pr oce d ures carrie d o ut at e ver y visit is pr o vi de d i n secti o n 7. 4. 
b , S u per vise d I P a p plicati o ns. T he ai m is f or partici pa nts t o u n derta ke 5 s u per vise d a p plicati o ns d uri n g t he first 2 wee ks of treat me nt t o m o nit or c o m plia nc e a n d e nc o ur a ge 
c o nsiste nt a d here nc e t o t he a p plic ati o n re gi me n.  T o mi ni mize t he b ur de n o n partici pa nts s ufficie nt varia nc e has bee n i ncl u de d t o all o w ga ps of u p t o 7 da ys bet we e n s u per vise d  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
a p plicati o ns. C o m plia nce visits ar e n ot e x pecte d t o ta ke pla ce o n we e ke n ds. O nl y o ne a p plicat i o n per da y is t o be s u per vise d. T he sessi o ns s h o ul d be arra n ge d s uc h t hat 
partici pa nts ca n f ull y a d here t o t he tre at me nt r e gi me n, re q uiri n g 2 a p plicati o ns per da y, o nce i n t he m or ni n g a n d o nc e i n t he after n o o n/e ve ni n g se par ate d b y at le ast 6 h o urs . 
S ee se cti o n 8. 1 1 “c o m plia nce m o nit ori n g”  f or details 
c , refer t o s u b-se cti o n 7. 2 “ Recr uit me nt”. Referr als will be se nt b y t he der mat ol o g y te a m f oll o wi n g s uc cessf ul pre-scre e ni n g. 
d , r ef er t o s u b-secti o n 7. 3 “ Scre e ni n g & C o nse nt” 
e , t he A d missi o n F or m pr o vi des a ste p b y ste p g ui de t o t he scree ni n g a n d a d missi o n pr ocess. A me dic all y q ualifie d st u d y I n vesti gat or m ust ma ke t he fi nal asses s me nt of 
eli gi bilit y. W her e p ote ntial partici pa nts are f o u n d t o r e q uir e a was h o ut peri o d at t he c o nse nt visit i n or der t o be c o me el i gi ble, a ne w a d missi o n f or m m ust be c o m plete d a n d 
si g ne d off b y a me dicall y q ualifie d st u d y i n vesti gat or pri or t o e nr ol me nt. 
f, f or ms are liste d i n t he A p pe n di x a n d a vaila ble se par atel y . Details o n r e p orti n g c o nc o mita nt me dicati o n are pr o vi de d i n se cti o n 8. 8 “ Pri or a n d c o nc o mita nt me dic ati o n ”. S ee 
se cti o n 9. 0 “ P har ma c o vi gila nce ” f or details o n A E re p orti n g.  
g , f e male partici pa nt s of c hil d beari n g p ote ntial o nl y 
h , Se e s u b-secti o n 7. 6 “ p r e g na nc y testi n g” f or f urt her details 
i, se e s u b-secti o n 6. 5 “c o ntra ce pt i o n” u n der t he 6. 0 “ partici pa nt eli gi bilit y criteria” se cti o n f or f urt her details 
j, se e s u b-secti o n 7. 7 “s ki n assess me nts” f or details of t he s ki n assess me nts a n d s u b -secti o n 7. 8 “sa m ple c olle cti o n” f or details of t he sa m ple c ollecti o n pr oce d ures.  
k , r ef er t o s u bse cti o n 7. 9 “tre at me nt a n d c o m plia nc e” i n t his secti o n a n d s u b -se cti o ns 8. 1 1 “c o m plia nce m o nit ori n g” a n d 8. 1 2 “tre at me nt d osi n g a n d c o m plia nce” i n t he “ Trial 
Tr eat me nts” secti o n ( 8. 0) f or f urt her i nf or mati o n. 
l, the wei g ht s h o ul d be e nter e d i nt o t h e treat me nt diar y , w hic h i ncl u des t he e x pe cte d a m o u nts partici pa nts s h o ul d ha ve use d at eac h visit s o t hat c o m plia nc e wit h t he d osi n g 
c a n be disc usse d wit h t he partici pa nt.  
m , S e e secti o n 7. 8. 2 f or f urt her i nf or mati o n. 
n , f or f urt her details se e s u b-se cti on 8. 1 2. 1 “ I M P a p plicati o n d uri n g t he m or ni n g of st u d y visits” 
o , se e secti o n 6. 4 “i nstr ucti o ns t o partici pa nts a n d lifest yle c ha n ges” f or details of t he criteria. If partici pa nts ha ve a p plie d t he test pr o d u cts i n t he m or ni n g bef ore t he st u d y 
visit t he a p p o i nt me nt s h o ul d be resc he d ule d. 
p , se e secti o n 1 1. 5. 1 “resear c h n otes” 
q , t he E A SI assess me nt s h o ul d be r e pe ate d w he ne ver t he a d missi o n pr oc ess is c o n d ucte d (i.e. at scr ee ni n g, after a gi ve n was h o ut peri o d, a n d if m ore t ha n 2 1 da ys has la pse d 
si nc e scre e ni ng)  
r, Re mi n ders are r e q uir e d t o pr e ve nt o ver d osi n g w her e s u per vise d o n -site a p plicati o ns are t o be c o n d ucte d a n d t o e ns ur e pr o d uct resi d ues d o n ot i nterfere wit h s ki n assess me nts. 
S ee s pe cial c o n diti o ns i n secti o n 8. 1 2. 1 r e gar di n g acti o n re q uire d o n Visits  6 a n d 7.  
s, m ust be ≥2 8 d a ys f oll o wi n g Visit 7 . 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7 . 2 Recr uit m e nt 
Recr uit me nt will be c o n d ucte d b y t he S heffiel d Der mat ol o g y Researc h Gr o u p i n se veral wa ys: 
1.  Ge ner al  a d vertise me nt  usi n g  p osters  (s ee  attac he d A dverts ).  T he  p oster  c o ntai ns tele p h o ne 
a n d e mail c o ntact details f or t he st u d y tea m. P osters (see attac he d) will be dis pla ye d at/i n: 
a.  T he U ni versit y of S heffiel d pre mises , i ncl u di n g t he Me dical Sc h o ol  
b.  S heffiel d Halla m U ni versit y ( S H U) pre mises  
c.  S heffiel d T eac hi n g H os pitals pre mises, i ncl u di n g t he R o yal Halla ms hire H os pital   
d.  O nli ne, o n t he  U ni versit y of S heffiel d  we bsite, S T H we bsite, S H U we bsite (st u de nt 
p ortal), Face b o o k, T witter, i ncl u di n g @ S hef _ Der m T witter  pa ges  
e.  Pri nte d me dia i ncl u di n g l ocal leaflets, ma gazi ne a n d ne ws pa pers.  
f. L ocal  s h o ps,  li br aries, c o m m u nit y  ce ntres  a n d  practices  wit h  t he  per missi o n  of  t he 
o w ner/ ma na ger i n eac h case.  
2.  E mail lists. A n e mail, c o ntai ni n g t he i nf or mati o n i n t he P oster (a n d a c o p y of t he P artici p a nt 
I nf or m ati o n le aflet, PI L), will be distri b ute d t o:  
a.  a n e mail list of pe o pl e w h o ha ve eit her e x presse d a n i nterest i n or ha ve ta ke n part i n 
o ur r esear c h pr ojects pr e vi o usl y ( w here c o nse nt has bee n pr o vi de d t o d o t his)  
b.  staff a n d st u de nts at t he U ni versit y of S heffiel d, S H U a n d S T H ( via t he me dia tea m) 
usi n g t he a p pr o priate m o dera te d e mail lists at eac h i nstit uti o n. 
3.  L ocal  G P  pr actices/ Patie nt  I de ntificati o n  Ce ntres . I ntereste d  G P’s  at  t hese  sites  will  hel p 
i de ntif y patie nts a n d r ef er t he m t o t he st u d y tea m f or scree ni n g a n d e nr ol me nt. T o s u p p ort t his 
acti vit y we will pr o vi de: 
a.  P oste rs t o dis pla y i n waiti n g areas 
b.  R ecr uit me nt  letters. Pr e -dr afte d i n vitati o n letters f or distri b uti o n t o patie nts wit h A D  
c.  P artici p a nt I nf or m ati o n  Le aflets (s u m mar y  PI S) t o be  dis pla ye d i n  waiti n g  areas, 
ha n de d o ut at sc he d ule d a p p oi nt me nts a n d distri b ute d wi t h patie nt letters.  
T o  s u p p ort  r ecr uit me nt,  we  will  set  u p  a  de dicate d  U ni versit y  of  S heffiel d  CI C S  ma na ge d  e mail 
acc o u nt f or t he st u d y.  
We  will  als o  esta blis h  a  we b -pa ge  o n  t h e  S heffiel d  Der mat ol o g y  Researc h  we bsite 
(htt p:// w w w.s heffiel d. ac. u k/iic d/ der mat ol o g y ) o n t he st u d y, re plicati n g i nf or mati o n fr o m t he P oster 
a n d PI L. A li n k t o a d o w nl oa da ble c o p y of t he PI S will be pr o vi de d.  All p oster a d verts, t he PI L a n d 
PI S will li n k t o t he we bsite.  
T he st u d y office ( U ni versit y) will ha n dle all e x pressi o ns of i nterest.  T he Pre -Scree ni n g L o g will be 
use d t o tr ac k ne w a p pr oac hes.  Partici pa nts res p o n di n g t o o ur a d verts/letters b y p h o ne/e mail will be 
as ke d t o c o m plete a re gistr ati o n f or m (t his ma y be d o ne b y p h o ne/e mail/ p ost). T he re gistr ati o n f or m 
will m ake it cle ar t h at t he next ste p will be a p h o nec all fr o m a res e arc her o n t he st u dy t o c o n d uct t h e 
pre -scr ee ni n g.  
A c o p y of t he f ull P artici p a nt I nf or m ati o n S heet ( PI S)  will be se nt b y p o st/e mail t o eac h v ol u nteer 
c o m pleti n g t he r e gistr ati o n f or m. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7 .2. 1  Pre -scree ni n g  
Pe o ple  r es p o n di n g  t o  st u d y  a d vertise me nts  will  be  pr o vi de d  wit h  a P artici p a nt I nf or m ati o n  S heet  
( PI S) a n d st u d y R e gistr ati o n F or m  as descri be d a b o ve.   
A me m ber of t he tea m wil l t he n c o ntact i ntereste d v ol u nteers  t o c o n d uct a pre-scree ni n g sessi o n b y 
p h o ne.  If t he partici pa nt d oes n ot a ns wer, a v oice mail t o a pers o nal m o bile n u m ber ma y be left o nce 
b ut t his will n ot detail a n y st u d y or cli nical i nf or mati o n, it will be li mite d t o  a re q uest t o call bac k o n 
a gi ve n n u m ber. F o ur  d oc u me nte d atte m pts will be ma de at m ost. D uri n g t he pre -scree ni n g sessi o n 
we will c o m plete t he st u d y Pre -Scree ni n g  F or m , w hic h  r u ns t hr o u g h t he basic i ncl usi o n/e xcl usi o n 
criteria –  t his will hel p a v oi d wastin g t he ti me of v ol u nteers w h o d o n ot meet t he eli gi bilit y criteria.  
C o m plete d Pr e -Scr ee ni n g  f or ms will be f or war de d t o t he researc h tea m at t he site researc h facilit y 
( b y sec ur e electr o nic deli ver y or i n pers o n, b y a me m ber of t he st u d y tea m) t o arra n ge the st u d y visits . 
All s t u d y a p p oi nt me nts ma y  be arr a n ge d u p o n s uccessf ul pre -scree ni n g, s uc h t hat partici pa nts ha ve 
u n der g o ne a 1 -wee k  was h -o ut peri o d f or a n y t o pical pr o d ucts (e xcl u des was h pr o d ucts) t he y ma y use 
t he o n t he s ki n of t heir test sites pri or t o visit 1/ baseli ne . A scree ni n g n u m ber will be assi g ne d usi n g 
t he P artici p a nt Scree ni n g , E nr ol me nt & C o m pleti o n L o g . 
7 .3  Scree ni n g & I nf or m e d C o nse nt  
At t he be gi n ni n g of t he c o nse nt st u d y visit (at least 2 4 h o urs after Partici pa nt I nf or mati o n S heet ha ve 
be e n iss ue d), A me dicall y q ualifie d me m ber of t he st u d y tea m , trai ne d i n i nf or me d c o nse nt ta ki n g, 
will c o n d uct t he i nf or me d c o nse nt pr ocess a n d c o m plete t he scree ni n g acc or di n g t o t he i ncl usi o n a n d 
e xcl usi o n  criteria  ( usi n g  t he  A d missi o n  F or m  te m plate).  All partici pa nts  will  be  pr o vi de d  wit h  a 
C o nse nt  F or m  t o  si g n bef or e  a n y  st u d y  relate d  pr oce d ures  are  u n derta ke n ,  of  w hic h  t he y  will  be 
pr o vi de d a c o p y t o kee p.  
O nce  i nf or me d  c o nse nt  has  bee n  pr o vi de d  partici pa nts  will  be  assess e d  f or  eli gi bilit y.  T his  will 
in v ol ve  ca pt uri n g  a  me dical  hist or y  a n d  ot her  bac k gr o u n d  i nf or mati o n  perti ne nt  t o  t he  st u d y. T he 
pr ocess is r ef err e d t o her e as t he a d missi o n pr ocess, a n d will be d oc u me nte d usi n g t he A d missi o n 
F or m . 
T he c ollecti o n of bac k gr o u n d i nf or mati o n i n v ol ves : 
•  Rec or d i n g t he partici pa nts date of birt h 
•  Rec or di n g t he partici pa nts se x at birt h  
•  Rec or di n g t he partici pa nts et h nicit y  
•  Assessi n g a n d r ec or di n g t he partici pa nts  Fitz patric k s ki n t y pe  (see secti o n 7. 3. 1) 
•  Assessi n g a n d r ec or di n g t he partici pa nts hist or y of ecze ma ac c or di n g t o t he U K W or k Part y 
Dia g n ostic Criteria  (see secti o n 7. 3. 2) 
•  G r a di n g a n d r ec or di n g t he se verit y of ecze ma usi n g t he E A SI sc ori n g s heet (see secti o n 7. 3. 3) 
•  G r a di n g a n d  r ec or di n g t he  se verit y  of  ecze ma acc or di n g  t o  t he  I n vesti gat or s  static gl o bal 
assess me nt  (see secti o n 7. 3. 4) 
•  Rec or di n g t he ti me si nce t he partici pa nts last flare  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  Rec or di n g h o w ma n y ti mes t he partici pa nt’s c o n diti o n has rela pse d/flare d u p i n t he last 1 2 
m o nt hs  
T her e ar e 3 p ossi ble o utc o mes of t he a d missi o n pr ocess: ( 1) t he partici pa nt is f o u n d n ot t o be eli gi ble; 
( 2)  t he  partici pa nt meets  all  of  t he  criteria  a n d  is  eli gi ble  t o  ta ke  part; or  ( 3)  t he  partici pa nt  ma y 
bec o me eli gi ble after a n a p pr o priate was h -o ut peri o d  ( defi ne d i n secti o n 8. 8). I n t he latter case, t he 
re q uir e d was h-o ut peri o d s h o ul d be d oc u me nte d i n t he A d missi o n f or m a n d t he a d missi o n pr ocess 
(i ncl u di n g scr ee ni n g) r e peate d at t he start of visit 1 T his will i n v ol ve c o m pleti n g a n ot her A d missi o n 
F or m (tic ki n g t he f oll o w-u p f or m o pti o n) t o e ns ure t hat t he partici pa nt is i n fact  eli gi ble t o ta ke part 
bef or e pr ocee di n g o nt o a n y st u d y pr oce d ures , a n d t hat vali d bac k gr o u n d i nf or mati o n is ca pt ure d. T he 
se verit y of ecze ma will be r eassesse d as part of t he f oll o w-u p a d missi o n pr ocess.   
I nf or me d  c o nse nt  will  n ot  be  r eta ke n  w here  t he  partici pa nt  is  ret ur ni n g  after  a  defi ne d/sc he d ule d 
was h o ut peri o d of u p t o 1 6 wee ks ( 1 2 wee ks + 2 8 da ys). V ol u nteers w h o rea p pl y t o ta ke part after 
t his ti me or w her e a was h o ut peri o d was n ot sc he d ule d (a n d d oc u me nte d i n t he a d missi o n f or m), will 
be r e q uir e d t o r e-c o nse nt.  
W here t he p artici p a nt meets all of t he eli gi bility criteri a at t he scree ni n g visit , Visit 1/ baseli ne ma y 
be arr a n ge d wit hi n 2 8 da ys  wit h o ut t he nee d t o re peat t he a d missi o n pr ocess. If  m ore t ha n 2 8 da ys 
la pses bef or e t he partici pa nt ca n atten d visit 1 t he a d missi o n pr ocess s h o ul d be c o m plete d t o e ns ur e 
t he  partici pa nt  is  still  eli gi ble  a n d  t hat  t he  bac k gr o u n d  i nf or mati o n  is  still  vali d  (t his  will  i n v ol ve 
c o m pleti n g a f oll o w -u p a d missi o n f or m). Visit 1 ma y als o be c o m bi ne d wit h t he scree ni n g v isit (sa me 
da y) I F t he partici pa nt is f o u n d t o be eli gi ble wit h o ut t he nee d f or a was h o ut peri o d.  
T he P artici p a nt Scree ni n g ,  E nr ol me nt  &  C o m pleti o n L o g  will  be  c o m plete d  a n d  all scree ne d 
partici pa nts assi g ne d a u ni q ue st u d y scr ee ni n g n u m ber.  
7. 3. 1  Assi g n m e nt of Fitz p atrick ski n ty pe ( b ack gr o u n d i nf or m ati o n f or m)  
T he Fitz patric k s ki n t y pe will be vis uall y assesse d b y t he i n vesti gat or usi n g t he scale i n t he fi g ure 
bel o w.  
 
7. 3. 2 T he U K W orki n g P arty Di a g n ostic Criteri a f or ecze m a  
Acc or di n g t o t he U K w or ki n g part y dia g n ostic criteria, ecze ma is defi ne d as e x hi biti n g a n itc h y s ki n 
c o n diti o n pl us 3 or m or e of: 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 5 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  Hist or y of i n v ol ve me nt of t he s ki n creases  
•  Pers o nal hist or y of ast h ma or ha y fe ver  
•  Hist or y of ge ner all y dr y s ki n i n past year  
•  Visi ble fle x ur al der matitis  
•  O nset bel o w a ge 2  
7 .3 .3  Gr a di n g t he severity of A D usi n g t he E A SI syste m  
T he E A SI is a vali date d meas ur e use d i n cli nical practice a n d cli nical trials t o assess t he se verit y a n d 
e xte nt of A D. T he E A SI is a c o m p osite i n de x wit h sc ores ra n gi n g fr o m 0 t o 7 2. F o ur A D disease 
c har acteristics  ( er yt he ma,  t hic k ness  [i n d urati o n,  pa p ulati o n,  e de ma],  scratc hi n g  [e xc oriati o n],  a n d 
lic he nificati o n) will eac h be assess e d f or se verit y b y t he i n vesti gat or or desi g nee o n a scale of “ 0” 
(a bse nt)  t hr o u g h  “ 3”  (se ver e).  I n  a d diti o n,  t he  area  of  A D  i n v ol ve me nt  will  be  assesse d  as  a 
per ce nta ge b y b o d y ar ea of hea d, tr u n k, u p per li m bs, a n d l o wer li m bs, a n d c o n verte d t o a sc ore of 0 
t o 6. I n eac h b o d y r e gi o n, t he ar ea is e x pr esse d as 0, 1 ( 1 % t o 9 %), 2 ( 1 0 % t o 2 9 %), 3 ( 3 0 % t o 4 9 %), 
4 ( 5 0 % t o 6 9 %), 5 ( 7 0 % t o 8 9 %), or 6 ( 9 0 % t o 1 0 0 %). T he deter mi nati o n of E A SI will be s u p p orte d 
b y  t he  use  of  t he  E A SI  sc ori n g  s heet .  T he  E A SI  assess me nt  s h o ul d  be  perf or me d  e ver y  ti me  a n 
A d missi o n f or m is c o m plete d.  
7. 3. 4 T he I nvesti g at or s St atic Gl o b al A ssess me nt (IS G A)  
T he se verit y of ecze ma is assess e d b y a n i n vesti gat or acc or di n g t o t he scale bel o w:  
Sc ore  
Gr a de  
Defi niti o n  
0  
Cle ar  
Mi n or resi d u al hy p o/ hy per pi g me nt ati o n; n o eryt he m a or 
i n d ur ati o n/ p a p ul ati o n; n o o ozi n g/cr usti n g 
1  
Al m ost Cle ar  
Tr ace f ai nt  pi nk eryt he m a, wit h b arely perce pti ble 
i n d ur ati o n/ p a p ul ati o n a n d n o o ozi n g/cr usti n g 
2  
Mil d  
F ai nt pi nk eryt he m a wit h mil d i n d ur ati o n/ p a p ul ati o n a n d n o 
o ozi n g/cr usti n g  
3  
M o der ate  
Pi nk -re d eryt he m a wit h m o der ate i n d ur ati o n/ p a p ul ati o n wit h 
or wit h o ut o ozi n g/cr usti n g  
4  
Severe  
Dee p or bri g ht re d eryt he m a wit h sever e i n d ur ati o n/ p a p ul ati o n 
a n d wit h o ozi n g/cr usti n g  
 
7 .4  St u d y visits  
Pr oce d ur es  c o n d ucte d  d uri n g  t he  st u d y  visits  will  be  rec or de d  usi n g pa per  C R Fs  first  (a n d  t he n 
tr a nsf err e d t o t he E D C) or dir ectly usi n g a n electr o nic f or m i n t he E D C s yste m ( w hic h d o u ble as tas k 
lists f or eac h visit). W her e dir ect electr o nic e ntr y is use d, a t t he e n d of eac h sessi o n t he data base e ntr y 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
will be pri nte d a n d si g ne d b y t he r esear c her t o verif y t he s o urce data a n d st ore d  i n t he site file. F urt her 
details ca n be f o u n d i n secti o n “ St u d y C o n d uct”.  
At t he start of e ver y visit c o nse nt will be rec o nfir me d a n d e n q uiries will be ma de a b o ut p ote ntial A E 
a n d c o nc o mita nt me dicati o n ( A E a n d C o nc o mita nt Me dicati o n f or ms will be c o m ple te d as re q uire d). 
A descri pti o n of t he visits is pr o vi de d bel o w:  
7. 4. 1 Scree ni n g & C o nse nt Visit ( a p pr ox. 3 0 -6 0 mi n)  
•  A  me m ber  of  t he  st u d y  tea m  s h o ul d  pr o vi de  a n  o ver vie w  of  t he  st u d y  a n d  a ns wer  a n y 
q uesti o ns. I nf or me d c o nse nt s h o ul d t he n be ta ke n.  
•  Parti ci pa nts s h o ul d be a d mitte d o nt o t he st u d y b y f oll o wi n g t he a d missi o n pr ocess detaile d i n 
t he A d missi o n F or m.  
o  C ollect basic de m o gr a p hic/ bac k gr o u n d i nf or mati o n a b o ut t he partici pa nt  
o  Me dical hist or y s h o ul d be c ollecte d t hr o u g h disc ussi o n wit h t he partici pa nt , a n d fr o m 
t he  patie nt  n otes  w her e  t he y  are  a vaila ble  ( n ot  all  partici pa nts  will  be  re gistere d  at 
S heffiel d T eac hi n g H os pitals).  
o  Details  of  c o nc o mita nt  me dicati o n  t o  be  ca pt ure d  a n d  rec or de d  i n  t he  C o nc o mita nt 
Me dicati o n L o g.  
o  A  p h ysical  e xa mi nati o n  of  t he  partici pa nts  s ki n  s h o ul d  be  perf or me d  b y  a  st u d y 
der mat ol o gist t o gr a de t he se verit y of ecze ma o verall. T he der mat ol o gist will nee d t o 
see t he si g ns of ecze ma t o assess its se verit y.  
o  Scr ee ni n g a gai nst t he st u d y criteria.  
•  Fe male partici pa nts s h o ul d be as ke d t o ta ke a uri ne pre g na nc y test  
•  F or  f e male  partici pa nts  o nl y,  t he  u n derta ki n g  of  a  relia ble  f or m  of  c o ntrace pti o n  f or  t he 
d ur ati o n of t he st u d y s h o ul d be disc usse d, a n d a met h o d a gree d.  
•  Access  a n d  u p date  patie nt me dical n ote s wit h  st u d y  details.  If  t h e  partici pa nt  has  n o  n otes 
alr ea d y, a ne w set of n otes s h o ul d be pre pare d . 
•  If  eli gi ble  t o  ta ke  part  t he site  staff will  t he n  arra n ge  t he  s u bse q ue nt  st u d y  visits  wit h  t he 
partici pa nt. W her e p ossi ble, de pe n de nt o n t he a vaila bilit y of t he partici pa nt a n d t he site staff 
a n d f acilities, eli gi ble partici pa nts ma y u n derta ke Visit 1 o n t he sa me date as t he scree ni n g 
a n d c o nse nt visit. If t he partici pa nt ma y bec o me eli gi ble f oll o wi n g a was h-o ut peri o d fr o m 
a n y c urr e nt me dicati o n, Visit 1 ca n be arra n ge d t o ta ke plac e after t he was h -o ut peri o d. I n 
t hese  cases,  t he  was h o ut  peri o d  s h o ul d  be  d o c u me nte d  i n  t he  A d missi o n  F or m  a n d  t he 
a d missi o n pr ocess r e peate d at t he start of Visit 1.  
7. 4. 2 W as h -o ut  
S o me partici pa nts, w h o ar e c urr e ntl y usi n g treat me nts f or ecze ma, will nee d t o u n der g o a ‘ was h o ut’ 
peri o d, w her e t he use of t hese tr eat me nts is st o p pe d, pri or t o t he first st u d y visit. T he d urati o n of t he 
was h -o ut de pe n ds o n t he t y pe of tr eat me nt, a n d varies fr o m 7 da ys f or e m ollie nts t o 1 2 wee ks f or 
i ntr a ve n o us bi ol o gic t her a pies.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7. 4. 3 Visit 1, D ay 1 ( a p pr ox. 2. 5 -3 h o urs)  
•  If a was h-o ut peri o d was r e q uir e d, or if m ore t ha n 2 8  da ys has la pse d si nce t he scree ni n g visit, 
t he a d missi o n pr ocess s h o ul d be r e peate d b y c o m pleti n g a ne w A d missi o n F or m a n d f oll o wi n g 
t he f oll o w-u p pr oc e d ur e: 
o  U p date basic de m o gr a p hic/ bac k gr o u n d i nf or mati o n a b o ut t he partici pa nt if necessar y  
o  U p date me dical hist or y  
o  U p date c o nc o mita nt me dicati o n  
o  Perf or m a p h ysical e xa mi nati o n of t he partici pa nts s ki n t o gra de t he se verit y of ecze ma 
o ver all.  
o  Re -assess eli gi bilit y a gai nst t he i ncl usi o n a n d e xcl usi o n criteria  
•  Ca pt ur e a d verse e ve nts a n d ne w c o nc o mita nt me dicati o ns  
•  Fe male partici pa nts s h o ul d be as ke d t o ta ke a uri ne pre g na nc y test  
•  C hec k t hat a n a p pr o priate met h o d of c o ntrace pti o n is i n use  
•  Iss ue a r a n d o mizati o n/st u d y I D n u m ber 
•  Tr a nsf er partici pa nt t o s ki n barrier s uite  
•  Partici pa nts will nee d t o accli matize t he s ki n o n t heir f orear ms t o t he r o o m c o n diti o ns f or 2 0 
mi n utes.  
•  T he meas ur e me nt sites s h o ul d be mar ke d o ut o n eac h ar m usi n g a mar ker pe n (as discreetl y  
as p ossi ble). T he mar ker is easil y re m o ve d b y was hi n g t he s ki n at t he e n d of t he st u d y visit. 
Hair i nterf er es wit h t he meas ur e me nts, s o w here prese nt we ma y nee d t o tri m it.  
•  O nce accli matise d t he c o n diti o n of t he s ki n s h o ul d be assess e d:  
o  Vis uall y sc or e s k i n dr y ness a n d re d ness/er yt he ma at eac h treat me nt area 
o  Ca pt ur e 2 D s ki n i ma ges of t he test areas of s ki n  
o  Perf or m Me xa meter meas ure me nts of o bjecti ve s ki n re d ness at eac h site  
o  T a ke O C T (str uct ur al & a n gi o gra p hic) i ma ges/sca ns wit h t he Vi v osi g ht at eac h test  
site  
o  T a ke P S -O C T i ma ges/sca ns wit h t he P S -O C T mac hi ne at eac h tests site  
o  Meas ur e T E W L at eac h test site  
o  C ollect F TI R s pectr a at eac h test site  
•  A m o ut h s wa b sa m ple s h o ul d be c ollecte d  
•  Tr a nsf er patie nts bac k t o t he site researc h facilit y (if differe nt) 
•  Iss ue I M P’s ( wei g he d) a n d pr o vi de de m o nstrati o n of d osi n g b y fi n gerti p u nit 
•  Iss ue tr eat me nt diar y, c o m plete t he rele va nt secti o ns, a n d pr o vi de trai ni n g o n its c o m pleti o n 
•  As k t he partici pa nt t o perf or m a s u per vise d pr o d uct a p plicati o n (after meas ure me nts).  
•  Arr a n ge ta xi tr a nsf er f or ne xt sessi o n  
7. 4. 4 R e mi n ders bet wee n visits  
•  Re mi n d partici pa nts n ot t o a p pl y pr o d ucts i n t he m or ni n g bef ore st u d y visits 2 -7. Re mi n ders 
s h o ul d  be  se nt  o ut  t he  da y  bef or e  t he  a p p oi nt me nt  is  d ue.  T e xt  messa ges  are  t he  preferre d 
met h o d; h o we ver, tele p h o ne calls or e mail ca n be use d i nstea d at t he re q uest of t he partici pa nt.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7. 4. 5 Visits 2 -5, D ays 1 t o 1 2 ( a p pr ox. 2 0 mi n e ac h)  
Tr eat me nt  usa ge  s h o ul d  be  m o nit or e d  o n  4  occasi o ns  d uri n g  t he  first  1 2  da ys  of  treat me nt.  T he 
sc he d uli n g of t hese visits is fle xi ble wit hi n t he c o nstrai nts i n t he pr ot oc ol sc he d ule of e ve nts. At eac h 
visit t he f oll o wi n g acti vities s h o ul d be carrie d o ut:  
•  Re -c o nfir m ver bal asce nt t o c o nti n ue t he st u d y  
•  Ca pt ur e a d verse e ve nts a n d ne w c o nc o mita nt me dicati o ns  
•  C hec k c o m plia nce wit h d osi n g c o n diti o ns  
•  Wei g h I M P’s, r ec or d wei g hts i n t he C R F a n d treat me nt diar y, a n d i nf or m partici pa nts of t heir 
usa ge i n t he c o nte xt of e x pecte d usa ge.  
•  C hec k all diar y e ntries f or missi n g a p plicati o ns a n d a d verse e ve nts (s ki n reacti o ns re p or te d at 
t he ti me of a p plicati o n). 
•  As k t he partici pa nt t o perf or m a s u per vise d pr o d uct a p plicati o n (after meas ure me nts).  
•  Pr o vi de r e -tr ai ni n g/ g ui da nce t o i m pr o ve o n a p plicati o n tec h ni q ue a n d/ or d osi n g ‘as re q uire d’ 
•  Arr a n ge ta xi tr a nsf er f or ne xt sessi o n  
7. 4. 6 Visit 6, D ay 1 5 +/ - 3 d ays ( a p pr ox. 2. 5 h o urs)  
•  Re -c o nfir m ver bal asce nt t o c o nti n ue t he st u d y  
•  Ca pt ur e a d verse e ve nts a n d ne w c o nc o mita nt me dicati o ns  
•  C hec k t hat a n a p pr o priate met h o d of c o ntrace pti o n is i n use  
•  C hec k c o m plia nce wit h d osi n g c o n diti o ns  
•  Tr a nsf er partici pa nt t o s ki n barrier s uite  
•  Partici pa nts will nee d t o accli matize t he s ki n o n t heir f orear ms t o t he r o o m c o n diti o ns f or 2 0 
mi n utes.  
•  T he meas ur e me nt sites s h o ul d be mar ke d o ut o n eac h ar m usi n g a mar ker pe n (as discreetl y 
as p ossi ble). T he mar k er is easil y re m o ve d b y was hi n g t he s ki n at t he e n d of t he st u d y visit. 
Hair i nterf er es wit h t he meas ur e me nts, s o w here prese nt we ma y nee d t o tri m it.  
•  O nce accli matise d t he c o n diti o n of t he s ki n s h o ul d be assess e d:  
o  Vis uall y sc or e s ki n dr y ness a n d re d ness/ er yt he ma at eac h treat me nt area 
o  Ca pt ur e 2 D s ki n i ma ges of t he test areas of s ki n  
o  Perf or m Me xa meter meas ure me nts of o bjecti ve s ki n re d ness at eac h site  
o  T a ke O C T (str uct ur al & a n gi o gra p hic) i ma ges/sca ns wit h t he Vi v osi g ht at eac h test 
site  
o  Meas ur e T E W L at eac h test site  
o  C ollect F TI R s pectr a at eac h test site  
•  Tr a nsf er patie nts bac k t o t he site researc h facilit y (if differe nt) 
•  Wei g h I M P’s, r ec or d wei g hts i n t he C R F a n d treat me nt diar y, a n d i nf or m partici pa nts of t heir 
usa ge i n t he c o nte xt of e x pecte d usa ge.  
•  C hec k all diar y e ntries f or missi n g a p plicati o ns a n d a d verse e ve nts (s ki n reacti o ns re p orte d at 
t he ti me of a p plicati o n). 
•  As k t he partici pa nt t o perf or m a s u per vise d pr o d uct a p plicati o n (after meas ure me nts).  
•  Pr o vi de r e -tr ai ni n g/ g ui da nce t o i m pr o ve o n a p plicati o n tec h ni q ue a n d/ or d osi n g ‘as re q uire d’ 
•  Arr a n ge ta xi tr a nsf er f or ne xt sessi o n  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7. 4. 7 Visit 6 a, D ay 2 2 +/ - 3 d ays  ( a p pr ox. 2 0 mi n) 
Sa me pr oce d ure as visits 2-5  
7. 4. 8 Visit 7, D ay 2 9 +/ - 3 d ays ( a p pr ox. 3 h o urs)  
•  Re -c o nfir m ver bal asce nt t o c o nti n ue t he st u d y  
•  Ca pt ur e a d verse e ve nts a n d ne w c o nc o mita nt me dicati o ns  
•  Fe male partici pa nts s h o ul d be as ke d t o ta ke a uri ne pre g na nc y test  
•  C hec k t hat a n a p pr o priate met h o d of c o ntrace pti o n is i n use  
•  C hec k c o m plia nce wit h d osi n g c o n diti o ns  
•  Tr a nsf er partici pa nt t o  s ki n barrier s uite 
•  Partici pa nts will nee d t o accli matize t he s ki n o n t heir f orear ms t o t he r o o m c o n diti o ns f or 2 0 
mi n utes.  
•  T he meas ur e me nt sites s h o ul d be mar ke d o ut o n eac h ar m usi n g a mar ker pe n (as discreetl y 
as p ossi ble). T he mar ker is easil y re m o ve d  b y was hi n g t he s ki n at t he e n d of t he st u d y visit. 
Hair i nterf er es wit h t he meas ur e me nts, s o w here prese nt we ma y nee d t o tri m it.  
•  O nce accli matise d t he c o n diti o n of t he s ki n s h o ul d be assess e d:  
o  Vis uall y sc or e s ki n dr y ness a n d re d ness/er yt he ma at eac h tre at me nt area 
o  Ca pt ur e 2 D s ki n i ma ges of t he test areas of s ki n  
o  Perf or m Me xa meter meas ure me nts of o bjecti ve s ki n re d ness at eac h site  
o  T a ke O C T (str uct ur al & a n gi o gra p hic) i ma ges/sca ns wit h t he Vi v osi g ht at eac h test 
site  
o  T a ke P S -O C T i ma ges/sca ns wit h t he P S -O C T mac hi ne at eac h tests site  
o  Meas ur e T E W L at eac h test site  
o  C ollect F TI R s pectr a at eac h test site  
o  Perf or m ta pe -stri p pi n g i n c o nj u ncti o n wit h T E W L a n d F TI R assess me nts 
o  C ollect ta pe -stri p sa m ples (i ncl u di n g N M F sa m ple c ollecti o n) 
•  Tr a nsf er patie nts bac k t o t he site researc h facilit y (if differe nt) 
•  Wei g h I M P’s, r ec or d wei g hts i n t he C R F a n d treat me nt diar y, a n d i nf or m partici pa nts of t heir 
usa ge i n t he c o nte xt of e x pecte d usa ge.  
•  C hec k all diar y e ntries f or missi n g a p plicati o ns a n d a d verse e ve nts (s ki n re acti o ns re p orte d at 
t he ti me of a p plicati o n). 
•  Retrie ve diar y a n d I M P’s  
•  Arr a n ge ta xi tr a nsf er f or ne xt sessi o n  
7. 4. 9  Visit 8, D ay 5 7 +/ - 4 d ays ( a p pr ox. 2. 5 h o urs)  
•  Re -c o nfir m ver bal asce nt t o c o nti n ue t he st u d y  
•  Ca pt ur e a d verse e ve nts a n d ne w c o nc o mita nt m e dicati o ns  
•  Tr a nsf er partici pa nt t o s ki n barrier s uite  
•  Partici pa nts will nee d t o accli matize t he s ki n o n t heir f orear ms t o t he r o o m c o n diti o ns f or 2 0 
mi n utes.  
•  T he meas ur e me nt sites s h o ul d be mar ke d o ut o n eac h ar m usi n g a mar ker pe n (as discreetl y 
as p ossi ble). T he mar ker is easil y re m o ve d b y was hi n g t he s ki n at t he e n d of t he st u d y visit. 
Hair i nterf er es wit h t he meas ur e me nts, s o w here prese nt we ma y nee d t o tri m it.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  O nce accli matise d t he c o n diti o n of t he s ki n s h o ul d be assess e d:  
o  Vis uall y sc or e s ki n dr y nes s a n d re d ness/er yt he ma at eac h treat me nt area 
o  Ca pt ur e 2 D s ki n i ma ges of t he test areas of s ki n  
o  Perf or m Me xa meter meas ure me nts of o bjecti ve s ki n re d ness at eac h site  
o  T a ke O C T (str uct ur al & a n gi o gra p hic) i ma ges/sca ns wit h t he Vi v osi g ht at eac h test 
site  
o  Me as ur e T E W L at eac h test site  
o  C ollect F TI R s pectr a at eac h test site  
•  As k partici pa nts t o c o m plete a clai m f or m f or t he re m u nerati o n  
7 .5  R a n d o miz ati o n & bli n di n g  
T he partici pa nt will be assi g ne d a r a n d o mizati o n n u m ber ( Trial N u m ber) at Visit 1. T his will b e t he 
ne xt a vaila ble n u m ber o n t he Ra n d o mizati o n list . T his n u m ber will be t he pri nci ple i de ntifier a gai nst 
w hic h t he st u d y data will be st or e d.  All ocati o n of t he ra n d o mizati o n n u m ber is c o nsi dere d t he p oi nt 
of  e ntr y  o nt o  t he  trial,  w hic h  s h o ul d  be  rec or de d  o n  t he P artici p a nt  Scree ni n g,  E nr oll me nt  & 
C o m pleti o n L o g . 
7 .5 . 1 R a n d o miz ati o n 
All ocati o n  of  t he  tr eat me nts  t o  t he  test  sites  (ri g ht/left  f orear m)  will  be  ra n d o mise d  (t o  a v oi d  site 
p ositi o n -de pe n de nt  artef acts)  1: 1  usi n g  a  ra n d o mizati o n  sc he d ule  (list)  p r o vi de d  b y  t he  Statistical 
Ser vices U nit. T he list will be n u m ber e d usi n g t he u ni q ue partici pa nt ra n d o mizati o n n u m ber, s uc h 
t hat partici pa nt 0 0 1 will be dis pe nse d pr o d ucts acc or di n g t o t he first a nat o mical site all ocati o n o n t he 
list  a n d  s o  o n. T he  S heffie l d  T eac hi n g  H os pitals  P har mac y  will  u n derta ke a n d d oc u me nt  t he 
ra n d o mizati o n a n d la bel t he I P’s wit h t he site of a p plicati o n u p o n iss ue t o t he site researc h facilit y 
tea m. O nl y t he P har mac y a n d st u d y Statisticia n ( S S U) will ha ve access t o t he ra n d o misati o n  master 
list. 
7 .5. 2  Bli n di n g  
T he st u d y will be c o n d ucte d o bser ver -bli n d . Beca use t he pr o d ucts  ha ve disti nct f or ms ( oi nt me nt vs 
cr ea m)  a n d  will  be  pr o vi de d  i n  clearl y i de ntifia ble  pac ka gi n g  st u d y  partici pa nts  will  be  usi n g  t he 
pr o d ucts o pe n -la bel. 
T he I P’s , la belle d a n d r elease d b y t he P har mac y, will be iss ue d b y u n bli n de d researc h staff wit hi n t he 
site  resear c h facilit y,  w h o  will  u n derta ke  all  I P  relate d  d uties,  i ncl u di n g  c o m plia nce  m o nit ori n g. 
Partici pa nts  will  be  as ke d  n ot  t o  disc uss/ me nti o n  t he  I P  i de nti ties  wit h  t he  st u d y  tea m  me m bers 
c ollecti n g t he data ( w h o will be bli n d –  o bser ver bli n di n g) . 
T he c ollecti o n of st u d y data will be c o n d ucte d i n a se parate area ( de dicate d s ki n barrier researc h s uite) 
b y a se par ate tea m ( c o m prisi n g s kille d der mat ol o g y resea rc hers) w h o will be bli n d .  
7. 5. 3 E mer ge ncy u n bli n di n g  
O nl y  t he  r esear c h  tea m  assessi n g  t he  st u d y  e n d p oi nts  are  bli n d  t o  t he  treat me nt  all ocati o n  a n d 
partici pa nts ar e all pr escri be d b ot h tr eat me nts.  T heref ore , n o e mer ge nc y u n bli n di n g arra n ge me nts 
ar e necessar y. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
 
 
7 .6  P re g n a nc y t esti n g   
F or  f e male partici pa nt s  of  c hil d beari n g  p ote ntial,  a  uri ne  pre g na nc y  test ( beta-h u ma n  c h ori o nic 
g o na d otr o pi n ( b -h C G), wit h se nsiti vit y of at least  2 5  mI U/ m L, will be perf or me d at scree ni n g, pri or 
t o d osi n g wit h i n vesti gati o nal pr o d uct o n Da y  1 a n d at t he e n d-of -treat me nt ( Da y 2 9) visit, t o c o nfir m 
t he partici pa nt  has n ot bec o me pr e g na nt d uri n g t he st u d y.   
A ne gati ve pr e g na nc y test r es ult is r e q uir e d bef ore t he partici pa nt  ca n recei ve i n vesti gati o nal pr o d uct.  
Pr e g na nc y tests  ma y als o b e r e peate d at t he dis creti o n of t he i n vesti gat or or his/ her desi g nee . I n t he 
case of a p ositi ve uri ne b -h C G test  d uri n g t he treat me nt peri o d , t he partici pa nt  will be wit h dra w n 
fr o m a d mi nistr ati o n of i n vesti gati o nal pr o d uct a n d fr o m t he st u d y 
7 .7  S ki n assess m e nts  
T he s ki n assess me nts will be u n derta ke n i n t he s ki n barrier s uite at t he R o yal Halla ms hire H os pital 
b y e x perie nce d der mat ol o g y r esear c hers.  
T he trial i n v ol ves t he use of a r a n ge of i nstr u me nts t o assess t he bi o p h ysical pr o perties of t he s ki n. 
T he i nstr u me nts use d o n t his st u d y ar e liste d i n t he ta ble bel o w. All t he i nstr u me nts are o w ne d a n d 
mai ntai ne d b y t he U ni versit y of S heffiel d Der mat ol o g y Researc h gr o u p . Wit h t he e xce pti o n of t he 
c ust o m -b uilt P S -O C T, all i nstr u me nts ar e use d as s u p pl ie d b y t he ma n ufact urer ( n o m o dificati o n) a n d 
f or t heir i nte n de d p ur p oses. E ac h i nstr u me nt will u n der g o a n n ual Bi o me dical E n gi neeri n g testi n g f or 
electrical saf et y at t he R o yal Halla ms hir e H os pital.  
T a ble 7 .2 : I nstr u me nts use d i n t his st u d y 
I nstr u me nt 
Ma n u fact urer 
Meas ur eme nts  
Vi v osi g ht 
O C T S ca n ner  
Mic hels o n 
Dia g n ostics Lt d.  
E pi der mal t hic k ness (str uct ural O C T) 
 
S u perficial ple x us de pt h ( µ m , a n gi o gra p hic O C T ) 
 
B l o o d vessel dia meter (µ m , a n gi o gra p hic O C T ) 
 
B l o o d vessel de nsit y (se g me nts/ m m2, a n gi o gra p hic O CT ) 
 
A q ua Fl u x 
A F 2 0 0 T E W L 
mac hi ne  
Bi o x S yste ms 
Lt d.  
Tra ns -E pi der mal Water L oss ( T E W L)  
P S -O C T  
mac hi ne  
U ni versit y of 
S heffiel d c ust o m 
b uil d  
C olla ge n i n de x (a n i n de x deri ve d fr o m birefri n ge nce 
i ma ges of c olla ge n de nsit y a n d arra n ge me nt) meas ure d b y 
p olarisat i o n se nsiti ve O C T  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
 
4 3 0 0 F TI R 
S pectr o meter  
A gile nt 
Tec h n ol o gies Lt d.  
C ar b o x ylate le vels (i n direct meas ure of nat ural m oist urisi n g 
fact or le vels) i n t he strat u m c or ne u m meas ure d b y F TI R 
s pectr osc o p y  
 
S trat u m c or ne u m li pi d str uct ure meas ure d b y F TI R 
s pectrosc o p y  
 
C -C u be 
ca mera  
Pi xie nce  
S ki n i ma ge d oc u me ntati o n o nl y  
 
Me xa meter  
C & K  
O bjecti ve  re d ness  
 
We ha ve n o affiliati o n wit h t he ma n uf act ures of t he i nstr u me nts use d  ( wit h t he e xce pti o n of t he P S-
O C T mac hi ne) , a n d t he i nstr u me nts t he msel ves are n ot directl y u n der i n vesti gati o n herei n as t o ols t o 
i nf or m cli nical decisi o n ma ki n g. I nstea d t he ai m is t o i de ntif y differe nces i n t he s ki n i n res p o nse t o 
tr eat me nt  t hr o u g h  r esear c h,  n ot  t o  dir ectl y  i nf or m  cli nical  decisi o n  ma ki n g.  It  is  p ossi ble  t hat  t he 
res ults of t his trial s u g gest t hat o ne or m ore of t he bi o mar kers meas ure d usi n g t he i nstr u me nts c o ul d 
be use d cli nicall y t o m o nit or tr eat me nt safet y. I n sai d case, e val uati n g t he i nstr u me nt as a me dical 
de vice will be t he partici pa nt  of a se par ate f ut ure st u d y.  
D efi niti o n of a me dic al device:  a ny i nstr u me nt, a p p ar at us, a p pli a nce, s oft w are, m ateri al or 
ot her article, w het her use d al o ne or i n c o m bi n ati o n, i ncl u di n g t he s oft w are i nte n de d by its 
m a n uf act urer  t o  be  use d  s pecific ally  f or  di a g n ostic  a n d/ or  t her a pe utic  p u r p os es  a n d 
necess ary  f or  its  pr o per  a p plic ati o n,  i nte n de d  by  t he  m a n uf act urer  t o  be  use d  f or  h u m a n 
bei n gs  f or  t he  p ur p ose  of:  di a g n osis,  preve nti o n,  m o nit ori n g,  tre at me nt  or  allevi ati o n  of 
dise ase.  
T he  l ocati o ns  of  t he  s ki n  assess me nt  sites  are  det aile d  i n  Fi g ure  7. 1,  a n d  t he  or der  i n  w hic h  t he y 
s h o ul d be c ollecte d pr o vi de d i n T a ble 7.3 . 
7. 7 . 1 A ccli m atiz ati o n  
T he  partici pa nt  s h o ul d  be  as ke d  t o  e x p ose  t he  s ki n  of  t he  test/treat me nt  areas  at  least  2 0  mi n utes 
bef or e ta ki n g t he first s ki n meas ur e me nts (i ncl u di n g vis ual sc ores) s o t hat t he s ki n at t hese sites ca n 
a dj ust t o t he r o o m c o n diti o ns. T his ma y i n v ol ve as ki n g t he partici pa nt t o re m o ve t heir jac ket/j u m per. 
T he r o o m te m per at ur e a n d h u mi dit y s h o ul d be i n t he ra n ge 2 0 ± 2 oC a n d 4 5 ± 1 0 % relati ve h u mi dit y.  
7. 7. 2  I de ntific ati o n a n d dem arc ati o n of t he test sites  
T he test/tr eat me nt sites ar e l ocate d o n t he v olar si de of t he f orear m ( Fi g ure 7 .1 ). T here are 2 treat me nt 
ar eas i n t otal, o ne o n eac h f or ear m. Wit hi n eac h treat me nt area t here are 2 defi ne d test or meas ure me nt 
ar eas. Bef or e  perf or mi n g  a n y  s ki n  assess me nts,  d uri n g  t he  accli matizati o n  peri o d,  t he  test  areas 
s h o ul d be mar ke d o ut discr etel y usi n g a r uler, a n d s ki n mar ki n g pe n wit h t he hel p of t he g ui de bel o w. 
T he ta ble lists t he meas ur e me nts perf or me d at eac h tes t area i n t he or der t he y s h o ul d be c ollecte d.  
 
 

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 6 7 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
Fi g ure 7. 1: T he l ocati o n of t he tr eat me nt areas a n d test sites 
T a ble 7. 3: T he meas ur e me nts t o be perf or me d at eac h test site
Test ar ea
Me as ur e me nt
R 1/ 2 ( c o m bi ne d), 
L 1/ 2 ( c o m bi ne d)
1.  
Vis ual sc ori n g of s ki n dr y ness a n d r e d ness at ea c h test site 
R 1, L 1
2. 
Ca pt ure of 2 D s ki n i ma ge usi n g t he c-c u be 
3.
Me xa meter meas ur e me nt at e ac h site (s ki n r e d ness, 4 r e peats )
4.
O C T (str uct ural & a n gi o gra p hic) i ma ge ca pt ure at e ac h site (i n tri plic ate)
5.
P S -O C T i ma ge ca pt ure at ea c h site (i n tri plic ate) 
6.
T E W L meas ure me nt at e ac h site (i n d u plicate )
7.
F TI R s pe ctr u m fr o m t he s ki n s urf ace c olle cte d at e ac h site 
R 2, L 2
2. 
Ca pt ure of 2 D s ki n i ma ge usi n g t he c-c u be 
3.
Me xa meter meas ur e me nt at e ac h site (s ki n r e d ness, 4 r e peats )
4.
T E W L meas ure me nt at e ac h site (i n d u plicate )
5.
F TI R s pe ctr u m fr o m t he s ki n s urf ace c olle cte d at e ac h site 
6.
Ta pe -stri p pi n g  i n  c o nj u ncti o n  wit h  T E W L  a n d  F TI R (t o  a c hie ve  f ull 
str at u m c or ne u m de pt h)
7.
Ta pe -stri p sa m ple c ollecti o n
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S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 6 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7 .7. 3  Vis u al sc ori n g of ski n dry ness  a n d re d ness /er yt he m a 
Vis ual dr y ness a n d r e d ness/er yt he ma of t he f orear ms ( w h ole v olar face/treat me nt area) will be sc ore d 
b y a n e x perie nce d gr a der usi n g t he scale s bel o w  at t he visits i n dicate d i n t he sc he d ule of e ve nts. 
T a ble 7 .4 : Vis ual assess me n t scale f or dr y ness –  t he over all dry ski n sc ore ( O D S) 
Sc or e  Descri pti o n  
0  
A bse nt  
1  
Fai nt scali n g, f ai nt r o u g h ness a n d d ull a p peara nce  
2  
S mall scales i n c o m bi nati o n wit h a fe w lar ger scales, sli g ht r o u g h ness, w hitis h 
a p pear a nce  
3  
S mall a n d lar ger scale s u nif or ml y distri b ute d, defi nite r o u g h ness, p ossi bl y sli g ht 
r e d ness a n d p ossi bl y a f e w s u perficial crac ks 
4  
D o mi nate d  b y  lar ge  scales,  a d va nce d  r o u g h ness, re d ness  prese nt,  ecze mat o us 
c ha n ges a n d cr ac ks  
 
T a ble 7 .5 : Vis ual assess me nt scale f or er yt he ma  
Sc or e  
Descri pti o n  
0  
N o r e d ness. 
0. 5 / +  Sli g ht, patc h y er yt he ma –  barel y perce pti ble  
1  
Sli g ht u nif or m er yt he ma –  mil d er yt he ma  
2  
M o der ate, u nif or m er yt he ma –  M o derate er yt he ma  
3  
Str o n g er yt he ma –  Mar ke d er yt he ma  
 
7. 7 . 4 2 D i m a ge c a pt ure wit h t he c -c u be c a mer a  
A cl ose -u p i ma ge of eac h test ar ea will be ca pt ure d usi n g t he c -c u be ( Pi xie nce, Fra nce)  t o d oc u me nt 
t he  s ki n  c o n diti o n.  A  1 6 x 1 2 m m  ar ea  of  t he  test  site  s ki n  is  i ma ge d  t heref ore  t here  are  n o  data 
c o nfi de ntialit y  c o ncer ns.  T he  i ma ges  ar e  st ore d  b y  t h e  c-c u be  cli nical  data base  s oft ware  wit hi n  a 
pr ot oc ol s pecific f ol der l ocall y a n d o n t he ser ver wit hi n t he st u d y s pecific f ol der. F urt her details o n 
ta ki n g s ki n i ma ges wit h t he c-c u be ca n be f o u n d i n S O P -0 5 0.  

S heffiel d Der mat ol o g y Researc h
T he S M A R T St u d y
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5
Pa ge 6 9 of 1 0 6
T his d oc u me nt is c o nfi de ntial – N o part of it ma y be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.
Fi g ure 7. 2: T he Pi xie nce c -c u be
7. 7 . 5 M ex a meter me as ure me nts of o bjective ski n re d ness/eryt he m a (t oler a bility)
S ki n r e d ness will be meas ur e d 4 ti mes wit hi n eac h test area ( 2 areas i n t otal per treat me nt area ) usi n g 
a C & K Me xa meter pr o be. After use i n eac h partici pa nt t he pr o be will be dec o nta mi nate d wit h a 
sa nitati o n/ deter ge nt wi pe. F urt her details o n h o w t o ta ke s ki n meas ure me nts wit h t he Me xa meter ca n 
be f o u n d i n S O P - 0 2 3.
Fi g ure 7 . 3: T he Me xa meter pr o be
7. 7. 6 Str uct ur al & A n gi o gr a p hic O C T sc a ns usi n g t he Viv osi g ht O C T m ac hi ne
O ptical c o her e nce t o m o gr a p h y ( O C T) is a n o n -i n vasi ve i ma gi n g m o dalit y c o nce pt uall y si milar t o 
ultr as o u n d  ( U S) b ut uses  near -i nfr ar e d  ra diati o n rat her t ha n  s o u n d. It  has a 2-1 0  micr o n de pt h  
res ol uti o n c o m par e d wit h 1 0 0-1, 0 0 0 micr o n t y pical f or cli nical U S; a n d 1 -2 m m i ma gi n g de pt h vs. 
1 0- 1 0 0 m m f or cli nical U S. It is t h us i deal f or i ma gi n g t he s urface la yers of accessi ble tiss ues s uc h 
as t he s ki n. It is attr acti n g i nter est t hr o u g h o ut t he me dical c o m m u nit y as a sca n ni n g t o ol a n d f or 
dia g n osis of ill nesses s uc h as e pit helial ca ncer, c o n necti ve tiss ue dis or ders, a n d at her oscler osis. 
Her e we will use t he Vi v o si g ht O C T mac hi ne, r u n ni n g bes p o ke s oft ware de vel o pe d b y t he U ni versit y 
of S heffiel d, t o ta ke v ol u metric sca ns (i ma ges) of t he s ki n. T he Vi v osi g ht is a C E mar ke d cli nical 
O C T de vice ( Mic hels o n Dia g n ostics Lt d) n o w r o uti nel y use d w orl d wi de t o i de ntif y vari o us s ki n 
ca ncers. T he  sca ns  ca pt ur e d  o n  t his  de vice  usi n g  o ur  s oft ware  c o m prise  b ot h  str uct ural  a n d  
a n gi o gr a p hic i nf or mati o n, mea ni n g t hat a si n gle sca n pr o vi des t he i nf or mati o n f or b ot h t he str uct ural 
O C T a n d a n gi o gr a p hic O C T o utc o mes.

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1.  Str uct ur al  O C T:  Wit h  a  de pt h  f oc us  of  1. 0 m m  a n d  o ptical  res ol uti o n  of  7. 5 x 5. 0 µ m t he 
Vi v osi g ht pr o vi des str uct ur al i ma ges of t he s ki n c o m para ble t o hist ol o g y secti o ns. Fr o m t hese 
i ma ges t he t hic k ness of t he e pi der mis, t he s u pra pa p ilar y e pi der mis a n d t he pa pillar y re gi o n 
ca n  be  e xtr a p olate d.  E pi der mal  t hic k ness  has  bee n  i de ntifie d  usi n g  hist ol o g y,  as  a  usef ul 
bi o mar ker of disease acti vit y a n d treat me nt effects i n A D. We ha ve pre vi o usl y utilize d O C T 
t o  q ua ntif y  e pi der mal  t hic k ness i n  viv o a n d  assess  t he  atr o p h o ge nic  effects  of  t o pical 
c ortic oster oi ds. 2 0 We ha ve als o st u die d t he effect of T C Ss o n t he s k i n barrier, t he disr u pti o n 
of w hic h is mec ha nisticall y ass ociate d wit h e pi der mal atr o p h y. 1 7, 2 1  
2.  A n gi o gr a p hic O C T:  Str uct ur al O C T perf or me d at hi g h i ma ge fra me rates ca n ma p areas of 
te m p oral dec orr elati o n d ue t o m ovi n g re d bl o o d cells. Base d o n t his, w e ha ve de m o nstrate d 
t hat  t he  Vi v osi g ht  ca n  ac q uir e hi g h -q ualit y  ma ps  of  t he  s u perficial  vasc ulat ure  i n  li vi n g 
partici pa nt s  a n d  is  a n  i deal  t o ol  t o  m o nit or  a n d  q ua ntif y  er yt he ma,  h y per plasia  a n d  T C S-
i n d uce d tiss ue r e m o delli n g.  
 
Fi g ure 7 . 4: T he Vi v o Si g ht O C T sca n ner  
T hr ee sca ns will be ta ke n fr o m eac h test area at eac h desi g nate d visit  (see sc he d ule of e ve nts). All 
i mages will be c hec ke d f or q ualit y u p o n c ollecti o n, a n d i ma ges wit h visi ble i ma gi n g artefacts will be 
re-ca pt ur e d. A n y part of t he de vice i n c o ntact wit h h u ma n s ki n (t he sta n d -off) will be clea ne d bet wee n 
uses.  F urt her details o n h o w t o c ollect O C T sca ns wit h  t he Vi v osi g ht ca n be f o u n d i n S O P-0 4 7.  
7. 7. 7 P ol ariz ati o n se nsitive ( P S) -O C T  sc a n usi n g t he c ust o m P S-O C T m ac hi ne  
C o m bi ni n g p olari metr y wit h O C T lea ds t o a ne w tec h ni q ue calle d P S -O C T. P S -O C T ca n detect areas 
of e n ha nce d or r e d uce d bir efri n ge nce i n cartil a ge. T his ca n be ass ociat e d wit h a re pair mec ha nis m, 
w her e  de ge nerate d  h yali ne  cartila ge  ( c hiefl y  t y pe -II  c olla ge n)  is  re place d  b y  fi br ocartila ge 
( pr e d o mi na ntl y  t y pe-I  c olla ge n).  D uri n g  i nfla m mati o n  e pi der mal  a n d  der mal  fi br osis  is  see n  a n d 
c o ntri b utes t o tiss ue h y per plasia. T his fi br osis occ urs as c olla ge n s y nt hesis is ele vate d a b n or mall y, 
a n d  s o  we  pr o p ose  usi n g  P S -O C T  t o  m o nit or  e pi der mal  fi br osis.  Pr ol o n ge d  use  of  T C S’s  ca uses 
a b n or mal l o weri n g of c olla ge n le vels, a f act or c o ntri b uti n g t o s ki n atr o p h y. Deter mi ni n g at w hat p oi nt 
c olla ge n le vels r et ur n t o n or mal, f oll o wi n g h y per plasia, bef ore bec o mi n g de presse d as a T C S si de 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
eff ect  will  e na ble  assess me nt  of  t he  T C S  ris k -be nefit  rati o.  A  P S -O C T  de vice  has  alrea d y  bee n 
de vel o pe d b y us a n d a p plie d t o t he a nal ysis of c olla ge n le vels i n cartila ge. 2 2 Ha vi n g bee n assesse d b y 
t he  S heffiel d  T eac hi n g  H os pitals  Bi o me dical  E n gi neeri n g  De part me nt  it  has  bee n  i de ntifie d  as 
s uita ble f or use o n patie nts. 
P S -O C T  i ma ges  will  be  ca pt u r e d  usi n g  a  c ust o m  de vice  de vel o pe d  b y  Pr of  Matc her’s  tea m.  T he 
de vice has bee n e val uate d f or saf e use i n h u ma ns b y t he S T H Bi o me dical E n gi neeri n g De part me nt. 
T hr ee i ma ges will be ta ke n fr o m eac h test area at eac h desi g nate d visit  (see sc he d ule of e ve nts). All 
i ma ges will be c hec ke d f or q ualit y u p o n c ollecti o n, a n d i ma ges wit h visi ble i ma gi n g artifacts will be 
re-ca pt ur e d. A n y part of t he de vice i n c o ntact wit h h u ma n s ki n (t he sta n d -off) will be dec o nta mi nate d 
bet wee n uses.  F urt her details o n h o w t o c ollect  P S -O C T sca ns ca n be f o u n d i n S O P -0 4 8.  
7. 7. 8  T E W L me as ure me nts  
T his  is  a  well -d oc u me nte d,  sta n dar dise d  der mat ol o gical  pr oce d ure  f or  meas uri n g  s ki n  barrier 
f u ncti o n.2 3 T he  st u d y  tea m  ha ve  e xte nsi ve  e x perie nce  i n  meas uri n g  T E W L  usi n g  a  C E  mar ke d, 
A q ua Fl u x  A F 2 0 0  c o n de nsi n g  c ha m ber  pr o be  ( Bi o x  S yste ms  Lt d,  U K)  i n  b ot h  a d ult  a n d  ba b y 
c o h orts. 2 1, 2 4 -2 8 T he T E W L mac hi ne will be cali brate d i n acc or da nce wit h t he ma n ufact urers s pecifie d 
rec o m me n dati o ns  bef or e  eac h  use.  N o  s pecific  s ki n  pre parati o n  is  re q uire d  pri or  t o  TE W L 
meas ur e me nts,  b ut  visi ble  c o nta mi na nts  will  be  re m o ve d  fr o m  t he  test  sites  usi n g  a  dr y  wi pe  if 
pr ese nt.  S ki n  sites  will  be  accli matise d  ( e x p ose d  t o  t he  o pe n  air)  f or  2 0  mi n utes  pri or  t o  starti n g 
T E W L meas ur e me nts. F urt her details o n h o w t o ta ke s ki n me as ure me nts wit h t he A q uafl u x T E W L 
mac hi ne ca n be f o u n d i n S O P -0 1 7.  
 
Fi g ure 7. 5 : T he A q uafl u x T E W L mac hi ne  
T w o  r e peat T E W L meas ur e me nt will be c ollecte d fr o m eac h test area (= 4  per treat me nt area)  at t he 
visits  i n dicate d  i n  t he  sc he d ule  of  e ve nts .  After  use  i n  eac h  partici pa nt  t he  pr o be  will  be 
dec o nta mi nate d wit h a 7 0 % alc o h ol wi pe.  
7. 7. 9  F TI R s pectr osc o py me as ure m e nt s of t he ski n s urf ace  
Atte n uate d T otal Reflecta nce ( A T R) F o urier -Tra nsf or m I nfrare d ( F TI R) s pectr osc o p y is a f or m of 
m olec ular s pectr osc o p y usef ul f or t he a nal ysis of s urfaces, i ncl u di n g s ki n. It has pr o ve d val ua ble f or 
q ua ntif yi n g  t he  li pi d,  water,  a n d  car b o x ylate  c o nte nt  of  t he  s ki n  barr ier  a n d  f or a nal ysi n g li pi d 
arr a n ge me nt/str uct ur e. 1 6, 2 9 -3 2 Usi n g a fi xe d be nc h t o p de vice, t his tec h ni q ue has rece ntl y bee n utilise d 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
b y  me m bers  of  t he  st u d y  tea m  t o  assess  t he  m olec ular  c o m p ositi o n  of  ba b y  a n d  a d ul t  s ki n  i n 
c o m bi nati o n wit h ta pe stri p pi n g. 3 3 M or e r ece ntl y t he 4 3 0 0 ha n d hel d, p orta ble  A T R -F TI R was use d 
b y o ur tea m t o assess t he s ki n of 1 2 0 ne w b or n ba bies i n t he S T A R st u d y (c urre ntl y recr uiti n g). It is 
t his p orta ble de vice t hat will be use d i n t his st u d y.  
 
Fi g ure 7. 6 : T he  A gile nt 4 3 0 0 A T R -F TI R s pectr o meter  
Meas ur e me nts  will  be  perf or m e d  b y  ge ntl y  b ut fir ml y  placi n g  t he  pr o be  i n  c o ntact  wit h  t he  s ki n . 
Si n gle meas ur e me nts will be c ollecte d fr o m eac h test site  at t he visits i n dicate d i n t he sc he d ule of 
e ve nts. T he q ualit y of s pectr a will be assesse d at t he p oi nt of c ollecti o n, a n d a n y t ha t d o n ot meet t he 
esta blis he d q ualit y par a meters (si g nal t o n oise rati o) will be re place d. After use i n eac h partici pa nt 
t he A T R ( pr o be hea d)  will be dec o nta mi nate d wit h a 7 0 % alc o h ol wi pe.  F urt her details o n h o w t o 
c ollect s ki n s pectr a wit h t he 4 3 0 0 s pect r o meter ca n be f o u n d i n S O P-0 3 9.  
7. 7. 1 0  T a pe -stri p pi n g i n c o nj u ncti o n wit h F TI R a n d T E W L me as ure me nts 
T a pe -stri p pi n g, t o st u d y dee per la yers of t he strat u m c or ne u m, i n v ol ves t he re peate d a p plicati o n a n d 
re m o val of D-S q ua me c uta ne o us stri p pi n g discs ( C u Der m  c o o perati o n, Dallas, U S A) t o/fr o m t he s ki n  
i n a sta n dar dise d ma n ner.1 6, 3 4 A s peciall y desi g ne d pl u n ger is use d t o e xert a sta n dar dise d press ure 
( 2 2 5 g/c m2) t o eac h disc. A p pr o xi matel y 3 c or ne oc yte la yers (i nc o m plet e la yers/ u ne ve n c o vera ge) are 
re m o ve d  per  disc,  de pe n di n g  o n  t he  v ol u nteer  a n d  t he  treat me nt  c o n diti o ns. T his  e na bles 
meas ur e me nts of dee per la yers of t he s ki n t o be c ollecte d b y T E W L mac hi ne or F TI R s pectr osc o p y.  
T a pe -stri p pi n g will be perf or me d o n da y 2 9 o nl y, o nce wit hi n eac h treat me nt area (test sites R 2 a n d 
L 2). At eac h site 2 0 c o nsec uti ve ta pe -stri p pi n gs will be perf or me d. T he de pt h t hr o u g h t he strat u m 
c or ne u m  is  deter mi ne d  b y  meas uri n g  t he  a m o u nt  of  c or ne ot y pes  re m o ve d  b y  eac h  disc  usi n g  t he 
S q ua me Sc a n De vice. S q ua mesca n r ea di n gs of eac h ta pe s h o ul d be c ollecte d i n tri plicate. T he ta pe -
stri ps, c o ntai ni n g a sa m ple of t he str at u m c or ne u m, will be c ollecte d as o utli ne bel o w. 
I n c o nj u ncti o n wit h ta pe-stri p pi n g, F TI R s pectra a n d T E W L meas ure me nts (si n gle) will be c ollecte d 
fr o m t he ta pe-stri p pe d site after e ver y 5 c o nsec uti ves ta pe-stri ps as descri be d a b o ve . T his data is use d 
t o deter mi ne t he li pi d str uct ur e t hr o u g h o ut t he strat u m c or ne u m. 
After  t he  2 0 t h ta pe-stri p  a n d  fi nal  F TI R  meas ure me nt,  a  si n gle  T E W L meas ure me nt  s h o ul d  be 
c ollecte d,  as  descri be d  a b o ve.  T his  is  ta ke n  t o  deter mi ne  strat u m  c or ne u m  i nte grit y  (s ki n  barrier 
f u ncti o n f oll o wi n g e x peri me ntal barrier pert ur bati o n). T he para meter is referre d t o here as T E W Lts 2 0 
F urt her details o n perf or mi n g ta pe -stri p pi n g ca n be f o u n d i n S O P-0 2 1.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
7. 8  S a m ple c ollecti o n  
7. 8 . 1 Su perfici al str at u m c or ne u m s a m ple c ollecti o n 
T he  s u perficial  s ki n  sa m ples  c ollecte d  o n  t he  ta pe -stri ps use d  i n  ta pe -stri p pi n g  (a b o ve) will  be 
retai ne d f or a nal ysis: 
•  T he first 7 ta pe -stri ps (tape -stri ps 1 -1 0) will be st ore d i n di vi d uall y i n 2 ml t u bes at -7 0 oC f or 
deter mi nati o n of N M F le vels b y H P L C  ( 3 ta pe-stri ps re q uire d per a nal ysis) a n d f ut ure a nal ysis 
of pr otei n a n d meta b ol o mic bi o mar kers  (re mai ni n g ta pe-stri ps).  
•  T he r e mai ni n g ta pe -stri ps (ta pe-stri ps 1 1-2 0) will be tra nsferre d t o R L T l ysis b uffer a n d st ore d 
-7 0 oC f or f ut ur e a nal ysis of ge ne e x pressi o n .  
T a pe stri p pi n g is a pai nless pr oce d ur e, t hat re m o ves t he dea d cells ( de n ucleate d c or ne oc ytes) fr o m 
t he s urf ace of t he s ki n t hat will e ve nt uall y be l ost/s he d as a res ult of n or mal des q ua mati o n. It ca n 
ca use s o m e disc o mf ort a n d r e d ness, b ut a n y re d ness us u all y dissi pates i n a matter of h o urs/ da ys. N o 
dr essi n gs  ar e  r e q uir e d . T a pe -stri p pi n g will  n ot  be  perf or me d  o n  br o ke n  s ki n.  T he  o nl y  s ki n 
pr e p ar ati o n  r e q uir e d  bef or e  ta pe  stri p pi n g  is  t he  re m o val  of  visi ble  c o nta mi na nts  b y  dr y  wi pe  if 
necess ar y.  
7. 8. 2  S aliv a s a m pl i n g ( b ucc al s w a b) f or F L G ge n oty pi n g 
A sali va sa m ple will be c ollecte d ( b y b uccal s wa b) fr o m t he i nsi de of t he partici pa nts c hee k d uri n g 
visit 1 i n or der t o o btai n a sa m ple of ge n o mic D N A. E xtracte d ge n o mic D N A will be ge n ot y pe d f or 
t he 3  m ost c o m m o n F L G  ge ne m utati o ns. T he fila g gri n ge ne ( F L G ) e nc o des pr otei ns t hat are ke y t o 
t he n or mal barrier f u ncti o n of t he s ki n. N ull m utati o ns i n F L G  are ass ociate d wit h a n i ncrease d ris k 
of ecze ma. U n dersta n di n g h o w t hese m utati o ns affect t he res p o nses t o T C S treat me nt is t heref ore of 
i nter est. 
7. 9  Tre at m e nt a n d c o m pli a nce  
D uri n g visit 1, after t he s ki n assess me nts, partici pa nts will be iss ue d wit h t he st u d y I M P’s.  
F or d oses t o be a d mi nister e d at h o me, t he partici pa nt  or care gi ver s h o ul d be i nstr ucte d t o mai ntai n 
t he pr o d uct i n its ori gi nal pac ka ge pr o vi de d t hr o u g h o ut t he c o urse of d osi n g a n d ret ur n t he pr o d uct 
a n d its ori gi nal pac ka ge (i ncl u di n g e m p t y, partial use d a n d u n use d t u bes) t o t he site at t he e n d of t he 
tr eat me nt r e gi me n. All pr e vi o usl y dis pe nse d i n vesti gati o nal pr o d uct t u bes will be retai ne d b y t he site. 
I n vesti gati o nal  pr o d uct  t u bes  will  be  wei g he d i n di vi d uall y  or  c ollecti vel y  b y  t he  st u d y site  bef ore 
dis pe nsi n g a n d after r et ur n a n d t he wei g hts will be rec or de d. T he rec or de d wei g hts will be use d t o 
esti mate usa ge ( m g/c m 2/ da y) b y eac h partici pa nt . N ote t hat t he wei g ht rec or de d o n t he i n vesti gati o nal 
pr o d uct la bel is a n o mi nal wei g ht a n d n ot a n e xact wei g ht of t he i n vesti gati o nal pr o d uct a n d t u be.  
T he site staff will pr o vi de a de m o nstr ati o n of t he d osi n g b y fi n gerti p u nit.  
A tr eat me nt diar y (see A p pe n di x) will be iss ue d, after c o m pleti o n of all rele va nt secti o ns b y t he trial 
tea m. T he partici pa nts s h o ul d be tr ai ne d i n t he c o m pleti o n of t he diar y.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T he partici pa nt s h o ul d t he n be as ke d t o u n derta ke a s u per vise d a p plicati o n ( b ot h treat me nts). T he site 
staff  s h o ul d  o bser ve  t he  partici pa nt  a n d  w here  necess ar y  pr o vi de  g ui da nce  t o  e nc o ura ge  g o o d 
tec h niq ue.  
At eac h s u bse q ue nt visit t he f oll o wi n g tas ks s h o ul d be u n derta ke n:  
•  Wei g h I M P’s, r ec or d wei g hts i n t he C R F a n d treat me nt diar y, a n d i nf or m partici pa nts of t heir 
usa ge i n t he c o nte xt of e x pecte d usa ge.  
•  C hec k all diar y e ntries f or missi n g a p plicati o ns a n d a d verse e ve nts (s ki n reacti o ns re p orte d at 
t he ti me of a p plicati o n). 
•  S u per vise d pr o d uct a p plicati o n ( after meas ure me nts).  
•  Pr o vi de r e -tr ai ni n g/ g ui da nce t o i m pr o ve o n a p plicati o n tec h ni q ue a n d/ or d osi n g as re q uire d 
At t he e n d of t he 2 8 -da y tr eat me nt r e gi me n, t he diar y a n d treat me nts, i ncl u di n g all pac ka gi n g a n d 
e m pt y c o ntai ners, s h o ul d be r etrie ve d. F urt her i nf or mati o n ca n be f o u n d i n secti o n 8.  
7. 1 0 P artici p a nt  c o m pleti o n/ wit h dr a w al 
7. 1 0 . 1 P artici p a nt  c o m pleti o n 
Partici pa nt s  ar e  c o nsi der e d  t o  ha ve  c o m pleted  t he  st u d y  w he n  all  st u d y  pr oce d ures  ha ve  bee n 
c o m plete d as desi g nate d b y t he pr ot oc ol.  C o m pleti o n s h o ul d be n ote d o n t he P artici p a nt Scree ni n g, 
E nr ol me n t & C o m pleti o n L o g . 
7. 1 0 . 2 P artici p a nt  w it h dr a w al  
W he n  a n  i n di vi d ual  w h o  has  si g ne d  t he  I nf or me d 
C o n se nt  F or m is  n ot  e nr olle d  i n  t he  st u d y  or 
wit h dr a ws/is  wit h dr a w n  pri or  t o  c o m pleti n g  t he  st u d y,  t he  reas o n  is  t o  be  d oc u me nte d  o n  t he 
P artici p a nt  Scree ni n g,  E nr ol me n t &  C o m pleti o n L o g .  Reas o ns  f or partici pa nt  wit h dra wal  ma y 
i ncl u de: 
1.  Partici pa nt is deter mi n e d t o be i neli gi ble after e nr ol me nt   
2.  Partici pa nt ’s c h oice t o wit h dr a w 
3.  E xcl usi o n criteria  met  
4.  N o n -c o m plia nce wit h t he st u d y pr ot oc ol . 
5.  A d verse e ve nt,  i ncl u di n g a r ela pse of A D (defi ne d as a n escal ati o n i n  treat me nt, i. e. t he nee d 
f or t o pical c ortic oster oi ds). 
6.  L oss -t o-f oll o w ( partici pa nt ca n n ot be c o ntacte d) 
7.  Ot her  
Partici pa nt s ma y wit h dr a w fr o m t he st u d y at a n y ti me at t heir re q uest, or t he y ma y be wit h dra w n at 
a n y ti me at t he discr eti o n of t he PI, or desi g nee f or safet y, be ha vi o ural , or a d mi nistrati ve reas o ns. If 
a partici pa nt  d oes  n ot  r et ur n  f or  a  sc he d ule d  visit,  at  least 2  atte m pts  will  be  ma de  t o  c o ntact  t he 
partici pa nt  i n or der t o esta blis h t he r eas o n f or wit h dra wal, a n d t he o utc o me will be d oc u me nte d, if 
reas o na bl y p ossi ble wit hi n t he c o nstr ai nts of t he st u d y desi g n. N o m ore t ha n 4 atte m pts will be ma de 
t o c o ntact partici pa nts; a v oice mail t o a pers o nal m o bile n u m ber ma y be left o nce b ut t his will n ot 
detail a n y st u d y or cli nical i nf or mati o n, it will be li mite d t o a re q uest t o call bac k o n a gi ve n n u m ber . 
T he PI or desi g nee s h o ul d i n q uir e a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he partici pa nt  ret ur n 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
f or  a  fi nal  visit,  if  a p plica ble (if  wit h dr a wi n g  fr o m  t he  st u d y  d uri n g  t he treat me nt  peri o d  bet wee n 
st u d y  visits),  a n d f oll o w-u p  wit h  t he partici pa nt  regar di n g  a n y  u nres ol ve d  a d verse  e ve nts. I n  s uc h 
cir c u msta nces, w her e t he tr eat me nt r e gi me n has n ot c o m plete d t he fi nal visit will be c o n d ucte d s olel y 
t o r etrie ve t he pr o d ucts a n d ca pt ur e a n y u nre p orte d A E’s. 
A d diti o nal partici pa nt s  ma y  be  e nr olle d  i n  t he  stu d y ,  u p  t o  t he  ma xi m u m  recr uit me nt  tar get, t o 
c o m pe nsate f or earl y partici pa nt  wit h dr a wal.  
7 .1 0 . 3 R e m u ner ati o n 
All partici pa nts e nr olle d o nt o t he st u d y will be re m u nerate d f or t heir ti me. Partici pa nts w h o fail t o 
c o m plete t he st u d y, f or w hate ver r eas o n, ma y clai m a pr o p orti o n of t he re m u nerati o n c o m me ns urate 
wit h  t he  e xte nt  of  t heir  partici pati o n. T a xi  tra nsfers  will  be  arra n ge d  t o/fr o m  t he  st u d y  site  f or all 
visits . 
F or partici pa nts w h o atte n d t he c o nse nt/ scree ni n g o nl y n o v o uc her  will be offere d. Pre -scree ni n g b y 
tele p h o ne will be c o n d ucte d t o li mit t he n u m ber of i nsta nces w here partici pa nts  atte n d t he site a n d 
ar e s u bse q ue ntl y n ot e nr olle d (f ail ur e t o meet eli gi bilit y criteria). T ra vel e x pe nses i nc urre d i n or der 
t o  atte n d  t he c o nse nt/scr ee ni n g  visit  will be  pai d  u p o n  re q uest,  a n d  re q uire  t he  c o m pleti o n  of  a 
U ni versit y of S heffiel d clai m f or m.  
7. 1 1  Defi niti o n of t he e n d of t ri al  
T he e n d of t he trial is defi ne d as t he p oi nt at w hic h all la b a nal yses re q uire d f or t he st u d y e n d p oi nts 
has bee n c o m plete d.  
7. 1 1. 1  E arly ter mi n ati o n of t he tri al  
T he criteria f or electi vel y st o p pi n g t he trial pre mat urel y i ncl u des:  
•  Ne w i nf or mati o n bec o mes a vaila ble o n eit her of t he st u d y i nter ve nti o ns or t he st u d y 
pr oce d ur es t hat s u g gests t hat partici pa nts or researc hers will be place d at u nacce pta ble ris k.  
T his will be deci de d b y t he CI a n d S p o ns or . 
•  T he CI  a n d S p o ns or , wit h t he s u p p ort of t he T M G, dee ms t hat nat ure a n d/ or fre q ue nc y of 
a d verse e ve nts is i nc o nsiste nt wit h e x pectati o ns a n d s u g gests t hat partici pa nts are bei n g 
place d at g r eater ris k. 
T he decisi o n t o ter mi nate ma y als o occ ur  beca use of a re g ulat or y a ut h orit y decisi o n  or a c ha n ge i n 
o pi ni o n of t he R E C.  
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8 . T RI A L T R E A T M E N T S  
8 . 1 N a m e a n d descri pti o n of i n vesti g ati o n al pr o d ucts  
 
T he tr eat me nts use d i n t his st u d y ar e liste d i n T a ble 9 . 1.  
T a ble 8 . 1: I n vesti gati o nal pr o d ucts 
N a m e , 
St re n gt h  & 
F or m  
Br a n d 
N a m e  
P ac k size  
a n d 
q u a ntit y 
per 
p artici p a nt  
M a n uf act urer  
F or m ul ati o n  
Beta met has o ne 
Valer ate 0. 1 % 
t o pical cr ea m 
Bet n o vate 
( 0. 1 %) 
cr ea m 
1 x 1 0 0 g 
t u be*  
Gla x o 
Wellc o me  U K 
Li mite d.  
 
B et a met h as o ne V aler ate 
B P 0. 1 2 2 % , C hl or ocres ol 
B P, Cet o macr o g ol 1 0 0 0 
B P, Cet ostear yl Alc o h ol 
B P, W hite S oft Paraffi n 
B P, Li q ui d Paraffi n B P, 
S o di u m Aci d P h os p hate 
B P, P h os p h oric Aci d B P, 
S o di u m H y dr o xi de B P, 
P urifie d Water  
Crisa b or ole 
2 % oi nt me nt  
N/ A  
2 x 6 0 g t u be  Pfizer  
Cris a b or ole  2 %,  W hite 
Petr olat u m, Pr o p yle ne 
Gl yc ol, M o n o - A n d Di -
Gl yceri des, Paraffi n, 
B ut ylate d H y dr o x yt ol ue ne, 
A n d E detate Calci u m 
Dis o di u m  
* A d diti o nal t u be ca n be pr escri be d  u p o n re q uest  w here usa ge trac ks c o nsiste ntl y hi g h  ( n oti n g u p per 
acce pta ble usa ge li mit of 1 1 2 g)  
8 . 2 Re g ul at or y st at us of t he dr u gs  
8 .2 . 1 B et a met h as o ne V aler ate ( 0. 1 %) cre a m 
Beta met has o ne Val er ate ( 0. 1 %) cr ea m is c urre ntl y lice nce d i n t he U K f or t he treat me nt of ecze ma 
a n d will be use d i n acc or da nce wit h t his lice nce i n t his st u d y (see Bet n o vate [ 0. 1 %] crea m S m P C).  
Beta met has o ne valer ate cr ea ms ar e ma n ufact ure d b y a n u m ber of c o m pa nies, h o we ver t his trial will 
be perf or me d usi n g t he Bet n o vate ( Gla x o Wellc o me U K Lt d) bra n d o nl y t o a v oi d t he i ntr o d ucti o n of 
varia bilit y arisi n g fr o m t he diff er e nces i n t o pical f or m ulati o n ( k n o w n t o affect bi oa vaila bilit y of t he 
acti ve). 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8 .2 . 2 Cris a b or ole ( 2 %) oi nt me nt  
Crisa b or ole ( 2 %) oi nt me nt is n ot c urr e ntl y lice nce d i n t he U K; h o we ver, it is lice nce d b y t he F D A 
f or use i n t he U nite d States of A merica a n d will be use d i n acc or da nce wit h t his lice nc e i n t his st u d y. 
8 . 3 P r o d uct c h ar act eristics 
8 .3 . 1 B et a met h as o ne V aler ate ( 0. 1 %) cre a m 
Please r ef er t o t he attac he d S m P C  
8 .3 . 2 Cris a b or ole ( 2 %) oi nt me nt  
Please r ef er t o t he attac he d crisa b or ole I n vesti gat or’s Br oc h ure (I B) 
8 . 4 Dr u g s u p pl y  
8 . 4. 1 B et a met h as o ne V aler ate ( 0. 1 %) cre a m 
Bet n o vate  ( 0. 1 %) cr ea m will be pr o vi de d as s u p plie d b y t he ma n ufact urer ( n o re-pac ka gi n g). W hilst 
t his pr o d uct is mar kete d i n t he U K t he P har mac y d oes n ot st oc k t his ite m (i nstea d s u p pl yi n g fr o m a 
ra n ge of ge neric ma n uf act ur ers wit h var yi n g f or m ulati o ns). T he P har mac y will t heref ore or der t he 
pr o d uct  as  (se gr e gate d)  cli nical  trial  st oc k.  A n ne x  1 3  c o m plia nt  la bels  will  be  a p plie d  pri or  t o 
dis pe nsi n g b y t he p har mac y ( e xa m ple att ac he d). 
8 . 4. 2 Cris a b or ole ( 2 %) oi nt me nt  
Crisa b or ole ( 2 %) oi nt me nt will be pr o vi de d b y Pfizer . T he pr o d uct will be i m p orte d b y Pfizer a n d 
release d  o nt o  t his  st u d y  b y  a s uita ble Q ualifie d  Pers o n  n o mi nate d  b y  Pfizer . T he  pr o d uct  will  be 
pr o vi de d i n plai n pac k a gi n g wit h A n ne x 1 3 c o m plia nt la bels (e xa m ple attac he d).  
8 .5  Dr u g s t or a ge  
T he  st u d y  p har macist  or  ot her  a p pr o priatel y  trai ne d  pers o n nel,  will  e ns ure  t hat  all  i n vesti gati o nal 
pr o d ucts ar e st or e d i n a sec ur e d ar ea wit h c o ntr olle d access u n der re q uire d st ora ge c o n diti o ns a n d i n 
acc or da nce wit h a p plica ble r e g ulat or y r e q uire me nts.  
I n vesti gati o nal  pr o d ucts  s h o ul d  be  st or e d  i n  t heir  ori gi nal  c o ntai ners  a n d  i n  acc or da nce  wit h  t he 
la bels. T he c o n diti o ns f or st ori n g b ot h pr o d ucts are:  
•  St or e  at  1 5 – 2 5 ° C  ( 5 9– 8 6° F)  f or crisa b or ole  ( 2 %)  oi nt me nt  a n d ≤2 5 oC  ( 7 7 oF)  f or 
beta met has o ne valer ate ( 0. 1 %) cr ea m . 
Site s yste ms m ust be ca pa ble of meas uri n g a n d d oc u me nti n g (f or e xa m ple, via a l o g), at a mi ni m u m, 
dail y  mi ni m u m  a n d  ma xi m u m  te m per at ures  f or  all  site  st ora ge  l ocati o ns  (as a p plica ble,  i ncl u di n g 
fr oze n, r efri ger ate d, a n d/ or r o o m-te m per at ure pr o d ucts).  T his s h o ul d be ca pt ure d fr o m t he ti me of 
i n vesti gati o nal pr o d uct r ecei pt t hr o u g h o ut t he st u d y.  E ve n f or c o nti n u o us-m o nit ori n g s yste ms, a l o g 
or site pr oce d ur e t hat e ns ur es act i ve e val uati o n f or e xc ursi o ns s h o ul d be a vaila ble.  T he i nte nt is t o 
e ns ur e t hat t he mi ni m u m a n d ma xi m u m te m perat ure is c hec ke d eac h b usi ness da y t o c o nfir m t hat n o 
e xc ursi o n occ urr e d si nce t he last e val uati o n a n d t o pr o vi de t he site wit h t he ca pa bilit y t o  st ore or vie w 
t he mi ni m u m/ ma xi m u m te m per at ur e f or all n o n-w or ki n g da ys u p o n ret ur n t o n or mal o perati o ns.  T he 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
o per ati o n  of  t he  te m per at ur e  m o nit ori n g  de vice  a n d  st ora ge  u nit  (f or  e xa m ple,  refri gerat or),  as 
a p plica ble, s h o ul d be r e g ularl y i ns pecte d t o e ns u re t he y are mai ntai ne d i n w or ki n g or der. 
A n y e xc ursi o ns fr o m t he pr o d uct la bel st or a ge c o n diti o ns s h o ul d be re p orte d t o t he CI  u p o n disc o ver y.  
T he site s h o ul d acti vel y p urs ue o pti o ns f or ret ur ni n g t he pr o d uct t o t he st ora ge c o n diti o ns descri be d 
i n t he la belli n g, as s o o n as p ossi ble. De viati o ns fr o m t he st ora ge re q uire me nts, i ncl u di n g a n y acti o ns 
ta ke n, m ust be d oc u me nte d. Per mitte d e xc ursi o ns re q uire n o f urt her acti o n.  
O nce  a n  e xc ursi o n  o utsi de  t he  per mitte d  ra n ge  is  i de ntifie d,  t he  i n vesti gati o nal  pr o d uct m ust  be 
q uar a nti ne d  a n d  n ot  use d  u ntil  t he CI  pr o vi des  per missi o n  t o  use  t he  i n vesti gati o nal  pr o d uct. F or 
crisa b or ole ( 2 %) oi nt me nt t he CI will see k per missi o n fr o m Pfizer  t o use t he i n vesti gati o nal pr o d uct 
O R r e q uest r e place me nt st oc k . It will n ot be c o nsi dere d a pr ot oc ol de viati o n if Pfizer  a p pr o ves t he 
use of t he i n vesti gati o nal pr o d uct after t he te m perat ure e xc ursi o n. Use of t he i n vesti gati o nal pr o d uct 
pri or t o Pfizer  a p pr o val will be c o nsi der e d a pr ot oc ol de viati o n. S pecific details re gar di n g i nf or mat i o n 
t he  site  s h o ul d  r e p ort  f or  eac h  e xc ursi o n  will  be  pr o vi de d  t o  t he  site. F or  beta met has o ne  valerate 
( 0. 1 %) cr ea m, r e place me nt st oc k will be pr oc ure d, wit h t he per missi o n of t he CI a n d w here necessar y 
t he F u n der, i n t he e ve nt of a n e xc ursi o n o utsi de t he per mitte d ra n ge.  
Recei pt  of  materials,  d o or  o pe ni n g  a n d  cl osi n g,  a n d  ot her  r o uti ne  ha n dli n g  o perati o ns  w here  t he 
pr o d ucts  ar e  briefl y  o ut  of  t he  te m per at ure  ra n ge  descri be d  i n  t he la belli n g are  n ot  c o nsi dere d 
e xc ursi o ns.  Site staff will i nstr uct partici pa nt s a n d/ or pare nts/le gal g uar dia ns o n t he pr o per st ora ge 
re q uir e me nts f or ta ke h o me i n vesti gati o nal pr o d ucts ( details ca n be f o u n d i n t he treat me nt diar y).  
8 . 6 P re p ar ati o n a n d dis pe nsi n g 
T he i n vesti gati o nal pr o d ucts  will be pr escri be d b y a me dicall y q uali fie d a n d a p pr o priatel y dele gate d 
me m ber of t he r esear c h tea m . 
T he i n vesti gati o nal pr o d uct s will be la belle d (as re q uire d) a n d dis pe nse d b y t he P har macist, acc or di n g 
t o t he r a n d o mizati o n sc he d ule, at t he r e q uest of t he site researc h facilit y. A n ne x 1 3 c o m pl ia nt la bels 
will be use d, c o ntai ni n g  st u d y s pecific usa ge i nstr ucti o ns i ncl u di n g d ose a n d a p plicati o n fre q ue nc y , 
a n d ca pt ur e t he u ni q ue partici pa nt I D, t he partici pa nt’s i nitials a n d t he ‘a p plicati o n site’ (acc or di n g 
t o t he r a n d o mizati o n).  
U n bli n de d r esear c hers at t he site r esear c h facilit y, as dele gate d b y t he PI, will iss ue t he i n vesti gati o nal 
pr o d ucts t o t he st u d y partici pa n ts d uri n g visit 1, pr o vi de t he de m o nstrati o n of pr o d uct a p plicati o n a n d 
u n derta ke all c o m plia nce m o nit ori n g. U n bli n de d researc hers will n ot be i n v ol ve d i n t he c ollecti o n of 
st u d y data. 
8 .7  Tre at m e nt re gi m e n  
E ver y  e nr olle d  partici pa nt  will  u n der g o  t he  sa me  i nter ve nti o n,  w hic h  i n v ol ves  t he  use  of  2 
i n vesti gati o nal pr o d ucts acc or di n g t o a pr e defi ne d re gi me n ( T a ble 8 .2 ). 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 7 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
T a ble 8 .2 : Tr ea t me nt c o n diti o ns 
Tre at m e nt sit e  
I n vesti g ati o n al P r o d uct 
Ri g ht/left f or ear m  
Beta met has o ne Valerate ( 0. 1 %) crea m  
Ri g ht/left f or ear m  
Crisa b or ole ( 2 %) oi nt me nt  
 
T wice -dail y self -a d mi nister e d a p plicati o n of 1  fi n ger-ti p u nits of eit her crisa b or ole ( 2 %) oi nt m e nt or 
beta met has o ne  valer ate  ( 0. 1 %)  cr ea m  t o  t he  desi g nate d  treat me nt  areas  o n  t he  v olar  si de  of  t he 
res pecti ve f or ear m f or 2 8 da ys. T he 2 dail y a p plicati o ns s h o ul d be c o n d ucte d o nce i n t he m or ni n g 
a n d o nce i n t he e ve ni n g, se par ate d b y at least 6 h o urs. W he n was hi n g, t he pr o d uct s h o ul d be a p plie d 
after was hi n g ( n ot bef or e). Ra n d o mize d site all ocati o n t o a v oi d site de pe n de nt effects.  
Partici pa nt  diaries  will  be  pr o vi de d  t o  rec or d  pr o d uct  usa ge  (c o m plia nce)  a n d  pr o vi de  usa ge 
i nstr ucti o ns, i ncl u di n g a vis ual g ui de t o t he I P all ocati o n.  
8 . 8 P ri or a n d c o nc o mit a nt m e dic ati o n  
All pri or me dicati o ns, i ncl u di n g all me dicati o ns, n o n -me dicati o n t hera pies, bla n d ( n o n -me dicate d) 
e m ollie nts, o ver t he c o u nter dr u gs, vita mi ns, a n d a ntaci ds  use d wit hi n 2 8 da ys  pri or t o Scree ni n g will 
be r ec or de d. A n y c ha n ges i n c o nc o mita nt me dicati o ns or d osa ge will be rec or de d at Baseli ne/ Da y 1 
a n d  at  eac h  s u bse q ue nt  visit  u ntil  c o m pleti o n  ( defi ne d  as  c o m pleti o n  of  t he  last  st u d y  visit) . 
Me dicati o n  e ntries  s h o ul d  pr o vi de  t he  c orrectl y  s pelle d  dr u g  or  t hera p y  na me  a n d  t he  d ose,  u nits, 
fr e q ue nc y, r o ute of a d mi nistr ati o n, start a n d st o p date, a n d reas o n f or use. T he use of a n y c o nc o mita nt 
me dicati o n m ust r elate t o t he partici pa nt 's me dical hist or y or t o a n A E, e xce pt f or vita mi ns/ n utriti o nal 
s u pple me nts a n d r o uti ne i m m u nizati o ns.   
8 .8 . 1 Pr o hi bite d M e dic ati o ns 
Class es of me dicati o ns a n d n o n -me dicati o n t hera pies t hat ma y alter t he u n derl yi n g (i nfla m mat or y) 
state  of  t he  s ki n  a n d  f or  w hic h  was h o ut  is  re q uire d  pri or  t o  Baseli ne/ Da y  1  are  liste d  bel o w.  If  a 
partici pa nt  r e q uir es  a  was h o ut,  t he  i n vesti gat or  or  his/ her  desi g nee  will  pr o vi de  i nstr ucti o ns  o n 
disc o nti n ui n g t he pr o hi bite d me dicati o n(s) or n o n -me dicati o n t hera p y at t he Scree ni n g Visit.  T he use 
of a n y e xcl u de d me dicati o ns d uri n g t he st u d y will r es ult i n disc o nti n uati o n of t he partici pa nt . 
•  Me dicati o ns Pr o hi bite d 1 2 wee ks p ri or t o Baseli ne/ Da y 1 a n d t hr o u g h o ut t he st u d y 
o  Bi ol o gical dr u gs.  
•  Me dicati o ns Pr o hi bite d 2 8 Da ys Pri or t o Baseli ne/ Da y  1 a n d t hr o u g h o ut t he st u d y  
o  Use of s yste mic ( or al, par e nter al) c ortic oster oi ds. I n hale d gl uc oc ortic oi ds of l o w t o 
m o der ate d oses f or tr eat me nt of ast h ma are all o we d.  
o  Use  of  s yste mic  i m m u n os u p pressi ve  a ge nts,  i ncl u di n g  b ut  n ot  li mite d  t o, 
met h otr e xate,  cicl os p ori n,  azat hi o pri ne,  h y dr o x yc hl or o q ui ne,  a n d  m yc o p he n olat e 
m of etil.  
o  L i g ht  t her a p y  Ultr a vi olet  ( U V),  Ultra vi olet  B  ( U V-B),  ps orale n – U V -A  [ P U V A])  
a n y w her e o n t he b o d y. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
o  Use of T C S, or T CI o n t he test are as . 
•  Me dicati o ns Pr o hi bite d 1 4 Da ys Pri or t o Baseli ne/ Da y 1 a n d t hr o u g h o ut t he st u d y  
o  Use of s yste mic a nti bi otics.  
o  Use of T C S, or T CI, a n y w here o n t he b o d y.  
o  Use of crisa b or ole oi nt me nt, 2 %, a n y w here o n t he b o d y.  
o  Use of t o pical r eti n oi ds or be nz o yl per o xi de o n t he test are as . 
o  Use of t o pical a nti hista mi nes o n t he test are as.  
•  Me dicati o ns Pr o hi bite d 7 Da ys Pri or t o Baseli n e/ Da y 1 a n d t hr o u g h o ut t he st u d y  
o  Hi g h d oses of s yste mic se dati n g a nti hista mi nes (e g, h y dr o x yzi ne or 
di p he n h y dr a mi ne or ot her se dati n g  a nti hista mi nes). Use of o ver -t he-c o u nter s yste mic 
se dati n g a n d n o n-se dati n g a nti hista mi nes is per mitte d at rec o m me n de d d oses f or 
aller gic r hi nitis/ ha y f e ver 
o  Use of bla n d ( n o n -me dicate d) e m ollie nts, m oist urisers or s u nscree n o n t he test are as , 
wit hi n 7 da ys pri or t o Baseli ne/ Da y 1. Use of bla n d ( n o n -me dicate d) e m ollie nt(s)  
a n d/ or s u nscr ee n  is per mitte d d uri n g t he st u d y t o ma nage dr y s ki n  a n d s u n e x p os ure  
i n ar eas s urr o u n di n g b ut n ot o n or o verla p pi n g t he test areas. 
•  Me dicati o ns pr o hi bite d fr o m Baseli ne/ Da y 1 a n d t hr o u g h o ut t he st u d y  
o  Use of n o nster oi dal a nti -i nfla m mat or y a ge nts ( N S AI D’s, e xcl u des paraceta m ol), 
i ncl u di n g i b u pr of en,  na pr o xe n, dicl ofe nac, celec o xi b, mefe na mic aci d, et oric o xi b, 
i n d o met haci n, hi g h-d ose as piri n.  
o  Use of vas oacti ve dr u gs i n a n o n -sta ble (e g, escalati n g or decreasi n g, or as nee de d) 
r e gi me n i ncl u di n g: metar a mi n ol, a dre nali ne/e pi ne p hri ne, 
n or a dr e nali ne/ n or e pi ne p hri ne, p he n yle p hri ne, d o b uta mi ne, d o pa mi ne, d o pe xa mi ne, 
o x y metaz oli ne.  
8 .9  I n vesti g ati o n al pr o d uct acc o u nt a bilit y 
T he  i n vesti gat or  site  m ust  mai ntai n  a de q uate  rec or ds  d oc u me nti n g  t he  recei pt,  use,  l oss,  or  ot her 
dis p ositi o n of t he i n vesti gati o nal pr o d uct s u p plies.  All i n vesti gati o nal pr o d ucts will be acc o u nte d f or 
usi n g a dr u g acc o u nta bilit y f or m/r ec or d.  
T hr o u g h o ut t he st u d y, detaile d i n vesti gati o nal pr o d uct acc o u nta bilit y rec or ds, i ncl u di n g t u be wei g hts, 
will be mai ntai ne d f or eac h partici pa nt  b y st u d y staff.  
T he partici pa nt s  a n d/ or  car e gi vers  will  be  as ke d  t o  bri n g  all  dis pe nse d  i n vesti gati o nal  pr o d uct 
(i ncl u di n g e m pt y, partial use d a n d u n use d t u bes) a n d t he treat me nt diar y t o t he cli nic at e ver y visit.  
Detaile d dr u g acc o u nta bilit y r ec or ds, i ncl u di n g f ort ni g htl y t u be wei g hts meas ure d i n t he site researc h 
facilit y, will be mai ntai ne d b y u n bli n de d pers o n nel f or eac h partici pa nt . 
T he ori gi nal i n vesti gati o nal pr o d uct acc o u nta bilit y l o g, or e q ui vale nt d oc u me nt, m ust be acc uratel y 
c o m plete d, a n d r etai ne d a t t he st u d y site w he n t he st u d y is c o m plete.  T he acc o u nta bilit y l o g will be 
a n u n bli n de d d oc u me nt u ntil st u d y c o m pleti o n a n d t heref ore s h o ul d o nl y be accesse d b y u n bli n de d 
site pers o n nel. 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8. 1 0  Dis p os al of t he st u d y t re at m e nts  
T he s p o ns or or desi g nee will  pr o vi de g ui da nce o n t he destr ucti o n of u n use d i n vesti gati o nal pr o d uct 
(e g, at t he site).  If destr ucti o n is a ut h orize d t o ta ke place at t he i n vesti gat or site, t he i n vesti gat or m ust 
e ns ur e  t hat  t he  materials  ar e  destr o ye d  i n  c o m plia nce  wit h  a p plica ble  e n vi r o n me ntal  re g ulati o ns, 
i nstit uti o nal p olic y, a n d all destr ucti o n m ust be a de q uatel y d oc u me nte d. 
F or  all  i n vesti gati o nal  pr o d uct  r et ur ne d  t o t he  i n vesti gat or  b y partici pa nt s  a n d/ or  t he  pare nts/le gal 
g uar dia ns, t he i n vesti gat or will mai ntai n t he ret ur ne d s u p pl y u ntil destr ucti o n is a ut h orize d  b y t he 
S p o ns or . 
O nl y  u n bli n de d  pers o n nel  s h o ul d  ha ve  access t o or  vie w  a n y  ret ur ne d  pr o d uct.  T he  s p o ns or  or 
desi g nee will pr o vi de i nstr ucti o ns as t o t he dis p ositi o n of a n y u n use d i n vesti gati o nal pr o d uct.  
8. 1 1  C o m pli a nce m o nit ori n g  
T he  I P  will  be  wei g he d  at  e ver y  visit  a n d  t he  diar y  re vie we d.  B ot h  pr o d uct  wei g hts  a n d  pr o d uct 
a p plicati o n i nf or mati o n will be ca pt ur e d i n t he E D C s yste m.  
Visits 2 -5  ar e c o n d ucte d f or t he p ur p oses of c o m plia nce m o nit ori n g a n d partici pa nt trai ni n g o nl y. T he 
ai m is f or partici pa nts t o u n derta ke 5 s u per vise d a p plicati o ns d uri n g t he first 2 wee ks of treat me nt 
(i ncl u di n g  at  t he  e n d  of  visit  1) t o m o nit or  c o m plia nce  a n d  e nc o ura ge  c o nsiste nt  a d here nce  t o  t he 
a p plicati o n r e gi me n. T o mi ni mize t he b ur de n o n partici pa nts s ufficie nt varia nce has bee n i ncl u de d t o 
all o w ga ps of u p t o 7 da ys bet wee n s u per vise d a p plicati o ns. It is a ntici pate d t hat after 5  o bser ve d 
a p plicati o ns d uri n g t he first 2 wee ks , partici pa nts will be s ufficie ntl y trai ne d t o relia bl y carr y out t he 
tr eat me nt. C o m plia nce visits ar e n ot e x pecte d t o ta ke place o n wee ke n ds. O nl y o ne a p plicati o n per 
da y is t o be s u per vise d. T he sessi o ns s h o ul d be arra n ge d s uc h t hat partici pa nts ca n f ull y a d here t o t he 
tr eat me nt  r e gi me n,  r e q uiri n g  2  a p plicati o ns  per da y,  o nce  i n  t he  m or ni n g  a n d  o nce  i n  t he 
after n o o n/e ve ni n g se par ate d b y at least 6 h o urs . 
Tr eat me nt  usa ge  s h o ul d  be  deter mi ne d  fr o m  t he  I M P  wei g hts  d uri n g  e ver y  visit  s o  t hat  t he 
i nf or mati o n ca n be s har e d wit h t he partici pa nt (a n d rec or de d i n t he treat me nt diar y) i n t he c o nte xt of 
e x pecte d usa ge, a n d a n y r e q uir e d c ha n ges i n d osa ge or a p plicati o n tec h ni q ue s u g geste d pri or t o t he 
s u per vise d a p plicati o n. S u per vise d a p plicati o ns s h o ul d be perf or me d at e ver y st u d y visit (after a n y 
sc he d ule d s ki n assess me nts) t o e ns ur e c o nsiste nt a d here nce t o t he d osi n g re gi me n.  Re -trai ni n g s h o ul d 
be pr o vi de d as r e q uir e d  base d o n c o m pleti o n of t he diar y, pr o d uct wei g hts a n d a p plicati o n tec h ni q ue . 
T he criteria f or assessi n g usa ge is pr o vi de d i n t he ne xt secti o n.  
T he diar y s h o ul d b e r e vie we d at e ver y visit f or c o m plete ness a n d a n y ga ps i n a p plicati o n disc usse d 
wit h t he partici pa nt. If , at all st u d y visits e xce pt visit 1-5,  t he partici pa nt is f o u n d t o ha ve misse d m ore 
t ha n 2 0 % of t he sc he d ule d a p plicati o ns, a n d/ or misse d m ore t ha n 4  c o nsec uti ve a p plicati o ns, a n d/ or 
miss e d eit her of t he 2 a p plicati o ns i m me diatel y prece di n g a st u d y visit i n v ol vi n g s ki n assess me nts 
t he partici pa nt s h o ul d be wit h dr a w n.  D uri n g Visits 1 -5 t he st u d y I n vesti gat ors ma y use t heir discreti o n 
t o j u d ge a partici pant’s a bilit y t o a d her e t o t he treat me nt re gi me n.  
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
8. 1 2  Tre at m e nt d osi n g a n d c o m pli a nce  
D osi n g is b y fi n ger -ti p u nit ( F T U) r at her t ha n b y gra m. T he d ose f or  b ot h i n vesti gati o nal pr o d ucts i n 
t his st u d y is 1 F T U a p plie d t o t he v olar f ace of o ne  f orear m eac h twice per da y  ( Fi g ure 8. 1).  
Des pite t he diff er e nt size t u bes f or crisa b or ole oi nt me nt a n d beta met has o ne valerate crea m, b ot h ha ve 
a n ozzle size of a p pr o x i matel y 7 m m  ( 3 8. 4 8c m2) e ns uri n g c o nsiste nt d osi n g bet wee n t he m .  
T his  mea ns  t he  a ntici pate d  wei g ht  per F T U  of  eac h  pr o d uct  is  a p pr o xi matel y  1. 0 g  ( base d  o n 
esta blis he d d osi n g of 0. 5 g fr o m a 5 m m n ozzle , ha vi n g a 1 9. 6 3 c m 2 area).  
T he tr eat me nt ar ea o n t he v olar f ace of t he f orear m fr o m t he el b o w crease d o w n t o t he wrist is t he 
e q ui vale nt of 2 ha n ds or 2 6 4 c m 2 ( 1. 4 6 % b o d y s urface area), ma ki n g the d osa ge  3. 8 ( 1. 9 -7. 6 ) m g/c m2.  
Wit h  2  a p plicati o ns  per  da y,  t he  e x pecte d  usa ge  is 
2 g  per  da y  of  eac h  pr o d uct .  O ver  t he  2 8-da y 
tr eat me nt r e gi me n t otal usa ge of eac h pr o d uct  is esti mate d at 5 6 g.  
D ue t o t he e x pecte d varia bilit y of t he F T U partici pa nts are e x pecte d t o a p pl y bet wee n 2 8  a n d 1 1 2 g 
of eac h pr o d uct ( assesse d at t he e n d of tr eat me nt) t o be c o m plia nt wit h t he pr ot oc ol.  
T he per gr a m d osi n g is c o nsiste nt wit h t he ma n ufact urer’s rec o m me n dati o ns f or crisa b or ole oi nt me nt 
(a n d wit h is i nter nati o nal mar keti n g a ut h orizati o ns). Retrai ni n g s h o ul d be pr o vi de d at eac h visit w here 
I M P usa ge f alls o utsi de t he e x pecte d par a meters pr o vi de d here.  
 
Fi g u re 8. 1 : A g ui de t o d osi n g t o pical crea ms  
Rat her t ha n e xcl u di n g partici pa nts base d o n t he a m o u nts of treat me nt use d, t he f oc us s h o ul d be o n 
e d ucati o n s o t hat partici pa nts ca n ac hie ve satisfact or y c o m plia nce b y t he e n d of t he st u d y. At  Visit  5 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
t he st u d y I n vesti gat ors ma y use t heir discr eti o n t o j u d ge a partici pa nt’s a bilit y t o meet t he tar get usa ge  
base d u p o n t heir a p plicati o n tec h ni q ue, t he a d here nce t o t he a p plicati o n sc he d ule a n d t he a m o u nts 
use d t o get her . Partici pa nts dee me d at Visit 5 t o be i nca pa ble of meeti n g t he usa ge re q uire me nts b y 
t he e n d of t he st u d y s h o ul d be wit h dr a w n.  
8. 1 2. 1 I M P a p plic ati o n d uri n g t he m or ni n g of st u dy visits  
Tr eat me nts  s h o ul d  n ot  be  a p plie d  o n  t he  da y  of  st u d y  visits  w here  a  s u per vise d  a p plicati o n  is 
sc he d ule d O R w her e s ki n assess me nts ar e sc he d ul e d (as per T a ble 7. 1). 
T o  r e mi n d  partici pa nts  n ot  t o  a p pl y  t he  m or ni n g  a p plicati o n re mi n ders  s h o ul d  be  iss ue d.  W here 
p ossi ble t his s h o ul d be d o ne b y te xt messa ge usi n g a w or k m o bile p h o ne. W here t his is n ot p ossi ble 
tele p h o ne or e mails r e mi n ders ca n be se nt acc or di n g t o t he prefere nce of t he partici pa nt.  
W here t he tre at me nts h ave bee n a p plie d o n t he d ay of st u dy visits 6 a n d 7 , t he visit will nee d t o be 
re-sc he d ule d, beca use tr eat me nt r esi d ues will i nterfere wit h t he assess me nts. Was hin g t he s ki n is n ot 
a n acce pta ble s u bstit ute.  Tre at m e nts s h o ul d n ot be a p plie d o n t he d a y of st u d y visits 6 a n d 7 u ntil 
aft er s ki n assess m e nts h a ve bee n c o n d ucte d.  
W here  t he  tre at me nts  h ave  bee n  a p plie d  o n  d ays  n ot  i nv olvi n g  ski n  assess me nts ,  a n d  6  h o urs  has 
passe d si nce t he last a p plicati o n t he visit ca n be c o n d ucte d as n or mal A N D t he a p plicati o n rec or de d 
as t he sec o n d dail y a p plicati o n ( n o f urt her a p plicati o n t hat da y). W here 6 h o urs has n ot passe d, t he 
s u per vise d  a p plicati o n  s h o ul d  n ot  be  perf or me d  t o  preve nt  o ver d osi n g.  T he  de viati o n  fr o m  t he 
pr ot oc ol s h o ul d be l o g ge d o n t he pr ot oc ol de viati o n f or m. I n t his sit uati o n t he sessi o n will n ot re q uire 
resc he d uli n g a n d all ot her acti vities s h o ul d be c o m plete d as n or mal.  
O n iss ui n g t he tr eat me nt diar y, t he r ele v a nt m or ni n gs s h o ul d be hi g hli g hte d t o re mi n d partici pa nts 
n ot t o a p pl y t he pr o d uct as descri be d a b o ve. 
8. 1 3  I n vesti g at or t er mi n ati o n of p artici p a nt i n v ol ve me nt 
E xa m ples of partici pa nt n o n -c o m plia nce t hat ma y arise are:  
•  T he  partici pa nt f ails  t o  satisf act or il y f oll o w  t he  st u d y  sc he d ule  (a p p oi nt me nts  n ot  atte n de d 
wit hi n t he gi ve n ti mefr a mes), as per t he sc he d ule of e ve nts a n d t his affects c ollecti o n of data 
pertai ni n g t o t he pri mar y o utc o me meas ures.  
•  T he partici pa nt f ails t o a p pl y t he pr o d uct at t he s pecifie d ti mes/ da ys. Partici pa nts w h o miss 
m or e  t ha n  2 0 %  of  t he  sc he d ule d  a p plicati o ns,  a n d/ or  miss  m ore  t ha n 
4  c o nsec uti ve 
a p plicati o ns,  a n d/ or  miss  eit her  of  t he  2  a p plicati o ns  i m me diatel y  prece di n g  a  st u d y 
a p p oi nt me nt s h o ul d be wit h dr a w n.  
•  T he  partici pa nt  f ails  t o  use  t he  i n vesti gati o nal  pr o d ucts  i n  acce pta ble  q ua ntities (see  
“tr eat me nt d osi n g a n d c o m plia nce”) . At eac h sessi o n usa ge s h o ul d be ass esse d. W here I P use 
is  a b o ve  or  bel o w  e x pectati o ns  a  ne w  de m o nstrati o n  s h o ul d  be  pr o vi de d.  S u per vise d 
a p plicati o ns ar e perf or me d at e ver y visit  as re q uire d .  
•  T he  partici pa nt  f ails  t o  bri n g t he  diar y  t o  a n y  visit  a n d  ca n n ot  pr o vi de  t heir  usa ge  hist or y. 
W her e  a  diar y  is  n ot  a vaila ble,  t he  partici pa nt  s h o ul d  be  as ke d  t o  recite  t heir  a p plicati o n 
hist or y f or t he gi ve n st u d y pe ri o d a n d bri n g t he diar y at t he ne xt visit. E ver y eff ort s h o ul d be 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
ma de t o r etrie ve t he diaries. W her e c o m plete d diaries ca n n ot be o btai ne d A N D  a partici pa nt’s 
a p plicati o n hist or y ca n n ot be d oc u me nte d t he partici pa nt s h o ul d be wit h dra w n.  
•  T he partici pa nt f a ils t o bri n g t he I P t o st u d y visits. If t he partici pa nt fails t o bri n g t he I P t o a n y 
visit t he y s h o ul d be as ke d t o r et ur n as s o o n as p ossi ble wit h t he I P f or wei g hi n g. A wei g ht 
p ost 4 -wee ks tr eat me nt is r e q uir e d f or c o m plia nce p ur p oses (it is desira ble f or  all ot her visits). 
•  Partici pa nts w h o i na d verte ntl y use t he I P i n t he m or ni n g bef ore t he st u d y visit –  I n t hese cases 
a  ne w  a p p oi nt me nt  s h o ul d  be  sc he d ule d  w here  p ossi ble –  if  t his  is  n ot  p ossi ble  wit hi n  t he 
c o nstr ai nts of t he st u d y t he partici pa nt s h o ul d b e wit h dra w n. 
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
9 . P H A R M A C O VI GI L A N C E 
9 . 1 Defi niti o ns 
Ter m  
Defi niti o n  
A d verse E ve nt ( A E)  
A n y  u nt o war d  me dical  occ urre nce  i n  a  partici pa nt  t o  w h o m  a  me dici nal 
pr o d uct  has  bee n  a d mi nistere d,  i ncl u di n g  occ urre nces  w hic h  are  n ot 
necess aril y ca use d b y or relate d t o t hat pr o d uct.  
A d verse Re acti o n 
( A R) 
 
A n  u nt o war d  a n d  u ni nte n de d res p o nse  i n  a  partici pa nt  t o  a n  i n vesti gati o nal 
me dici nal  pr o d uct  w hic h  is  relate d  t o  a n y  d ose  a d mi nistere d  t o  t hat 
partici pa nt.  
T he p hr ase "r es p o nse t o a n i n vesti gati o nal me dici nal pr o d uct" mea ns t hat a 
ca usal  r elati o ns hi p  bet wee n  a  trial  me dicati o n  a n d  a n  A E  is  at  least  a 
r eas o na ble p ossi bilit y, i. e. t he relati o ns hi p ca n n ot be r ule d o ut. 
All  cases  j u d ge d  b y  eit her  t he  re p orti n g  me dicall y  q ualifie d  pr ofessi o nal  or 
t he S p o ns or as ha vi n g a reas o na ble s us pecte d ca usal relati o ns hi p t o t he trial 
me dicati o n  q ualif y  as  a d verse  reacti o ns.  It  is  i m p orta nt  t o  n ote  t hat  t his  is 
e ntir el y se par ate t o t he k n o w n si de effects liste d i n t he S m P C. It is s pecificall y 
a te m p or al r elati o ns hi p bet wee n ta ki n g t he dr u g, t he half -life, a n d t he ti me of 
t he e ve nt or a n y vali d alter nati ve aeti ol o g y t hat w o ul d e x plai n t he e ve nt. 
Seri o us A d verse E ve nt 
( S A E) 
A seri o us a d verse e ve nt is a n y u nt o war d me dical occ urre nce t hat:  
•  r es ults i n deat h 
•  is lif e-t hreate ni n g 
•  r e q uir es  in patie nt  h os pitalisati o n  or  pr ol o n gati o n  of  e xisti n g 
h os pitalisati o n  
o  I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n 
detai ne d ( us uall y i n v ol vi n g at least a n o ver ni g ht sta y) at t he 
h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat m e nt t hat 
w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s office or 
o ut patie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n are A Es.  If a c o m plicati o n pr ol o n gs 
h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us.  Whe n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d 
or was necessar y, t he A E s h o ul d be c o nsi dere d seri o us.  
o  H os pitalizati o n  f or  electi ve  treat me nt  of  a  pree xisti n g  c o n diti o n 
t hat di d n ot w orse n fr o m baseli ne is n ot c o nsi dere d a n A E. 
•  r es ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
o  T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s 
a bilit y t o c o n d uct n or mal life f u ncti o ns.  
o  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y 
mi n or  me dical  si g nifica nce  s uc h  as  u nc o m pli cate d  hea dac he, 
na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma (e g, 
s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt e ver y da y life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
•  c o nsists of a c o n ge nital a n o mal y or birt h defect  
O t her  ‘i m p orta nt  me dical  e ve nts’  ma y  als o  be  c o nsi dere d  seri o us  if  t he y 
je o par dise  t he  partici pa nt  or  re q uire  a n  i nter ve nti o n  t o  pre ve nt  o ne  of  t he 
a b o ve c o nse q ue nces.  
N O T E: T he ter m "life -t hreate ni n g" i n t he defi niti o n of "seri o us" refers t o a n 
e ve nt i n w h ic h t he partici pa nt was at ris k of deat h at t he ti me of t he e ve nt; it 
d oes n ot r ef er t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca use d deat h if it 
wer e m or e se vere.  
Seri o us A d verse 
Re acti o n ( S A R)  
A n  a d verse  e ve nt  t hat  is  b ot h  seri o us  a n d,  i n  t he  o pi ni o n of  t he  re p orti n g 
I n vesti gat or, belie ve d wit h reas o na ble pr o ba bilit y t o be d ue t o o ne of t he trial 
tr eat me nts, base d o n t he i nf or mati o n pr o vi de d. 
S us pect e d U ne x pect e d 
Seri o us A d verse 
Re acti o n ( S U S A R)  
A seri o us a d verse reacti o n, t he nat ure a n d se verit y of w hic h is n ot c o nsiste nt 
wit h  t he  i nf or mati o n  a b o ut  t he me dici nal  pr o d uct  i n  q uesti o n  set  o ut  i n  t he 
r ef er e nce saf et y i nf or mati o n: 
•  i n t he case of a pr o d uct wit h a mar keti n g a ut h orisati o n, t his c o ul d be 
i n t he s u m mar y of pr o d uct c haracteristics ( S m P C) f or t hat pr o d uct, s o 
l o n g as it is bei n g use d wit hi n it’s lice nce. If it is bei n g use d off la bel 
a n assess me nt of t he S m P Cs s uita bilit y will nee d t o be u n derta ke n.  
•  i n  t he  case  of  a n y  ot her  i n vesti gati o nal  me dici nal  pr o d uct,  i n  t he 
i n vesti gat or’s br oc h ure (I B) relati n g t o t he trial i n q uesti o n  
 
9 . 2 Re p orti n g P eri o d 
T he r e p orti n g peri o d f or a d ve rse e ve nts will be fr o m t he date of i nf or me d c o nse nt u ntil a p pr o xi matel y 
2 8 da ys after t he last a d mi nistr ati o n of I M P  (ra n ge fr o m 2 5 da ys t o 3 6 da ys f oll o w-u p) . All A E’s wil l 
be f oll o we d u p u ntil ca usalit y has bee n assi g ne d. O nce ca usalit y has bee n assi g ne d, o nl y S A Es  t hat 
ar e o n g oi n g at t he cl ose of t he r e p orti n g peri o d will be f oll o we d u p b y t he st u d y tea m  u ntil t he y are 
eit her r es ol ve d or sta bilise d wit h pr o perl y assess e d e x pecte d ness assess me nt f or t h ose S A Es w hic h 
ar e c o nsi der e d ca usall y r elate d . 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
F or partici pa nts w h o ar e scr ee n f ail ur es, t he acti ve c ollecti o n peri o d e n ds w he n scree n fail ure stat us 
is deter mi ne d. 
I n vesti gat ors  ar e  n ot  o bli gate d  t o  acti vel y  see k  A Es  or  S A Es after  c o ncl usi o n  of  t he  st u d y 
partici pati o n.  H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after a 
partici pa nt  has  bee n  disc har ge d  fr o m  t he  st u d y,  a n d  he/s he  c o nsi ders  t he  e ve nt  t o  be  reas o na bl y 
relate d  t o  t he  st u d y  i nterve nti o n  or  st u d y  partici pati o n,  t he  i n vesti gat or  m ust  pr o m ptl y  n otif y  t he 
s p o ns or.  
9 . 3 O per ati o n al defi niti o ns f or ( S) A E’s  
A n A d verse E ve nt ( A E) is defi ne d as a n y u nt o war d me dical occ urre nce i n a partici pa nt  d uri n g t he 
c o urse of t he trial. Pr e -e xisti n g c on diti o ns, alt h o u g h t he y will be rec or de d, will n ot be re gar de d as 
A Es u nless t he y w orse n si g nifica ntl y.  
Rec o g nise d  si de  eff ects  of  t he  I M P  ar e  f ull y  d oc u me nte d  i n  t he  I n vesti gat or  Br oc h ure (I B) f or 
crisa b or ole or t he S m P C f or beta met has o ne valerate .  
W hil st t he st u d y ai ms t o i n vesti gate t he s u b-cli nical a d verse effects of t he st u d y I P’s, f or t he p ur p oses 
of t his st u d y o nl y cli nicall y o bser va ble a d verse effects will be m o nit ore d fr o m a safet y pers pecti ve i n 
li ne wit h n or mal pr actice. T his is j ustifie d b y t he fact t hat ( 1) s u b -cli nical c ha n ges will o nl y bec o me 
e val ua ble after a nal ysis w hic h is li kel y t o occ ur after cessati o n of treat me nt, a n d ( 2) it is n ot clear at 
t his sta ge w hat le vel of s u b-cli nical c ha n ges c orres p o n d wit h t he ris ks of de vel o pi n g cli nical a d verse 
eff ects.  
All a d verse e ve nts will be r ec or de d i n a Case Re p ort F or m a n d assesse d f or seri o us ness, e x pecte d ness  
(seri o us A E’s o nl y), i nte nsit y a n d ca usalit y  as o utli ne d bel o w .  
9 . 3. 1 Seri o us ness 
A Seri o us A d verse E ve nt ( S A E) will be defi ne d as a n A E w hic h eit her  
1.  Res ults i n deat h  
2.  Is lif e-t hr eate ni n g  
3.  Re q uir es h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n  
4.  Res ults i n persiste nt disa bilit y or i nca pacit y  
5.  C o nsists of a c o n ge nital a b n or malit y or birt h defect  
I m p orta nt  me dical  e ve nts  t hat  ma y  not  be  i m me diatel y  life -t hreate ni n g  or  res ult  i n  deat h  or 
h os pitalisati o n b ut ma y je o par dise t he patie nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he defi niti o n a b o ve will als o be c o nsi dere d seri o us.  
T he i n vesti gat or will d eter mi ne t he seri o us ness of eac h a d verse e ve nt as per t hese criteria.   
All S A E ar e s u bject t o e x pe dite d r e p orti n g t o b ot h t he S p o ns or A N D Pfizer (as t he ma n ufact urer of 
crisa b or ole, e ve n w her e t he S A E is u nr elate d t o crisa b or ole) as o utli ne d bel o w. S A E wil l be re p orte d 
usi n g b ot h t he S T H S A E f or m a n d Pfizer I n vesti gat or -I nitiate d or Cli nical Researc h C olla b orati o n 
I nter ve nti o nal St u d y Seri o us A d verse E ve nt Re p ort F or m. W he n c o m pleti n g t he S p o ns or S A E f or m 
t he  t y pe  of  r e p ort  (i nitial  or  f oll o w-u p)  s h o ul d  be clearl y  i n dicate d. W he n  pr o vi di n g  f oll o w -u p 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
i nf or mati o n t o Pfizer, a ne w f or m s h o ul d be use d i n eac h case t hat i ncl u des t he data t hat are ne w or 
re vise d  fr o m  t he  pr e vi o us  r e p ort. F oll o w -u p  i nf or mati o n  s h o ul d  ne ver  be  a d de d  t o  a  pre vi o usl y 
s u b mitte d r e p ort f or m. F urt her g ui da nce o n t he c o m pleti o n of t he Pfizer f or m ca n be f o u n d i n t he 
Pfizer -pr o vi de d Saf et y Re p orti n g Ref er e nce Ma n ual a n d S A E F or m G ui de.  
9 . 3. 2 C a us ality  
Ca usalit y ass ess me nt:  
•  T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h 
occ urr e nce of eac h A E/ S A E.  
•  T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, 
as well as t he te m p or al r elati o n s hi p of t he e ve nt t o st u d y i nter ve nti o n a d mi nistrati o n will be 
c o nsi der e d a n d i n vesti gate d.  
•  T he i n vesti gat or will als o c o ns ult t he i n vesti gat or’s br oc h ure (I B) a n d/ or pr o d uct i nf or mati o n, 
f or mar kete d pr o d ucts, i n his/ her assess me nt. 
•  F or  eac h  A E/ S A E,  t he  i n vesti gat or m ust  d oc u me nt  i n  t he  me dical  n otes  t hat  he/s he  has 
r e vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
•  T her e  ma y  be  sit uati o ns  i n  w hic h  a n  S A E  has  occ urre d  a n d  t he  i n vesti gat or  has  mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he s p o ns or.  H o we ver, it is i m p orta nt t hat t he 
i n vesti gat or  al wa ys  ma ke  a n  assess m e nt  of  ca usalit y  f or  e ver y  e ve nt  bef ore  t he  i nitial 
tr a ns missi o n of t he S A E data t o t he F u n der (t his is n ot a re q uire me nt f or i nitial re p orti n g t o 
t he S p o ns or). 
•  T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n 
a n d se n d a n S A E f oll o w -u p r e p ort wit h t he u p date d ca usalit y assess me nt.  
•  T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
r e q uir e me nts. 
•  If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he i n vesti gati o nal pr o d uct ca use d t he e ve nt, 
t he n t he e ve nt will be ha n dle d as “relate d t o i n vesti gati o nal pr o d uct” f or re p orti n g p ur p oses, 
as defi ne d b y t he s p o ns or .  I n a d diti o n, if t he i n vesti gat or deter mi nes t hat a n S A E is ass ociate d 
wit h  st u d y  pr oce d ur es,  t he  i n vesti gat or  m ust  rec or d  t his  ca usal  relati o ns hi p  i n  t he  s o urce 
d oc u me nts a n d C R F, a n d r e p ort s uc h a n assess me nt i n t he de dicate d secti o n of t he C T S A E 
Re p ort F or m a n d i n acc or da nce wit h t he S A E re p orti n g re q uire me nts.  
T he i n vesti gat or will deter mi ne t he ca usalit y of eac h a d verse eve nt as defi ne d here:  
•  U nr elate d  or  u nli kel y:  a  cli nical  e ve nt  i ncl u di n g  la b orat or y  test  a b n or malit y  wit h  te m p oral 
r elati o ns hi p  t o  trial  tr eat me nt  or  I M P  a d mi nistratio n,  t hat  ma kes  a  ca usal  relati o ns hi p 
i nc o m pati ble or f or w hic h ot her dr u gs, c he micals or disease pr o vi de a pla usi ble e x pla nati o n. 
T his will be c o u nte d as “ u nr elate d” f or n otificati o n p ur p oses.  
•  P ossi ble: a cli nical e ve nt, i ncl u di n g la b orat or y test a b n or mali t y, wit h te m p oral relati o ns hi p t o 
trial  tr eat me nt  or  I M P  a d mi nistrati o n  w hic h  ma kes  a  ca usal  relati o ns hi p  a  reas o na ble 
p ossi bilit y, b ut w hic h c o ul d als o be e x plai ne d b y ot her dr u gs, c he micals or c o nc urre nt disease. 
T his will be c o u nte d as “r elate d” f or n ot ificati o n p ur p oses. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 8 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  Pr o ba ble: a cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h te m p oral relati o ns hi p 
t o  trial  tr eat me nt  or  I M P  a d mi nistrati o n  w hic h  ma kes  a  ca usal  relati o ns hi p  a  reas o n a ble 
p ossi bilit y, a n d is u nli kel y t o be d ue t o ot her dr u gs,  c he micals or c o nc urre nt disease. T his will 
be c o u nte d as “r elate d” f or n otificati o n p ur p oses.  
•  Defi nite: a cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h te m p oral relati o ns hi p t o 
trial  tr eat me nt  or  I M P  a d mi nistrati o n  w hic h  ma kes  a  ca usal  relati o ns hi p  a  reas o na ble 
p ossi bilit y, a n d w hic h ca n defi nitel y n ot be attri b ute d t o ot her ca uses. T his will be c o u nte d as 
“r elate d” f or n otificati o n p ur p oses.  
A S A E w h ose ca usal r elati o ns hi p t o a st u d y I M P is assess e d b y t he C hief I n vesti gat or as “ p ossi ble”, 
“pr o ba ble” or “ defi nite” will be c o nsi der e d ‘relate d’ a n d is a Seri o us A d verse Dr u g Reacti o n.  
9 . 3. 3 E x pecte d ness 
E x pecte d ness will be assesse d f or S A E’s o nl y. A S U S A R is a n y e ve nt w hic h q ualifies as a n S A E a n d 
meets t he criteria of bei n g j u d ge d as p ossi bl y,  pr o ba bl y or defi nitel y relate d t o st u d y I M P a n d has a 
nat ur e a n d/ or se verit y of w hic h is n ot c o nsiste nt wit h t he i nf or mati o n a b o ut t he me dici nal pr o d uct i n 
q uesti o n as set o ut i n t he s u m mar y of pr o d uct c haracteristics, i n vesti gat or br oc h ure or I M P d ossier  
f or t hat pr o d uct (ie it is ‘ u ne x pecte d’).  
A S U S A R will r e q uir e e x pe dite d r e p orti n g as per t he Cli nical Trials Re g ulati o ns. All seri o us a d verse 
e ve nts t hat f all or ar e s us pecte d t o f all wit hi n t hese criteria s hall be treate d as a S U S A R u ntil dee me d 
ot her w ise. 
9 . 3. 4 I nte nsit y 
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d d uri n g t he 
st u d y a n d assi g n it t o 1 of t he f oll o wi n g cate g ories:  
•  Mil d: A n e ve nt t hat is easil y t oler ate d b y t he partici pa nt, ca usi n g mi ni mal disc o mf ort  a n d 
n ot i nterf eri n g wit h e ver y da y acti vities.  
•  M o der ate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e ver y da y 
acti vities.  
•  Se ver e: A n e ve nt t hat pr e ve nts n or mal e ver y da y acti vities.  A n A E t hat is assesse d as se vere 
s h o ul d n ot be co nf use d wit h a n S A E.  Se vere is a cate g or y utilize d f or rati n g t he i nte nsit y of 
a n e ve nt; a n d b ot h A Es a n d S A Es ca n be assesse d as se vere.  
A n e ve nt is defi ne d as “seri o us” w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi niti o n o f a n S A E, N O T w he n it is rate d as se vere. 
9 . 4 Re p orti n g ti m e-f r a m es 
T he ti me fr a me f or r e p orti n g a n S A E t o t he S p o ns or A N D Pfizer is:  
•  I m me diatel y u p o n a war e ness, if t he S A E is fatal or life-t hreate ni n g (i. e., ca uses a n i m me diate 
ris k of deat h) — r e gar dless of t he e xte nt of a vaila ble i nf or mati o n  
O R  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  Wit hi n 2 4 h o urs of first a war e ness of t he S A E, if t he S A E is n ot fatal or life t hreate ni n g  
T hese ti mefr a mes ar e a p plica ble t o all r e p orta ble S A Es  
9 .5  Res p o nsi bilities  
T he Pri nci pal I n vesti gat or will:  
•  Assess t he e ve nt f or seri o us ness, e x pecte d n ess  a n d relate d ness t o t he st u d y I M P as set o ut 
a b o ve 
•  Rec or d  all  S A Es  o n  sta n dar dise d  S A E f or ms  a n d  re p ort  t he m  t o  t he  S p o ns or  b y fa x ( S T H 
R & D 0 1 1 4 2 2 6 5 9 3 7) or e mail ( sae @st h. n hs. u k) wit hi n 2 4 h o urs of t he bec o mi n g a ware of 
t he e ve nt. 
•  C o m plete t he Pfizer -pr o vi de d S A E R e p ort F or m , a n d s u b mit it t o Pfizer, wit h t he R e p ort a ble 
E ve nts  F ax  C over  S heet,  i m me diatel y  f or  a  deat h  or  life-t hreate ni n g  e ve nt,  a n d  wit hi n 
2 4  h o urs f or all ot her r e p orta ble  S A Es . It s h o ul d be n ote d t hat t he C T S A E Re p ort F or m f or 
r e p orti n g of S A E i nf or mati o n is n ot t he sa me as t he A E pa ge of t he C R F.  W he n t he sa me 
data  ar e  c ollecte d,  t he  f or ms  m ust  be  c o m plete d  i n  a  c o nsiste nt  ma n ner.    A Es  s h o ul d  be 
r ec or de d usi n g c o ncise me dical ter mi n ol o g y a n d t he sa me A E ter m s h o ul d be use d o n b ot h 
t he C R F a n d t he C T S A E Re p ort F or m f or re p orti n g of S A E i nf or mati o n. 
 
•  T a ke a p pr o priate me dical acti o n, w hic h ma y i ncl u de halti n g t he trial a n d i nf or m t he S p o ns or 
of s uc h acti o n  
•  T he  i n vesti gat or  is  o bli gate d  t o  perf or m  or  arra n ge  f or  t he  c o n d uct  of  s u p ple me ntal 
meas ur e me nts  a n d/ or  e val uati o ns  as  me dicall y  i n dicate d  or  as  re q ueste d  b y  t he  s p o ns or or 
Pfizer t o el uci date t he nat ur e a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble.  T his ma y 
i ncl u de  a d diti o nal  la b or at or y  tests  or  i n vesti gati o ns,  hist o pat h ol o gical  e xa mi nati o ns,  or 
c o ns ultati o n wit h ot her healt hcar e pr ofessi o nals.  
•  If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w u p peri o d, 
t he i n vesti gat or will pr o vi de Pfizer Safet y wit h a c o p y of a n y p ost m orte m fi n di n gs i ncl u di n g 
hist o pat h ol o g y.  
•  Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y c o m plete d C R F.  
 
T he S p o ns or will:  
•  Re p ort  S U S A Rs  w hic h  ar e  f atal  a n d  life -t hreate ni n g  t o  t he  C o m pete nt  A ut horit y  wit hi n  7 
da ys.  
•  Re p ort  S U S A Rs  w hic h  ar e  n ot  f atal  a n d  n ot  life -t hreate ni n g  t o  t he  C o m pete nt  A ut h orit y 
wit hi n 1 5 da ys.  
•  S hall, wit hi n a f urt her ei g ht da ys se n d a n y f oll o w -u p i nf or mati o n a n d re p orts t o t he M H R A.  
•  Ma ke a n y a me n d me nts as r e q uir e d t o t he st u d y pr ot oc ol a n d i nf or m t he et hics a n d re g ulat or y 
a ut h orities as r e q uir e d 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
9 .6  P re g n a nc y re p orti n g  
•  All  pr e g na ncies  wit hi n  t he  trial  ( li mite d  t o t he  trial  partici pa nt,  wit h  partici pa nts  c o nse nt) 
s h o ul d  be  r e p orte d  t o  t he  C hief  I n vesti gat or  a n d  t he  S p o ns or  usi n g  t he S T H  Pre g n a ncy 
R e p orti n g  F or m  A N D  Pfizer -pr o vi de d  S A E  R e p ort  F or m  WI T H  a n 
E x p os ure  D uri n g 
Pre g n a ncy  s u p ple me nt al re p ort f or m wit hi n 2 4 h o urs of n otificati o n  
o  T he  s pecific  details  t hat  nee d  t o  be  i ncl u de d  i n  t he  re p ort  of  a n  E x p os ure  D uri n g 
Pr e g na nc y de pe n d o n w het her t he e x p os ure was mater nal or pater nal , n oti n g t hat o nl y 
mater nal i nsta nces will be r e p orte d i n t his st u d y . F urt her g ui da nce o n t he c o m pleti o n 
of t he Pfizer f or ms ca n be f o u n d i n t he Pfizer -pr o vi de d Safet y Re p orti n g Refere nce 
Ma n ual a n d S A E F or m G ui de.  
o  T he  a ntici pate d  date  of  deli ver y  s h o ul d  be  i ncl u de d  i n  t he  Narrati ve  secti o n  of  t he 
r e p ort.  
•  W hilst a n S A E f or m is use d f or r e p orti n g, Pre g na nc y is n ot c o nsi dere d a n A E u nless a ne gati ve 
or c o nse q ue ntial o utc o me is r ec or de d f or t he m ot her or c hil d/f oet us. If t he o utc o me meets t he 
seri o us criteria, t his w o ul d be c o nsi dere d a n S A E a n d re q uires re p orti n g as s uc h . 
•  T he Pri nci pal I n vesti gat or m ust t he n f oll o w t he partici pa nt  t hr o u g h o ut t he pre g na nc y a n d is 
t o n otif y t he S p o ns or a n d Pfizer of t he o utc o me as a f oll o w -u p t o t he i nitial E x p os ure D uri n g 
Pr e g na nc y  r e p ort. 
9 .7  S af et y u p d at es  
I nf or mati o n r e gar di n g u ne x pecte d cli nical st u d y S A Es t hat are ca usall y relate d t o crisa b or ole (a Pfizer 
pr o d uct ) will be  pr o vi de d t o i n vesti gat ors via se mi -a n n ual li ne listi n gs.  
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 0 . S T A TI S TI C S A N D D A T A A N A L Y SI S  
1 0 . 1 S a m ple Size 
T he pri mar y s tatistical a nal yses will c o m pare t he c ha n ge i n e pi der mal t hic k ness fr o m baseli ne t o 2 8 
da ys bet wee n tr eat me nts: beta met has o ne valerate crea m vs crisa b or ole, utilisi n g t he wit hi n p artici pa nt 
c o m paris o ns  of  left  vs  ri g ht  f or ear m.  Ass u mi n g  t hat  t he  c ha n ge  fr o m  baseli ne  at  da y  2 8  i n  t he 
beta met has o ne valer ate gr o u p will be a p pr o xi matel y -4. 4 4 µ m a n d a sta n dar d de viati o n of 5 µ m (f or 
t he c ha n ge fr o m baseli ne wit hi n eac h partici pa nt ), t o detect a re d ucti o n i n t his c ha n ge of 8 0 % t o -0. 8 8 
µ m  i n  t he  crisa b or ole  ar m  wit h  8 0 %  p o wer,  a  parallel  gr o u p  st u d y  ( o ne  gr o u p  f or  beta met has o ne 
valer ate  a n d  o ne  gr o u p  f or crisa b or ole)  w o ul d  re q uire  3 3  partici pa nts  i n  eac h  gr o u p.  T he  st u d y 
descri be d  her e  is  c o m pari n g  wit hi n partici pa nts  (left  vs  ri g ht  ar m)  rat her  t ha n  a  parallel  gr o u p 
( bet wee n partici pa nts) desi g n, h o we ver it is ass u me d t hat t his wit hi n patie nt c o m paris o n will ha ve 
gr eater p o wer t ha n t he par allel gr o u p desi g n.  T his ass u m pti o n is necessar y b eca use n o i nf or mati o n 
is  a vaila ble  i n  t he  liter at ur e  as  t o  t he  sta n dar d  de viati o n  of  t he  differe nce  bet wee n  c ha n ge  fr o m 
baseli ne  o n  t he  T C S  ar m  a n d  c ha n ge  fr o m  baseli ne  o n  t he  crisa b or ole  ar m.    Ass u mi n g  t hat  t he 
c orr elati o n  bet wee n  t hese  t w o  ‘ c ha n ge  fr o m  b aseli ne’  meas ures  will  be  greater  t ha n  zer o t he n  t he 
wit hi n partici pa nt c o m paris o ns ca n be ass u me d t o ha ve greater p o wer t ha n a parallel gr o u p desi g n.  
T a ble 1 0 . 1: Sa m ple size calc ulati o ns  
 
1 0 . 2 Pl a n ne d recr uit m e nt r at e 
A si n gle c o h ort of u p t o 3 7 partici pa nts will be recr uite d a n d treat me nt iss ue d t o meet t he  tar get of 3 3 
f or c o m pleti o n ( all o wi n g f or a 1 0 % dr o p o ut rate). Recr uit me nt is esti mate d t o ta ke u p t o 6 m o nt hs at 
a r ate of ≥7 r ecr uits per m o nt h  
1 0 .3 A n al ysis p o p ul ati o n a n d pr ot oc ol de vi ati o ns  
T he  a nal ysis  p o p ulati o n  will  i ncl u de  all  partici pa n ts  w h o  pr o vi de d  i nf or me d  c o nse nt A N D  were 
iss ue d t he tr eat me nts, t his will be k n o w n as t he i nte nti o n t o treat p o p ulati o n. 
All pr ot oc ol de viati o ns, i ncl u di n g missi n g or s p uri o us data, will be rec or de d i n t he pr ot oc ol de viati o ns 
l o g. T he  pr ot oc ol  de viati o ns l o g  will  be  re vie we d  at  t he  cl ose  of  t he  st u d y  a n d  (if  a p pr o priate) 
de viati o ns will be liste d i n t he r e p ort.  O nl y i m p orta nt de viati o ns, as defi ne d b y I C H will be liste d.  
I m p orta nt  pr ot oc ol  de viati o ns  ar e  defi ne d  b y  I C H  as:  a  s u bset  of  pr ot oc ol  de viati o ns t hat  ma y 
Par a meter  
A nat o mi
cal 
l ocati o n 
A D  
Mea n 
c ha n ge  fr o m 
baseli ne  
S D  (c ha n g e 
fr o m 
baseli ne)  
Cli nicall y 
rele va nt 
differe nce ( %)  
Sa m ple 
size  
per 
c o h ort 
P o wer  
E pi der mal 
t hic k ness 
(µ m)  
F or ear m  
-4. 4 4  
5  
3. 5 5 ( 8 0)  
3 3  
> 8 0 %  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
si g nifica ntl y  i m pact  t he  c o m plete ness,  acc urac y,  a n d/ or  relia bilit y  of  t he  st u d y  data  or  t hat  ma y 
si g nifica ntl y aff ect a partici pa nt 's ri g hts, safet y, or well-bei n g . 
Pr ot oc ol de viati o ns will be r e vie we d w hilst t he data is still bli n d a n d if t here  are c o ncer ns t hat a lac k 
of c o m plia nce t o t he pr ot oc ol ma y i m pact t he a nal yses t he n a per pr ot oc ol p o p ulati o n ma y be defi ne d 
a n d use d f or a se nsiti vit y a nal ysis.  T he I T T p o p ulati o n will re mai n t he pri mar y a nal ysis p o p ulati o n.  
I n  a d diti o n, s u m maries  of  eac h  of  t he  e n d p oi nts will  clearl y  s h o w  t he  a m o u nt  of  missi n g  data  (if 
a p pr o priate). 
1 0 .4 St atistic al a n al yses pl a n  
A statistical a nal ysis pla n will be pr o d uce d bef ore t he start of t he st u d y.  
1 0 . 4. 1 S u m m ary of b aseli ne d at a a n d fl o w of p atie nts 
Rele va nt bas eli ne a n d de m o gr a p hic data (i ncl u di n g Fitz patric k s ki n t y pe) will be s u m marise d.  
Tr eat me nt e mer ge nt a d verse e ve nts a n d seri o us a d verse e ve nts will be s u m marise d f or all partici pa nts 
w h o  si g ne d  t he  c o nse nt. All a d verse  e ve nts  will  be liste d  (i ncl u di n g  t h ose w hic h  be ga n  bef ore 
i nitiati o n of st u d y tr eat me nt or after t he f oll o w u p peri o d). 
1 0 . 4. 2 Pri m ary o utc o me a n alysis 
A nal ysis of t he pri mar y e n d p oi nt ( c ha n ge i n e pi der mal t hic k ness meas ure d b y str uct ural O C T at da y 
2 9 , c o m par e d bet wee n crisa b or ole ( 2 %) oi nt me nt  a n d beta met has o ne valerate ( 0. 1 %) crea m) will use 
a pair e d a nal ysis t o calc ulate t he mea n differe nce a n d a 9 5 % c o nfi de nce i nter val f or t hat differe nce.  
T he  distri b uti o n  of  t he  diff er e nces  will  be  re vie we d  a n d  if  t he  data  re q uires  it  a n o n -para metric  
a nal ysis ma y be utilise d a n d a me dia n ma y be prese nte d.  
1 0 . 4. 3 Sec o n d ary o utc o me a n alysis 
A t his is a n e x pl or at or y st u d y  i n vesti gati n g a n u m ber of p ossi ble bi o mar kers n o f or mal a dj ust me nts 
f or m ulti plicit y  will be ma de , h o we ver r es ults will be prese nte d al o ngsi de c o nfi de nce i nter vals a n d 
will be i nter pr ete d ca uti o usl y.  A f ut ur e st u d y is pla n ne d t o c o nfir m t he selecti o n of bi o mar kers fr o m 
t his st u d y. 
T he a nal ysis of t he sec o n dar y e n d p oi nts:  
•  C ha n ge i n str uct ur al O C T meas ur e me nts of e pi der mal t hic k ness  
•  C ha n ge  i n r e d ness/er yt he ma  
•  C ha n ge i n Tr a ns -E pi der mal Water L oss ( T E W L)  
•  C ha n ge i n vis ual s ki n dr y ness   
•  Nat ur al M oist urisi n g Fact or  
will  use  pair e d  a nal yses  t o  c o m par e  t he  c ha n ge  o ver  ti me  bet wee n crisa b or ole ( 2 %) oi nt me nt  a n d 
beta met has o ne valer ate ( 0. 1 %) cr ea m . 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 0 . 4. 4 E x pl or at ory o utc o me a n alysis 
T he pri mar y a n d sec o n dar y a nal yses will i de ntif y w here t here is e vi de nce of a differe nce bet wee n 
crisa b or ole  oi nt me nt  a n d  beta met has o ne  valerate  crea m  i n  t he  c ha n ge  fr o m  baseli ne a n d  w hic h 
bi o mar kers ar e a ble t o i de nt if y t his diff er e nce i n t he cli nical trial setti n g. 
T he e x pl or at or y a nal ysis will i n vesti gate w het her a s u b set of t he O C T e n d p oi nts ca n be use d t o n o n -
i n vasi vel y i de ntif y  s ki n  c ha n ges.  T his  a nal ysis  will  use m ulti ple  l o gistic  re gressi o n  t o  deter mi ne 
w hic h of  t he  ne w  bi o mar kers  pr o vi de  t he  m ost  i nf or mati ve  a n d  se nsiti ve  data  pertai ni n g  t o  t he 
atr o p hic c ha n ges i n d uce d b y T C S tr eat me nt. T his will be acc o m plis he d b y assessi n g t he a bilit y of 
eac h bi o mar ker t o diff er e ntiate t he s ki n of partici pa nts bef ore a n d aft er treat me nt wit h t he p ote nt T C S, 
w hic h is k n o w n t o i n d uce s u b -cli nical atr o p hic s ki n c ha n ges wit hi n t he treat me nt wi n d o w.   
T he bi o mar ker ( or s u bset of bi o mar kers) w hic h are i de ntifie d b y t his a nal ysis will als o be rec or de d 
i n  a  s u bse q ue nt  st u d y  c o m pari n g crisa b or ole  t o  a  m o deratel y  p ote nt  T C S.    T his  will  e na ble  t he 
c o nfir mati o n of t he a bilit y of t he bi o mar kers t o i de ntif y s ki n c ha n ges i n a sec o n d i n de pe n de nt dataset.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 1 . S T U D Y C O N D U C T 
1 1 .1 St u d y l oc ati o n  
T he R o yal Halla ms hir e H os pital, Gl oss o p R oa d, S hef fiel d S 1 0 2J F 
•  St u d y e nr ol me nt, r a n d o mizati o n a n d I P relate d acti vities will be c o n d ucte d  i n a n a p pr o priate 
l ocati o n b y s uita bl y q ualifie d me m bers of t he researc h tea m as a gree d wit h t he st u d y s p o ns or  
•  St u d y pr oce d ur es will be carrie d o ut o n K -fl o or i n t he S heffiel d der mat ol o g y researc h S ki n 
Barrier  V ol u nteer  S uite,  a  de dicate d  s pace  f or  h u ma n  s ki n  researc h  wit h  f ull  cli mate -
c o ntr olle d c o n diti o ns. 
1 1 .2 St u d y st aff  
All st u d y tea m me m bers ar e tr ai ne d i n g o o d cli nical practice. A rec or d of tra i ni n g a n d dele gatio n of 
d uties will be  ke pt i n t he site file.  
1 1 .3 P artici p a nt t r ac ki n g  
All  partici pa nts  e nr olle d  i nt o  t his  st u d y  will  be  trac ke d  usi n g  t he  e xcel Partici pa nt  Trac ki n g  L o g , 
l ocate d o n t he gr o u ps o nli ne Filest or e 
1 1 .4 S a m ple t r ac ki n g  a n d st or a ge  
All sa m ples c o llecte d as part of t his st u d y will be l o g ge d i n t he Sa m ple Trac ki n g L o g a n d all use 
d oc u me nte d o n t he Sa m ple Tr ac ki n g L o g . 
T he n u m ber, t y pe a n d desti nati o n of sa m ples is i n dicate d i n t he ta ble bel o w.  
S a m ple  
Rele v a nt m at eri al u n der 
H T A ?  
St or a ge/ Desti n ati o n  
Sali va sa m ple 
( b uccal s wa b) 
Yes  
Ge n o mic D N A is olate d f or F L G  ge n ot y pi n g. 
All sa m ples will be pr ocesse d wit hi n 1 2 
m o nt hs f oll o wi n g t he last partici pa nt last visit.  
S pecific c o nse nt will be s o u g ht t o kee p g D N A 
be y o n d t he e n d of t his st u d y i n or der t o 
s u p p ort f ut ure researc h pr ojects. 
S u perficial s ki n 
sa m ples 
c ollecte d o n 
ta pe stri ps 1 -1 0  
N o ( c o m prises e n ucleate d 
c or ne oc ytes)  
St ora ge at -7 0 oC . Re q uire d f or strat u m 
c or ne u m meta b olite ( N M F) q ua ntificati o n. 
Sa m ples will be pr ocesse d wit hi n 1 2 m o nt hs 
f oll o wi n g the last partici pa nt last visit.  
Re mai ni n g * u n use d) sa m ples retai ne d  f or 
f ut ure pr otei n a n d meta b ol o mic a nal ysis. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
S pecific c o nse nt will be s o u g ht fr o m 
partici pa nts t o retai n t hese sa m ples f oll o wi n g 
c o m pleti o n of t he st u d y. 
S u perficial s ki n 
sa m ples 
c ollected o n 
ta pe stri ps 1 1-
2 0  
P ossi bl y ( as sa m pli n g de pt h 
i ncr eases t her e is a n 
i ncr easi n g ris k of c ollecti n g 
via ble ker ati n oc ytes fr o m t he 
s ki n la yer bel o w t he strat u m 
c or ne u m)  
Sa m ples will be l yse d i m me diatel y i n R L T 
l ysis b uffer t o re n der t he m e n ucleate. St orage 
at -7 0 oC f or f ut ure pr otei n a nal ysis. S pecific 
c o nse nt will be s o u g ht fr o m partici pa nts t o 
retai n t hese sa m ples f oll o wi n g c o m pleti o n of 
t he st u d y. 
 
All  sa m ples  will  be  st or e d  at -7 0 oC  i n  a  freezer wit h  re m ote  hi g h  te m perat ure  alar m  s yste m  ( 2 4 h 
m o nit ori n g f or hi g h te m per at ur e b y m o bile p h o ne).  
1 1 .5 D at a c ollecti o n t o ols a n d s o urce d oc u me nt i de ntific ati o n  
All r esear c h data will be c ollecte d first ha n d b y t he st u d y tea m a n d rec or de d i n se veral wa ys t o pr o vi de 
verifia ble s o ur ce : 
•  Usi n g  pr e desi g ne d  cas e  r ec o r d  f or ms. F or ms  c o m plete d  b y  ha n d  d uri n g  visits  will  be 
tr a nsf err e d t o t he c ust o m electr o nic data ca pt ure s yste m b y data c o or di nat ors.  
•  Dir ect  e ntr y  i nt o  a  c ust o m  electr o nic  data  ca pt ure ( E D C) s yste m d uri n g  visits . C o m plete d 
electr o nic f or ms will be pri nte d a n d si g ne d t o pr o vi de verifia ble s o urce data.  
•  C ollecti o n of r a w data files  
A se par ate data ma na ge me nt pla n will be de vel o pe d t o pr o vi de a d diti o nal details o n h o w data will be 
ma na ge d i n t his st u d y .  
T he  c ust o m  electr o nic  data  ca pt ur e  s yste m  base d  o n  t he  Pr os pect  cli nical  trial  s oft ware  will  be 
desi g ne d b y E pi ge n esy s, a U ni versit y of S heffiel d c o m pa n y. 
1 1 . 5. 1 R ese arc h n otes 
W hilst r esear c h n otes will n ot be use d t o gat her s o urce data, t he n otes will be accesse d a n d u p date d 
wit h details of partici pati o n i n  t his trial. T his will i ncl u de a d di n g a Researc h Alert a n d a c o p y of t he 
c o nse nt f or m t o t he h os pital n otes.  
F or partici pa nts n ot c urr e ntl y u n der g oi n g care at t he h os pital ne w n otes will be create d.  
1 1 .6  D at a h a n dli n g a n d rec or d kee pi n g  
Resear c h  data  will be  st or e d  i n  Pr os pect,  C T R U's  bes p o ke  electr o nic  data  ca pt ure  ( E D C)  s yste m 
de vel o pe d  i n  c olla b or ati o n  wit h  e pi Ge nes ys . D ata  e ntere d  directl y  i nt o  t he  E D C  s yste m  will  be 
q ualifie d usi n g pr e -esta blis he d par a meter ra n ges. Pri nte d rec or ds create d at t he ti me o f data e ntr y will 
be si g ne d t o pr o vi de s o ur ce verificati o n. Researc h data c ollecte d o n pa per C R F’s a n d t he n tra nsferre d 
t o t he E D C s yste m will be partiall y verifie d b y c hec ki n g 1 0 % of all rec or ds a gai nst t he ori gi nal s o urce. 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 7  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 1 .7  D at a Access  
Dir ect access will be gr a nte d t o a ut h orise d re prese ntati ves fr o m t he S p o ns or, h ost i nstit uti o n a n d t he 
re g ulat or y  a ut h orities  t o  per mit  trial-r elate d  m o nit ori n g,  a u dits  a n d  i ns pecti o ns- i n  li ne  wit h 
partici pa nt c o nse nt.  
1 1 .8  Arc hi vi n g  
•  T he site will be r es p o nsi ble f or ar c hi vi n g all st u d y data  
•  Ar c hi vi n g will be a ut h orise d b y t he S p o ns or f oll o wi n g s u b missi o n of t he e n d of trial re p ort  
•  All esse ntial d oc u me nts will be ar c hi ve d f or a mi ni m u m of 1 5 years after c o m pleti o n of trial  
•  Destr ucti o n of esse ntial d oc u me nts will re q uire a ut h orisati o n fr o m t he S p o ns or  
 
1 2 . M O NI T O RI N G, A U DI T & I N S P E C TI O N  
1 2 . 1 M o nit ori n g 
T he  st u d y  will  u n der g o  m o nit ori n g  b y  t he  researc h  G o ver na nce  S p o ns or,  S heffiel d  T eac hi n g 
H os pitals Tr ust ( S T H). S T H will pr e par e a se parate m o nit ori n g pla n f or t his st u d y. Mo nit ori n g will 
be c o n d ucte d wit h t he e x pr ess p ur p ose of e ns uri n g t he st u d y meets all re g ulat or y re q uire me nts.  
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 8  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 3 . E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
1 3 . 1 Rese arc h Et hics C o m mitt ee ( R E C) re vie w a n d re p orts 
•  Bef or e t he start of t he trial, a p pr o val will be s o u g ht fr o m a R E C a n d t he H R A f or t he trial 
pr ot oc ol, i nf or me d c o nse nt f or ms a n d ot her rele va nt d oc u me nts e. g. A d vertise me nts a n d G P 
i nf or mati o n letters 
•  A me n d me nts t hat r e q uir e r e vie w b y t he R E C a n d t he H R A will n ot be i m ple me nte d u ntil a 
f a v o ur a ble o pini o n has bee n gi ve n  ( n ote t hat a me n d me nts ma y als o nee d t o be re vie we d a n d 
acce pte d b y t he M H R A , a n d/ or N H S R & D de part me nts bef ore t he y ca n be i m ple me nte d i n 
pr actice)  
•  All c orr es p o n de nce wit h t he R E C will be retai ne d i n t he Trial Master File/I n vesti gat or S ite 
File  
•  A n  a n n ual  pr o gr ess  r e p ort  ( A P R)  will  be  s u b mitte d  t o  t he  R E C  wit hi n  3 0  da ys  of  t he 
a n ni versar y date o n w hic h t he f a v o ura ble o pi ni o n was gi ve n, a n d a n n uall y u ntil t he trial is 
declar e d e n de d  
•  It is t he C hief I n vesti gat or’s r es p o nsi bilit y t o pr o d uce t he a n n ual re p orts as re q uire d. 
•  T he C hief I n vesti gat or will n otif y t he R E C of t he e n d of t he trial  
•  If  t he  trial  is  e n de d  pr e mat ur el y, t he  C hief  I n vesti gat or  will  n otif y  t he  R E C,  i ncl u di n g  t he 
r eas o ns f or t he pr e mat ur e ter mi nati o n 
•  Wit hi n o ne year after t he  e n d of t he trial, t he C hief I n v esti gat or will s u b mit a fi nal re p ort wit h 
t he r es ults, i ncl u di n g a n y p u blicati o ns/a bstracts, t o t he R E C 
1 3 . 2 P eer re vie w 
T he  pr ot oc ol  has  u n der g o ne  peer  r e vie w  or ga nise d  b y  Pfizer.  A  c o p y  of  t he  pa nels  fee d bac k  is 
a vaila ble. 
1 3 . 3 P u blic a n d P atie nt I n v ol ve m e nt 
T he  st u d y  has  bee n  desi g ne d  off  t he  bac k  of  a  p u blic  c o ns ultati o n t o  i de ntif y researc h pri orities 
i m p orta nt t o patie nts.9 F urt her t o t his t he p u blic a n d patie nts will be i n v ol ve d i n t he re vie w of t he 
partici pa nt i nf or mati o n s heets t o e ns ur e t he y are eas y t o u n dersta n d a n d i nf or mati ve.  
1 3 . 4 Re g ul at or y c o m pli a nce 
•  T he  trial will n ot c o m me nce u ntil a Cli nical Trial A uth orisati o n ( C T A) is o btai ne d fr o m t he 
M H R A a n d a Fa v o ur a ble R E C a n d H R A o pi ni o n  has bee n gi ve n   
•  T he  pr ot oc ol  a n d  trial  c o n d uct  will  c o m pl y  wit h  t he  Me dici nes  f or  H u ma n  Use  ( Cli nical 
Trials) Re g ulati o ns 2 0 0 4 a n d a n y r ele va nt a me n d me nts  
•  Bef or e t he site ca n enr ol patie nts i nt o t he st u d y, t he C hief I n vesti gat or/ Pri nci pal I n vesti gat or 
or  desi g nee  will  e ns ur e  t hat  a p pr o priate  a p pr o vals  fr o m t he partici pati n g  or ga nisati o n is i n 
place.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 9 9  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
•  F or a n y a me n d me nt t o t he st u d y, t he C hief I n vesti gat or or desi g nee, i n a gree me n t wit h t he 
s p o ns or will s u b mit i nf or mati o n t o t he a p pr o priate b o d y i n or der f or t he m t o iss ue a p pr o val 
f or t he a me n d me nt. T he C hief I n vesti gat or or desi g nee will w or k wit h t he site (N H S R & D 
de part me nt as well as t he st u d y deli ver y tea m) s o t he y ca n p ut t he  necessar y arra n ge me nts i n 
place t o i m ple me nt t he a me n d me nt t o c o nfir m t heir s u p p ort f or t he st u d y as a me n de d.  
1 3 . 5 P r ot oc ol c o m pli a nce 
Pr ot oc ol n o n -c o m plia nces ar e de part ur es fr o m t he a p pr o ve d pr ot oc ol.  
Pr os pecti ve, pla n ne d de viati o ns or wai vers t o t he pr ot oc ol are n ot all o we d u n der t he U K re g ulati o ns 
o n Cli nical Trials a n d m ust n ot be use d e. g. It is n ot acce pta ble t o e nr ol a partici pa nt if t he y d o n ot 
meet t he eli gi bilit y criteria or r estricti o ns s pecifie d i n t he trial pr ot oc ol  
Acci de ntal pr ot oc ol de viat i o ns ca n ha p pe n at a n y ti me. T he y m ust be a de q uatel y d oc u me nte d o n t he 
rele va nt f or ms a n d r e p orte d t o t he C hief I n vesti gat or a n d S p o ns or i m me diatel y.  
Pr ot oc ol de viati o ns s h o ul d be a v oi de d w he ne ver p ossi ble.  
De viati o ns  fr o m  t he  pr ot oc ol  w hic h  ar e  f o u n d  t o  fre q ue ntl y  rec ur  are  n ot  acce pta ble,  will  re q uire 
i m me diate acti o n a n d c o ul d p ote ntiall y be classifie d as a seri o us breac h. 
W he n  a  pr ot oc ol  de viati o n  occ urs,  it  m ust  be  ca pt ure d  o n 
a  pr ot oc ol  de viati o n  l o g a n d  o n  t he 
i n di vi d ual partici pa nt  s o ur ce d oc u me ntati o n, as a p plica ble.  
Maj or pr ot oc ol de viati o ns, defi ne d as de viati o ns t hat c o m pr o mise eit her t he safet y of partici pa nts or 
c o m plia nce wit h C T r e g ulati o ns , r e q uir e e x pe dite d ( wit hi n 2 4 h o urs of disc o ver y) re p orti n g t o t he 
G o ver na nce S p o ns or.  
1 3 . 6 N otific ati o n of seri o us bre ac hes t o G C P a n d/ or t he pr ot oc ol 
A “seri o us br eac h” is a br eac h w hic h is li kel y t o effect t o a si g nifica nt de gree –  
•  T he saf et y or p h ysical or me ntal i nte grit y of t he partici pa nts of t he trial; or  
•  T he scie ntific val ue of t he trial  
T he s p o n s or will be n otifie d i m me diatel y of a n y case w here t he a b o ve defi niti o n a p plies d uri n g t he 
trial c o n d uct p hase 
T he s p o ns or will n otif y t he lice nsi n g a ut h orit y i n writi n g of a n y seri o us breac h of  
•  T he c o n diti o ns a n d pri nci ples of G C P i n c o n necti o n wit h t hat trial; or  
•  T he pr ot oc ol r elati n g t o t hat trial, as a me n de d fr o m ti me t o ti me, wit hi n 7 da ys of bec o mi n g 
a war e of t hat br eac h  
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 0  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 3. 7 D at a pr ot ecti o n a n d p atie nt c o nfi de nti alit y  
All i n vesti gat ors a n d trial site staff m ust c o m pl y wit h t he re q uire me nts of t he Data Pr otecti o n Act 
2 0 1 8  wit h r e gar ds t o t he c ollecti o n, st or a ge, pr ocessi n g a n d discl os ure of pers o nal i nf or mati o n a n d 
will u p h ol d t he Act’s c or e pri nci ples.  
1 3 . 7. 1 P atie nt C o nfi de nti ality 
All i n vesti gat ors will f oll o w et hical a n d le gal practice a n d all i nf or mati o n a b o ut t he st u d y partici pa nts 
will be ke pt strictl y c o nfi de ntial. A n y i nf or mati o n a b o ut a partici pa nt t hat lea ves t he h os pital ( o ur 
site) will ha ve t he na me a n d a d dr ess delete d, s o t hat t he y ca n n ot be rec o g nise d b y it. T his i ncl u des 
data t hat ar e tr a ns mitte d electr o nicall y.  
E ac h  partici pa nt  will  be  all ocate d  a  u ni q ue  st u d y  n u m ber,  w hic h  will  be  use d  f or  rec or di n g 
de m o gr a p hic a n d st u d y data.  
All electr o nic data will be st or e d o n a sec ure ser ver, ma na ge d b y t he U ni versit y of S heffiel d, a n d will 
b e i de ntifia ble o nl y b y t he u ni q ue st u d y n u m ber. Pers o nal c o ntact details will be rec or de d se paratel y, 
a n d  o nl y  be  accessi ble  b y  t he  dir ect  st u d y  tea m.  A n y  i nf or mati o n  i ncl u de d  i n  writte n 
re p orts/ pr ese ntati o ns will n ot i de ntif y partici pa nts b y na me. O nl y t he me m bers of t he researc h tea m 
will ha ve access t o pers o nal i de ntifia ble data.  
1 3 .7 .2  D at a st or a ge  
Pers o nal i de ntifia ble i nf or mati o n ( PII), ca pt ure d o n t he pa per P artici p a nt Scree ni n g, E nr ol me n t & 
C o m pleti o n L o g  a n d R e gistr ati o n F or m ,  will  be hel d  i n  a  st ud y  site  file,  ke pt i n  a  l oc ke d  ca bi net 
wit hi n b ot h t he st u d y office (l oc ke d a n d wit hi n a s wi pe-c ar d restricte d z o ne) a n d t he site researc h 
facilit y.  At  t he  e n d  of  t he  st u d y  all  PII  st ore d  o n  pa per,  e xce pt  t he  i nf or mati o n  ca pt ure d  i n  t he 
P artici p a nt  Scree ni n g,  E nr ol me n t &  C o m pleti o n L o g  a n d  o n  t he  c o nse nt  f or ms,  will  be  destr o ye d 
( wit hi n 1 year of t he e n d of  t he trial). T he P artici p a nt Scree ni n g, E nr ol me n t & C o m pleti o n L o g  a n d 
c o nse nt  f or ms  will  be  ke pt  f or  1 5  years  after  t he  e n d  of  t he  trial  i n  li ne  wit h  c u rre nt  re g ulat or y 
re q uir e me nts. 
C o ntact  details  ca pt ur e d  o n  t he r e gistr ati o n f or m will  be  tra nsferre d  t o  a n  electr o nic  data base  a n d 
st or e d f or a ma xi m u m of 5 years b y t he S heffiel d Der mat ol o g y Researc h gr o u p t o e na ble t he gr o u p 
t o  n otif y  partici pa nts  a b o ut f ut ur e  st u dies. T he  c o nse nt  f or m  i ncl u des  a  li ne  t o  s pecificall y  o btai n 
c o nse nt f or t his ( w her e a partici pa nt d oes n ot pr o vi de t his s pecific c o nse nt, he/s he will n ot be e ntere d 
o nt o  t he  electr o nic  data base).  T he  data base  will  be  pass w or d  pr otecte d  a n d  st or e d  o n  t he  gr o u ps 
filest or e (sec ur e ser ver) wit h access r estricte d t o t he PI a n d t he st u d y dele gates o nl y.  
All pse u d o -a n o n y mise d r esear c h data will be c ollecte d i n pa per or electr o nic f or m wit h pa per rec or ds 
ke pt i n a site file i n a l oc ke d ca bi net a n d elect r o nic rec or ds st ore d o n t he sec ure Pr os pect ( E pi ge n ysis) 
ser ver  a n d/ or  t he  gr o u ps  filest or e  ( CI C S  ma na ge d  sec ure  ser ver  wit h  access  c o ntr ol).  Pse u d o -
a n o n y mise d r esear c h data will be ke pt i n defi nitel y u n der t he c ust o dia ns hi p of t he PI f or p ote ntial use 
i n fut ur e r esearc h a p plicati o ns.  
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 1  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 3 .8  Fi n a nci al a n d ot her c o m peti n g i nt erests  
MJ C , has  bee n/is  a  Cli nical Trial  I n vesti gat or  f or  t he  f oll o wi n g  or ga nisati o ns: At o pi x,  Gala pa g os,  
H y p he ns, J o h ns o n & J o h ns o n, K y ma b, Le o, L' Oreal/ La R oc h e P ossa y,  N o vartis, Pfizer , Re ge ner o n, 
a n d  Sa n ofi -Ge nz y me.  He  is  a n  A d vis or y  B oar d  me m ber,  C o ns ulta nt  &/ or  i n vite d  lect urer  f or  t he 
f oll o wi n g or ga nisati o ns: A b b vie, A mlar, Astellas, At o pi x, B o ots, Der ma va nt, Gala pa g os, Gal der ma, 
H y p he ns,  J o h ns o n  &  J o h ns o n,  K y ma b,  Le o,  L’ Oreal/ La R oc he P ossa y,  Me nl o,  N o vartis,  O xa ge n, 
Pfizer, Pr octer & Ga m ble, Rec kitt Be nc kiser, Re ge ner o n, Sa n ofi -Ge nz y me.  
S G D , has  r ecei ve d f ees f or gi vi n g lect ur es a n d/ or atte n di n g a d vis or y b oar ds a n d u nrelate d researc h 
f u n di n g fr o m Al mir all, Astellas P har ma, Ba yer Der mat ol o g y, Le o P har ma, M S D, Pfizer, a n d Stiefel -
G S K  w h o ma n uf act ur e t o pical a nti -i nfla m mat or y treat me nts f or ecze ma.  
SJ M , N o ne t o declar e 
R T , N o ne t o declar e 
R B , N o ne t o declar e 
1 3 .9  I n de m nit y 
T he f oll o wi n g i n de m nit y pr otecti o n is i n place:  
1.  N H S i n de m nit y p r otecti o n is i n place t o meet t he p ote ntial le gal lia bilit y of t he s p o ns or f or 
har m t o partici pa nts arisi n g fr o m t he ma na ge me nt of t he researc h  
2.  N H S i n de m nit y pr otecti o n is i n place t o meet t he p ote ntial le gal lia bilit y of t he s p o ns or f or 
har m t o partici pa n ts arisi n g fr o m t he desi g n of t he researc h 
3.  N H S a n d U ni versit y of S heffiel d i ns ura nce pr otecti o n is i n place t o meet t he le gal lia bilit y of 
i n vesti gat ors/c olla b or at ors f or ne gli ge nt har m arisi n g fr o m t he c o n d uct of t he st u d y 
4.  Pfizer i n de m nit y pr otecti o n is i n place t o meet t he p ote ntial le gal lia bilit y of t he ma n ufact urer 
f or har m t o partici pa nts arisi n g fr o m a n i n here nt ma n ufact uri n g defect i n t he Pfizer Pr o d uct  
crisa b or ole ( 2 %) oi nt me nt  
1 3 .1 0  A m e n d m e nts  
U n der t he Me dici nes f or H u ma n Use ( Cli nical Trials) Re g ulati o ns 2 0 0 4, t he s p o ns or ma y ma ke  a 
n o n -s u bsta ntial  a me n d me nt  at  a n y  ti me  d uri n g  a  trial. N o n -s u bsta ntial  a me n d me nts  t o  st u d y 
d oc u me nts  i ncl u de d  i n  t he  ori gi nal  Healt h  Researc h  A ut h orit y  ( H R A)  s u b missi o n  pac ka ge  will 
re q uir e H R A a p pr o val bef or e i m ple me ntati o n. If t he s p o ns or wis hes t o ma ke a s u bsta ntial a me n d me nt 
t o t he C T A or t he d oc u me nts t hat s u p p orte d t he ori gi nal a p plicati o n f or t he C T A, t he s p o ns or m ust 
s u b mit  a  vali d  n otice  of  a me n d me nt  t o  t he  lice nci n g  a ut h orit y  ( M H R A) f or  c o nsi derati o n.  If  t he 
sp o ns or wis hes t o ma ke a s u bsta ntial a me n d me nt t o t he R E C a p plicati o n or t he s u p p orti n g d oc u me nts, 
t he s p o ns or m ust s u b mit a vali d n otice of a me n d me nt t o t he R E C a n d t he H R A f or c o nsi derati o n. T he 
M H R A a n d/ or t he R E C will pr o vi de a r es p o nse re gar di n g t he a m e n d me nt wit hi n 3 5 da ys of recei pt 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 2  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
of t he n otice. It is t he s p o ns or’s r es p o nsi bilit y t o deci de w het her a n a me n d me nt is s u bsta ntial or n o n -
s u bsta ntial f or t he p ur p oses of s u b missi o n t o t he M H R A a n d/ or R E C. 
If  a p plica ble,  ot her  s pecialist  r e vie w  b o dies  (e. g. C A G)  nee d  t o  be  n otifie d  a b o ut  s u bsta ntial 
a me n d me nts i n case t he a me n d me nt aff ects t heir o pi ni o n of t he trial.  
1 3 . 1 1 P ost t ri al c are  
Partici pa nts ar e n ot e nr olle d o nt o t his st u d y beca use of t heir nee d f or care (i ncl u di n g t he nee d f or t he 
i nter ve nti o n), an d t her ef or e t her e is n o r e q uire me nt t o pr o vi de o n g oi n g or p ost -trial care ( wit h t he 
e xce pti o n of u nr es ol ve d A E’s).  
1 3 . 1 2 Access t o t he fi n al t ri al d at aset 
T he f oll o wi n g sta ke h ol ders will ha ve access t o t he fi nal, a n o n y mise d, dataset:  
•  T he S p o ns or  
•  T he I n ve sti gat ors at t he Site 
•  T he F u n der, Pfizer I nc.  
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 3  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 4 . DI S S E MI N A TI O N P O LI C Y 
1 4 . 1 Disse mi n ati o n p olic y 
•  T he dat a arisi n g fr o m t his trial will be o w ne d b y t he U ni versit y of S heffiel d  
•  o n c o m pleti o n of t he trial, t he data will be a nal yse d a n d ta b ulate d a n d a Fi nal Trial Re p ort 
pr e par e d  
•  T he i n vesti gat ors ha ve t he ri g ht t o p u blis h a n y of t he trial data  s u bject t o fair re vie w b y t he 
st u d y f u n der as defi ne d i n a se par ate a gree me nt ( 3 0-da y n otice peri o d)  
•  T he F u n der, Pfizer, will be ac k n o wle d ge d wit hi n t he p u blicati o ns f o r t heir s u p p ort 
•  A s u m mar y of t he st u d y fi n di n gs will be s hare d wit h st u d y partici pa nts after t he Fi nal Trial 
Re p ort has bee n c o m pile d a n d t he res ults ha ve bee n p u blis he d  
1 4 .2 Fi n al re p ort  
A dr aft r e p ort will be writte n a n d s u b mitte d t o t he Fi na ncial S p o ns o r f or re vie w a n d c ha n ges ma y be 
ma de t o t he dr aft r e p ort at t he Fi na ncial S p o ns or’s re q uest. U p o n a p pr o val b y t he st u d y tea m a n d t he 
Fi na ncial S p o ns or, t he r e p ort will be fi nalize d. T he fi nal re p ort will i ncl u de ( b ut is n ot li mite d t o) t he 
f oll o wi n g:  st u d y p o p ulati o n  de m o gr a p hics,  statistical  met h o d ol o g y,  res ults,  descri pti o n  of  a d verse 
e ve nts a n d de viati o ns (if a n y), a n d c o ncl usi o ns.  T he re p ort will n ot i ncl u de patie nt le vel st u d y data 
or patie nt i de ntifiers.  
1 4 .3 P u blic ati o n  
Res ults  fr o m  t his  st u d y  ma y  be  p u blis he d  i n  me dical  or  scie ntific  j o ur nals/ b o o ks,  p u blicati o ns, 
pr ese ntati o n materials, or a d vertisi n g materials.  Partici pa nt  na mes a n d i de ntifia ble i nf or mati o n will 
n ot be use d i n t h ose materials or p u blicati o ns.  
 
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 4  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 5 . R E F E R E N C E S 
1  
O d hia m b o J A, Willia ms H C, Cla yt o n T O  et al. Gl o bal variati o ns i n pre vale nce of ecze ma s y m pt o ms 
i n c hil dre n fr o m I S A A C P hase T hree. J Aller gy Cli n I m m u n ol  2 0 0 9; 1 2 4 : 1 2 5 1-8 e 2 3.  
2  
Kerr O A, Ti d ma n MJ, Wal ker JJ  et al. T he pr ofile of der mat ol o gical pr o ble ms  i n pri mar y care. Cli n 
Ex p Der m at ol  2 0 1 0; 3 5 : 3 8 0-3.  
3  
C or k MJ, Da n b y S G, Vasil o p o ul os Y  et al.  E pi der mal barrier d ysf u ncti o n i n at o pic der matitis. J I nvest 
Der m at ol  2 0 0 9; 1 2 9 : 1 8 9 2-9 0 8.  
4  
P u ne kar Y S, S hei k h A. Esta blis hi n g t he se q ue ntial pr o gressi o n of m u lti ple aller gic dia g n oses i n a U K 
birt h c o h ort usi n g t he Ge neral Practice R esearc h Data base. Cli n Ex p Aller gy  2 0 0 9; 3 9 : 1 8 8 9-9 5.  
5  
G u pta R, S hei k h A, Strac ha n D P  et al. B ur de n of aller gic disease i n t he U K: sec o n dar y a nal yses of 
nati o nal data bases. Cli n Ex p Aller gy  2 0 0 4; 3 4 : 5 2 0-6.  
6  
Le wis -J o nes  S,  C or k  MJ,  Clar k  C et  al. At o pic  ecze ma  i n  c hil dre n - G ui deli ne  c o ns ultati o n:  A 
s yste matic re vie w of t he treat me nts f or at o pic ecze ma a n d g ui deli ne f or its ma na ge me nt. I n: Nati o nal 
I nstit ute f or Cli nical E xcelle nce ( NI C E), De part me nt of Healt h. 2 0 0 7. 
7  
He n g ge U R, R uzic ka T, S c h wartz R A  et al. A d verse effects of t o pical gl uc oc ortic oster oi ds. J A m Ac a d 
Der m at ol  2 0 0 6; 5 4 : 1-1 5; q uiz 6 -8.  
8  
S c h mitt J, v o n K o b yletz ki L, S ve nss o n A  et al. Efficac y a n d t olera bilit y of pr oa cti ve treat me nt wit h 
t o pical  c ortic oster oi ds  a n d  calci ne uri n  i n hi bit ors  f or  at o pic  ecze ma:  s yste matic  re vie w  a n d  meta-
a nal ysis of ra n d o mize d c o ntr olle d trials. Br J Der m at ol  2 0 1 1; 1 6 4 : 4 1 5-2 8.  
9  
Batc hel or  J M,  Ri d d  MJ,  Clar ke  T  et  al.  T he  ecze ma  Pri orit y  S e tti n g  P art ners hi p:  A  c olla b orati o n 
bet wee n  patie nts,  carers,  cli nicia ns  a n d  researc hers  t o  i de ntif y  a n d  pri oritize  i m p orta nt  researc h 
q uesti o ns f or t he treat me nt of Ecze ma. Britis h J o ur n al of Der m at ol o gy  2 0 1 3; 1 6 8 : 5 7 7-8 2.  
1 0  
B yers  R,  Maiti  R,  Da n b y  S G  et al.  S u b -cli nical  assess me nt  of  at o pic  der matitis  se verit y  usi n g 
a n gi o gra p hic o ptical c o here nce t o m o gra p h y Bi o me dic al o ptics ex press  2 0 1 8; U n d er re vie w . 
1 1  
Ma nsfiel d J C, Wi nl o ve C P, M o ger J  et al. C olla ge n fi ber arra n ge me nt i n n or mal a n d disease d cartila ge 
st u die d b y p olarizati o n se nsiti ve n o nli near micr osc o p y. J Bi o me d O pt  2 0 0 8; 1 3 : 0 4 4 0 2 0. 
1 2  
U gr y u m o va  N,  Jac o bs  J,  B o nesi  M  et  al.  N o vel  o ptical  i ma gi n g  tec h ni q ue  t o  deter mi ne  t he  3 -D 
orie ntati o n  of  c olla ge n  fi bers  i n  cartila ge:  varia ble -i nci de nce  a n gle  p olarizati o n-se nsiti ve  o ptical 
c o here nc e t o m o gra p h y. Oste o art hritis a n d c artil a ge / O A R S, Oste o art hritis Rese arc h S ociety  2 0 0 9; 
1 7 : 3 3-4 2.  
1 3  
Da n b y S, Br o w n K, Hi g gs -B a yliss T  et al. T he effect of a c o m ple x e m ollie nt crea m c o ntai ni n g 5 % 
urea, cera mi de 3 a n d la ctic aci d, c o m pare d wit h a si m ple e m ollie nt, o n t he s ki n barrier i n ol der pe o ple 
wit h dr y s ki n. Britis h J o ur n al of Der m at ol o gy  2 0 1 4; 1 7 1 : 5 7. 
1 4  
Da n b y S G, Wa n H, C hitt oc k J  et al. C haracterisati o n of t he s ki n barrier defect i n at o pic der matitis 
usi n g i n vi v o A T R -F TI R m olec ular s pectr osc o p y. J I nvest Der m at ol 2 0 1 6; 1 3 6 : S 1 8 2. 
1 5  
B o nc he va  M,  Da mie n  F,  N or ma n d  V.  M olec ular  or ga nizati o n  of  t he  li pi d  matri x i n  i ntact  Strat u m 
c or ne u m usi n g A T R -F TI R s pectr osc o p y. Bi oc hi mic a et bi o p hysic a act a  2 0 0 8; 1 7 7 8 : 1 3 4 4-5 5.  
1 6  
Da mie n F, B o nc he va M. T he e xte nt of ort h or h o m bic li pi d p hases i n t he strat u m c or ne u m deter mi nes 
t he barrier efficie nc y of h u ma n s ki n i n vi v o. J I nvest Der m at ol  2 0 1 0; 1 3 0 : 6 1 1-4.  
1 7  
C hitt oc k  J,  Br o w n  K,  C or k  M  et  al.  C o m pari n g  t he  Effect  of  a  T wice -We e kl y  Tacr oli m us  a n d 
Beta met has o ne Valerate D ose o n t he S u bcli nical E pi der mal B arrier Defe ct i n At o pic Der matitis. Act a 
Der m at o Ve nere ol o gic a  2 0 1 4: 0.  
1 8  
Da n b y S, C hitt oc k J, Br o w n K  et al.  T he Effect Of Tacr oli m us C o m pare d T o B eta met has o ne Valerate 
O n T he S ki n B arrier I n V ol u nteers Wit h Q uiesce nt At o pic Der matitis. Britis h J o ur n al of Der m at ol o gy  
2 0 1 4; 1 7 0 : 9 1 4-2 1.  
1 9  
Kezic S, O' R e ga n G M, Ya u N  et al. Le vels of fila g gri n de gra dati o n pr o d ucts are i nfl ue nce d b y b ot h 
fila g gri n ge n ot y pe a n d at o pic der matitis se verit y. Aller gy  2 0 1 1; 6 6 : 9 3 4-4 0.  
2 0  
L u  Z,  B oa di  J,  Da n b y  S  et  al.  O ptical  c o here nce  t o m o gra p h y  de m o nstrates  differe ntial  e pi der mal 
t hi n ni n g of h u ma n f orear m v olar s ki n after 2 wee ks a p plicati o n of a t o pical c ortic oster oi d vs a n o n-
ster oi dal a nti-i nfla m mat or y alter nati ve. Pr oc. S PI E  2 0 1 3; 8 5 6 5 : 8 5 6 5 0 C. 
2 1  
Da n b y S G, C hitt oc k J, Br o w n K  et al. T he effect of tacr oli m us c o m pare d wit h beta met has o ne valerate 
o n t he s ki n barrier i n v ol u nteers wit h q uiesce nt at o pic der matitis. Br J Der m at ol  2 0 1 4; 1 7 0 : 9 1 4-2 1.  
2 2  
L u Z, Kasara g o d D, Matc her SJ. C o nical sca n p olarizati o n -se nsiti ve o ptical c o here nce t o m o gra p h y. 
Bi o me dic al o ptics ex press  2 0 1 4; 5 : 7 5 2-6 2.  

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 5  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
2 3  
I m h of  R E,  De  Jes us  M E,  Xia o  P et  al. Cl ose d -c ha m ber  tra nse pi der mal  water  l oss  meas ure me nt: 
micr ocli mate, cali brat i o n a n d perf or ma nce. I nt J C os met Sci 2 0 0 9; 3 1 : 9 7-1 1 8.  
2 4  
C hitt oc k  J,  Br o w n  K,  C or k  MJ  et  al. C o m pari n g  t he  Effect  of  a  T wice -wee kl y  Tacr oli m us  a n d 
Beta met has o ne Valerate D ose o n t he S u bcli nical E pi der mal B arrier Defe ct i n At o pic Der matitis. Act a 
Der m Ve n ere ol  2 0 1 5; 9 5 : 6 5 3-8.  
2 5  
C hitt oc k J, C o o ke A, La ve n der T  et al.  De vel o p me nt of strat u m c or ne u m c h y m otr y psi n -li ke pr otease 
acti vit y  a n d  nat ural  m oist urizi n g  fact ors  fr o m  birt h  t o  4  wee ks  of  a ge  c o m par e d  wit h  a d ults. Br  J 
Der m at ol  2 0 1 6.  
2 6  
Da n b y S, Al E nezi  T, S ulta n A  et al. T he effect of A q ue o us crea m B P o n t he s ki n barrier i n v ol u nteers 
wit h a pre vi o us hist or y of at o pic der matitis. Br J Der m at ol  2 0 1 1; 1 6 5 : 3 2 9-3 4.  
2 7  
Da n b y S G, Al E nezi T, S ulta n A  et al.  Effect of oli ve a n d s u nfl o wer see d oil o n t he a d ult s ki n barrier: 
i m plicati o ns f or ne o natal s ki n care. Pe di atric der m at ol o gy  2 0 1 3; 3 0 : 4 2-5 0.  
2 8  
Da n b y S G, Br o w n K, Hi g gs -B a yliss T  et al. T he Effect of a n E m ollie nt C o ntai ni n g Urea, C era mi de 
N P,  a n d  Lactate  o n  S ki n  B arrier  Str uct ure  a n d  F u ncti o n  i n  Ol der  P e o p le  wit h  Dr y  S ki n. Ski n 
p h ar m ac ol o gy a n d p hysi ol o gy  2 0 1 6; 2 9 : 1 3 5-4 7.  
2 9  
B o nc he va  M,  Da mie n  F,  N or ma n d  V.  M olec ular  or ga nizati o n  of  t he  li pi d  matri x i n  i ntact  Strat u m 
c or ne u m usi n g A T R -F TI R s pectr osc o p y. Bi oc hi m Bi o p hys Act a  2 0 0 8; 1 7 7 8 : 1 3 4 4-5 5.  
3 0  
Bra ncale o n L, B a m ber g M P, S a ka ma ki T  et al. Atte n uate d t otal reflecti o n -F o urier tra nsf or m i nfrare d 
s pectr osc o p y as a p ossi ble met h o d t o i n vesti gate bi o p h ysical para meters of strat u m c or ne u m i n vi v o. 
J I nvest Der m at ol  2 0 0 1; 1 1 6 : 3 8 0-6.  
3 1  
Ri n g A, S c hrei ner V, We nc k  H  et al. Mi d -i nfrare d s pectr osc o p y o n s ki n usi n g a sil ver hali de fi bre 
pr o be i n vi v o. Ski n Res T ec h n ol  2 0 0 6; 1 2 : 1 8-2 3.  
3 2  
Ta ka da S, Nait o S, S o n o da J  et al. N o ni n vasi ve I n Vi v o Meas ure me nt of Nat ural M oist urizi n g Fact or 
C o nte nt i n Strat u m C or ne u m of H u ma n S ki n b y Atte n uate d T otal R eflecti o n I nfrare d S pectr osc o p y. 
A p plie d S pectr osc o py  2 0 1 2; 6 6 : 2 6-3 2.  
3 3  
C o o ke A, C or k MJ, Vict or S  et al. Oli ve Oil, S u nfl o wer Oil or n o Oil f or B a b y Dr y S ki n or Massa ge: 
A  Pil ot,  Assess or -bli n de d,  R a n d o mize d  C o ntr olle d  Trial (t he  Oil  i n  B a b y  S ki nca R E  [ O B S e R v E] 
St u d y). Act a der m at o -ve nere ol o gic a  2 0 1 6; 9 6 : 3 2 3-3 0.  
3 4  
Ka o J S, Fl u hr J W, Ma n M Q  et al.  S h ort -ter m gl uc oc ortic oi d treat me nt c o m pr o mises b ot h per mea bilit y 
barrier h o me ostasis a n d strat u m c or ne u m i nte grit y: i n hi biti o n of e pi der mal li pi d s y nt hesis acc o u nts 
f or f u ncti o nal a b n or malities. J I nvest Der m at ol 2 0 0 3; 1 2 0 : 4 5 6-6 4.  
 
 
 

S heffiel d Der mat ol o g y Researc h  
 
T he S M A R T St u d y  
S M A R T St u d y 1 Pr ot oc ol V 5. 0 _ 2 7Ja n 2 1. d oc x , I R A S 2 6 9 4 1 5 
Pa ge 1 0 6  of 1 0 6  
T his d oc u me nt is c o nfi de ntial –  N o part of it ma y  be tra ns mitte d, r e pr o d uc e d, or use d b y ot her pers o ns wit h o ut 
pri or writte n a ut h orisati o n fr o m T he U ni versit y Of S heffiel d.  
 
1 6 . A P P E N DI X  
A p pe n di x A : Ris k assess m e nt  
A p pe n di x B : List of s per at e d oc u m e nts  rel ati n g t o t his tri al 
•  S M A R T A 4 P oster  
•  S M A R T La n dsca pe A d vert  
•  S M A R T Par tici pa nt I nf or mati o n L eaflet ( PI L) 
•  S M A R T Partici pa nt I nf or mati o n S heet  a n d C o nse nt F or m  
A p pe n di x C: List of I M P i nf or m ati o n a v ail a ble as se p ar ate d oc u me nts  
•  Bet n o vate cr ea m Pr o d uct I nf or mati o n Leaflet  
•  Bet n o vate cr ea m S m P C  
•  F D A s u m mar y r e vie w o n Crisa b or ole ( 2 %) oi nt me nt  
•  Crisa b or ole P F -0 6 9 3 0 1 6 4 I B  
A p pe n di x D: Pfizer s af et y re p orti n g m ateri al  a v ail a ble as se p ar ate d oc u me nts  
•  I n vesti gat or i nitiate d r esear c h S A E f or m g ui de  
•  Saf et y Re p orti n g Ref er e nce Ma n ual  
•  Fa x  c o ver  s heet 
•  Seri o us  A d verse  E ve nt  Re p ort  F or m