Clinical trial NCT04194814
Conditions: Atopic Eczema/Dermatitis (Non-Specific)
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
Start date: 2020-11-20; Completion date: 2021-09-30
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study aims to investigate two new non-invasive technologies for assessing skin properties to identify and validate a range of safety biomarkers that may be considered useful as primary outcome measures for evaluating the safety of topical treatments in atopic dermatitis. The method of assessing these biomarker technologies will be to determine whether twice daily treatment with crisaborole (2%) ointment, compared to betamethasone valerate (0.1%) cream, for up to 4 weeks, may cause skin structure or function changes, like skin atrophy, in patients with atopic dermatitis (AD).

Detailed description:
The first-line drug treatment for mild-moderate AD are currently topical corticosteroids (TCS) with recognized efficacy. However, their prolonged or inappropriate use, can lead to local adverse effects. Side-effects of topical corticosteroids comprise a variety of skin changes in the sense of skin atrophy thinning of the skin and in some cases development of telangiectasia, spontaneous scars, folliculitis, striae distensae (stretch marks), contact dermatitis, acne or rosacea depending on potency, galenic formulation, patient age and body area to which the medication will be applied, exposure time.

Assessing the safety (local adverse effects) of current or new treatments and new treatment approaches using existing treatments through noninvasively monitor on possible early skin (subclinical) changes associated with the local clinical adverse effects of treatment may be an effective step for an enhanced AD treatment management.

Primary Aim: To further develop and validate two new non-invasive technologies for the assessment of early sub-clinical skin changes associated with adverse effects and to derive an optimum panel of safety biomarkers for use in future clinical trials of topical anti-inflammatory treatments.

The safety of two topical anti-inflammatory treatments for AD will be compared in this clinical trial, with a focus on early sub-clinical signs: crisaborole 2% ointment and betamethasone valerate 0,1% cream. Step 1 involves the collection of data on the early sub-clinical skin changes using the non-invasive technologies: OCT and FTIR spectroscopy. The data from this study will then be used to identify and refine biophysical biomarkers of skin atrophy and skin barrier disruption in steps 2 and 3.

Secondary Aim: To determine the relative local skin effects of crisaborole (2%) ointment compared to a potent and moderately potent TCS in participants with mild to moderate AD. The focus is on 'early biomarkers' of 'local skin changes'and not clinical efficacy, which has been established in previous trials.

Rationale for selecting the two comparators are related to prescription behaviors in UK (Betamethasone valerate 0,1% cream) and with no reported TCS-like local adverse effects profile (crisaborole 2% ointment)

Arms: arm 1: crisaborole (2%) ointment on the other forearm, twice daily application for 4 weeks (randomised site allocation)

betamethasone valerate (0.1%) cream on one forearm, twice daily application for 4 weeks (randomised site allocation)
Interventions: intervention 1: crisaborole (2%) ointment intervention 2: betamethasone valerate 0.1% cream
Intervention descriptions: intervention 1: twice daily application on one forearm for 4 weeks (randomised site allocation) intervention 2: twice daily application on one forearm for 4 weeks (randomised site allocation)

Protocol documents:
ICF_002.pdf: 
S h effi el d D er m at ol o g y R es e ar c h
T h e S M A R T St u d y
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P a g e 1
S ki n bi o M A R k ers f or at o pi c e c z e m a T h er a p y e v al u ati o n: 
P ati e nt I nf or m ati o n S h e et a n d I nf or m e d C o ns e nt F or m
St u d y Titl e
V ali d ati o n of a n o v el c o m p osit e of s ki n bi o m ar k ers as a pri m ar y o ut c o m e 
m e as ur e f or e v al u ati n g t h e s af et y of tr e at m e nts f or at o pi c d er m atitis: a 
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Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 2  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
P art 1 t ells yo u t h e p ur pos e of t his st u d y a n d w h at will h a p p e n to yo u if yo u t a k e p art.  
P ar t 2 gi v es y o u m or e d e t ail e d i nf or m a ti o n a b o u t t h e s t u d y.  
P A R T 1  
W h a t a r e w e t r yi n g t o fi n d o u t ?  
T h e  first -c h oic e  dr u g  tr e at m e nt  f or  mil d-m o d er at e  ecz e m a  is  c urr e ntl y  a  t o pic al 
c ortic ost er oi d,  li k e B et a m et h as o n e  v al er at e cr e a m. B y  t o pic al,  w e  m e a n  t h e  tr e at m e nt  is 
i nt e n d e d  f or  a p plic ati o n  dir ectl y  t o  t h e  s ki n. W hilst t o pic al  c ortic ost er oi ds ar e  eff ect i v e  at 
tr e ati n g ecz e m a, t h e y h a v e b e e n f o u n d t o c a us e u n w a nt e d  s ki n c h a n g es, s uc h as s ki n t hi n ni n g, 
if us e d i n a p pr o pri at el y o v er l o n g p eri o ds of ti m e. Ex actl y h o w m uc h u n w arr a nt e d t hi n ni n g is 
c a us e d  b y  diff er e nt  tr e at m e nt r o uti n es is  u ncl e ar,  s o  we  w a nt  t o  i d e ntif y  s o m e  s ki n  bi o-
m ar k ers of s ki n t hi n ni n g . W e ar e s p ecific all y l o o ki n g f or e arl y s ki n d a m a g e si g n als t h at m a y 
a p p e ar b ef or e  a d v ers e eff ects c a n b e o bs er v e d i n t h e cli nic. T his will b e d o n e b y usi n g n o n -
i n v asi v e s ki n i m a gi n g t ec h ni q u es t h at ar e si milar t o ultr as o u n d.  
T o pic al c ris a b or ol e oi nt m e nt is a n e w n o n -st er oi d al dr u g tr e at m e nt f or ecz e m a t h at a p p e ars 
t o b e as eff ecti v e as s o m e t o pic al c ortic ost er oi ds, a n d is n ot ex p ect e d t o c a us e a b n or m al s ki n 
t hi n ni n g. A c o m p aris o n b et w e e n cris a b or ol e a n d a t o p ic al c ortic ost er oi d is t h er ef or e a g o o d  
w a y  t o  fi n d i m p ort a nt s ki n  m ar k ers. B et a m et h as o n e  v al er at e  cr e a m  is o n e  of t h e  m ost 
c o m m o nl y  pr escri b e d  t o pic al  c ortic ost er oi d s f or  ecz e m a  i n  t h e  U K.  B ot h  cris a b or ol e  a n d 
b et a m et h as o n e v al er at e h a v e alr e a d y b e e n t est e d i n cli nic al tri als f or cli nic al effic ac y, a n d s o 
effic ac y will n ot b e ass ess e d a g ai n h er e . T his st u d y will c o nfir m w h et h er or n ot cris a b or ol e 
c a us es t h e s a m e u n w arr a nt e d  s ki n  t hi n ni n g c a us e d  b y b et a m et h as o n e  v al er at e  i n  a  dir ect 
c o m p aris o n of t h e t wo tr e at m e nts . H a vi n g a b ett er u n d erst a n di n g of t h e u n w a nt e d eff ects of 
t h es e tr e at m e nts will b e i nf or m ati v e f or pr escri b ers/ d oct ors a n d p ati e nts . 
W h y h a v e I b e e n i n vi t e d ?  
Y o u ar e b ei n g i n vit e d t o t a k e p art b ec a us e y o u ar e o v er t h e a g e of 1 8 y e ars a n d h a v e r ec e ntl y 
s uff er e d fr o m ecz e m a ( als o k n o w n as d er m atitis). B y t his w e m e a n t h at y o u h a v e ex p eri e nc e d 
s y m pt o ms or dis pl a y e d si g ns of t his itc h y s ki n c o n diti o n wit hi n t h e p ast 1 2 m o nt hs. Y o u d o 
n ot n e e d t o h a v e visi bl e si g ns of ecz e m a at t h e m o m e nt.  
W e ar e s p ecific all y l o o ki n g f or p e o pl e w h o ar e ‘cl e ar’ or ‘ al m ost cl e ar’ of t h e si g ns of ecz e m a 
o n t h eir f or e ar ms b as e d o n a n ass ess m e nt b y t h e st u d y i n v esti g at or (si g ns of ecz e m a i n t h e 
ar e as ar o u n d t h e f or e ar m, i ncl u di n g t h e el b o w fl ex ur e ar e fi n e). Ass essi n g t h is is pr o n e t o 
diff er e nt i nt er pr et ati o ns, s o if y o u w o ul d li k e t o t a k e p art pl e as e f e el fr e e t o g et i n t o uc h a n d 
t h e st u d y i n v esti g at or will b e h a p p y t o m a k e t h e ass ess m e nt. 
D o I h a v e t o t a k e p a r t ?  
N o. It is u p t o y o u w h et h er y o u w o ul d li k e t o t a k e p art. Co nsi d er t h e i nf or m ati o n i n t his s h e et 
t o h el p y o u d eci d e, a n d f e el fr e e t o c o nt act us if y o u h a v e a n y q u esti o ns. If y o u d o d eci d e t o 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 3  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
t a k e p art y o u ar e fr e e t o wit h dr a w at a n y ti m e, wit h o ut gi vi n g a r e as o n - j ust l et a m e m b er of 
t h e st u d y t e a m k n o w of y o ur wis h t o wit h dr a w.  
W h a t will h a p p e n i f I t a k e p a r t ?  
A n o v er vi e w of t h e st u d y is pr es e nt e d i n t h e 
fl o w-di a gr a m  b el o w ,  wit h  f urt h er  d et ail 
pr o vi d e d b el o w.  
Pr e - s cr e e ni n g p h o n e c all ( a p pr o x. 5- 1 0 
mi n) : T h e  first  st e p  will  b e  t o  arr a n g e  a 
p h o n e  c all  wit h  y o u  s o  t h at  w e  c a n 
d et er mi n e  h o w  li k el y  it  is  t h at  y o u  ar e 
eli gi bl e  t o  t a k e  p art  i n  t h e  st u d y .  W e’ll  d o 
t his b y  as ki n g  y o u  a  c o u pl e  of  q u esti o ns, 
i ncl u di n g q u esti o ns a b o ut y o ur s ki n h e alt h. 
If  it  l o o ks  li k e  y o u  m a y  b e  eli gi bl e  w e  will 
arr a n g e  f or  s o m e o n e  fr o m  t h e st u d y  t e a m 
t o c o nt act y o u t o b o o k y o ur scr e e ni n g a n d 
c o ns e nt visit at a c o n v e ni e nt ti m e f or y o u . 
Y o u will b e off er e d a c o m pli m e nt ar y t axi t o  
a n d fr o m  t h e t est sit e. Pl e as e n ot e t h at w e 
c a n n ot  f ull y  ass ess  y o ur  eli gi bilit y  t o  t a k e 
p art  o v er  t h e  p h o n e,  a n d  s o  c a n n ot 
g u ar a nt e e y o u a pl ac e o n t h e st u d y.  
S cr e e ni n g & C o ns e n t Visi t ( a p pr o x. 3 0 -
6 0  mi n):  A  m e m b er of t h e st u d y t e a m  will 
pr o vi d e  a n  o v er vi e w  of  t h e  st u d y  a n d 
a ns w er  a n y  q u esti o ns  y o u  m a y  h a v e. Y o u 
will  t h e n  b e  as k e d  t o  si g n  a  c o ns e nt  f or m, 
a n d y o u will b e gi v e n  a c o p y of t h e f or m t o 
k e e p.  T h e n w e’ll  d et er mi n e w h et h er  y o u 
m e et t h e crit eri a t o t a k e p art i n t his st u d y  
b y:  
•  A s ki n g y o u  a  s eri es  of  q u esti o ns, 
i ncl u di n g  q u esti o ns  a b o ut  y o ur  h e alt h 
a n d a n y m e dici n es y o u m a y t a k e .  
•  P erf or mi n g  a p h ysic al  ex a mi n ati o n  of  y o ur  s ki n  t o  gr a d e  t h e  s e v erit y  of  y o ur  ecz e m a  
o v er all . T h e d er m at ol o gist will n e e d t o s e e t h e si g ns of ecz e m a o n y o ur b o d y t o ass ess its 
s e v erit y.  
•  As ki n g  f e m al e  p artici p a nts  t o  t a k e  a  pr e g n a nc y  t est  a n d  u n d ert a k e  a  r eli a bl e  f or m  of 
c o ntr ac e pti o n f or t h e d ur ati o n of t h e st u d y (f urt h er d et ails b el o w).  
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 ays 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 ay 2 2 ± 3
Tr e at m e nt c h ec k


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 4  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
If y o u ar e eli gi bl e t o t a k e p art t h e st u d y t e a m will t h e n arr a n g e y o ur s t u d y visits wit h y o u. W e 
will als o n otif y y o ur G P of y o ur i n v ol v e m e nt i n t h e st u d y; t his is st a n d ar d pr actic e f or a cli nic al 
st u d y li k e t his. 
W as h - o u t:  S o m e p artici p a nts, w h o ar e c urr e ntl y usi n g tr e at m e nts f or ecz e m a, will n e e d t o 
u n d er g o a ‘ w as h o ut’ p eri o d, w h er e t h e us e of t h es e tr e at m e nts is st o p p e d, pri or t o t h e first 
st u d y visit. T h e d ur ati o n of t h e w as h-o ut d e p e n ds o n t h e t y p e of tr e at m e nt , a n d v ari es fr o m 
7 d a ys f or e m olli e nts t o 1 2 w e e ks f or i ntr a v e n o us bi ol o gic t h er a pi es .  
W e a p pr eci at e t h at t his m a y b e c h all e n gi n g f or p ati e nts wit h m or e s e v er e ecz e m a a n d as k 
t h at y o u disc uss y o ur t o pic al tr e at m e nt n e e ds wit h a m e m b er of t h e st u d y t e a m pri or t o y o ur 
visit. Y o u c a n w as h y o ur s ki n as n or m al.  
Visi t 1, D a y 1 ( a p pr o x. 2. 5 - 3 h o urs ):  If y o u'v e u n d er g o n e a w as h -o ut p eri o d w e’ll n e e d 
t o r ec o nfir m eli gi bilit y at t h e st art of t his visit ( a p pr ox. 3 0 mi n) .  
T h e  s ki n  sit es  w e  ar e  i nt er est e d  i n  ar e  y o ur  f or e ar ms.  At  e ac h  visit  w e  will  as k  y o u  t o 
accli m atiz e t h e s ki n o n y o ur f or e ar ms t o t h e r o o m c o n diti o ns f or 2 0 mi n ut es. Pl e as e w e ar 
a p pr o pri at e  cl ot hi n g  f or  t his  (i. e.  s h ort  sl e e v es).  W e  will  n e e d  t o  m ar k  o ut  s e v er al 
m e as ur e m e nt sit es o n e ac h of y o ur ar ms usi n g a m ar k er p e n ( as discr e etl y as p ossi bl e). T h e 
m ar k er is e asil y r e m o v e d b y w as hi n g t h e s ki n at t h e e n d of t h e st u d y  visit . H air d o es i nt erf er e 
wit h t h e m e as ur e m e nts, s o if y o u h a v e h air o n y o ur ar ms w e m a y n e e d t o tri m it.  
O nc e accli m atis e d w e will ass ess t h e c o n diti o n of y o ur s ki n i n a n u m b er of w a ys , all of w hic h 
ar e n o n -i n v asi v e (s e e “w h at pr oc e d u r es will w e d o ?” b el o w  f or f urt h er i nf or m ati o n). W e will 
t h e n c oll ect  a  m o ut h  s w a b  s a m pl e  a n d  pr o vi d e  y o u  wit h  t h e t w o st u d y  tr e at m e nts 
(B et a m et h as o n e v al er at e cr e a m a n d Cris a b or ol e oi nt m e nt ) a n d a tr e at m e nt di ar y t o r ec or d 
y o ur us a g e. Y o u’ll n e e d t o a p pl y  b ot h t h e tr e at m e nts t o diff er e nt  ar e as o n y o ur ri g ht a n d l eft 
f or e ar ms t wic e d ail y f or 4 w e e ks. T h e s ki n sit e all oc ati o n (ri g ht/l eft) will b e r a n d o m.  
W hilst t a ki n g p art i n t h e st u d y, p artici p a nts s h o ul d c o ns ult wit h t h e st u d y t e a m b ef or e usi n g 
a n y ot h er m e dic ati o ns.  
Visi ts 2 - 5  a n d 6 a , D a ys 1 t o 1 2  a n d d a y 2 2 ± 3 d a ys  ( a p pr o x. 2 0 mi n e a c h):   W e 
n e e d t o m o nit or y o ur tr e at m e nt us a g e o n 4 occ asi o ns d uri n g t h e first 2 w e e ks . T his m e a ns 
att e n di n g t h e t est c e ntr e s o t h at w e c a n w ei g h y o ur tr e at m e nts, r e vi e w y o ur tr e at m e nt di ar y 
a n d o bs er v e y o u m a ki n g a  s ki n a p plic ati o n.  T h e sc h e d uli n g of t h es e visits is fl exi bl e d uri n g t h e 
first 1 2 d a ys of tr e at m e nt. 
S o  t h at  w e  c a n  o bs er v e  y o u  a p pl yi n g  t h e  tr e at m e nts  w e  will  s e n d  y o u  r e mi n d ers  b y  t ext 
m ess a g e ( or t el e p h o n e c a ll if y o u pr ef er) t o n ot a p pl y t h e st u d y tr e at m e nts i n t h e m or ni n g 
b ef or e visits 2 -7.  
Visi t 6 ,  D a y 1 5  + / -  3  d a ys  ( a p pr o x. 2. 5  h o urs ): At t his visit w e will r e p e at t h e s a m e 
pr oc e d ur es as i n visit 1 , exc e pt w e will n ot n e e d t o c oll ect a n ot h er m o ut h s w a b s a m pl e. 
Visi t 7 ,  D a y 2 9  + / -  3  d a ys  ( a p pr o x. 3  h o urs ): At  t his  visit  w e  will  r e p e at  t h e  s a m e 
pr oc e d ur es  as  i n  visit 6 a n d a d diti o n all y c oll ect a  s a m pl e of  y o ur  d e a d  s ki n  c ells  b y  usi n g 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 5  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
a d h esi v e discs  (li k e S ell ot a p e) i n a pr oc ess c all e d t a p e-stri p pi n g (s e e “ w h at s a m pl es will w e 
c oll ect ?” f or f urt h er i nf or m ati o n). Tr e at m e nt st o ps at t his p oi nt, s o y o u’ll n e e d t o r et ur n y o ur 
di ar y a n d us e d tr e at m e nts.  
Visi t 8 ,  D a y 5 7  + / -  4  d a ys  ( a p pr o x. 2. 5  h o urs ): At t his visit w e will r e p e at t h e s a m e 
pr oc e d ur es as i n visit 6 . 
P r e g n a n c y t e s ti n g a n d c o n t r a c e p ti o n c h e c k s f o r f e m al e p a r ti ci p a n t s  
T h er e is n o e vi d e nc e t o s u g g est t h at cris a b or ol e oi nt m e nt c a n n ot b e us e d d uri n g pr e g n a nc y. 
H o w e v er, si nc e t his dr u g is n e w a n d its us e h as n ot y et b e e n t est e d i n pr e g n a nt w o m e n , w e 
ar e t a ki n g t h e pr ec a uti o n ar y m e as ur e of e ns uri n g p artici p a nts ar e n ot pr e g n a nt a n d d o n ot 
b ec o m e  pr e g n a nt  d uri n g  t h e  st u d y.  T his  m e a ns  f e m al e  p artici p a nts  will  b e  r e q uir e d  t o 
u n d ert a k e  a  uri n e  pr e g n a n c y  t est  b ef or e,  d uri n g  a n d  aft er  t h e  st u d y.  T h e  t est  kit  will  b e 
pr o vi d e d.  I n  a d diti o n , all  f ertil e  f e m al e  p artici p a nts  w h o  ar e s ex u all y  acti v e  a n d  at  ris k  f or 
pr e g n a nc y  m ust  a gr e e  t o  us e  a  hi g hl y  eff ecti v e  m et h o d  of  c o ntr ac e pti o n  c o nsist e ntl y  a n d 
c orr ectly f or  t h e scr e e ni n g p eri o d, t h e d ur ati o n of t h e acti v e tr e at m e nt p eri o d a n d f or at l e ast 
2 8  d a ys aft er t h e l ast d os e of st u d y tr e at m e nt. T h e st u d y i n v esti g at or will disc uss t h e o pti o ns 
f or c o ntr ac e pti o n wit h p artici p a nts as a p pr o pri at e d uri n g t h e scr e e ni n g visit.  
W h a t p r o c e d u r e s will w e d o ?  
W e will c oll ect i nf or m ati o n i n s e v er al w a ys, usi n g a r a n g e of n o n -i n v asi v e t ec h ni q u es…  
Vis u al ass ess m e n t  
T his will i n v ol v e l o o ki n g at t h e c o n diti o n of y o ur s ki n b y e y e, if y o ur s ki n h as si g ns of ecz e m a 
t his will i n v ol v e gr a di n g h o w s e v er e t h e l esi o n(s) a p p e ar t o b e. W e will p erf or m b ot h a l oc al 
(j ust at t h e t esti n g sit es) a n d w h ol e -b o d y  ass ess m e nt  of t h e ext e nt a n d s e v erit y of ecz e m a . 
F or t h e w h ol e -b o d y ass ess m e nt, t h e d er m at ol o gist will n e e d t o s e e t h e si g ns of e cz e m a o n 
y o ur b o d y t o ass ess its s e v erit y.  
2 D p h o t o gr a p hs   
T his  i n v ol v es  pl aci n g  a  h a n d h el d c a m er a pr o b e  g e ntl y 
a g ai nst  y o ur  s ki n  at  t h e  i m a gi n g  sit es  f or  a  f e w  s ec o n ds. 
T his t ec h ni q u e c a pt ur es ‘p h ot o gr a p hs ’ of y o ur s ki n usi n g a 
hi g h -d efi niti o n  c a m er a  a n d  c o ntr oll e d  L E D  li g hti n g.  
B ec a us e t h e p h ot o gr a p hs ar e t a k e n of s m all ar e as of s ki n 
cl os e-u p y o u will n ot b e i d e ntifi a bl e fr o m t h e m, a n d y o u 
c a n  r e vi e w  all of t h e  p h ot o gr a p hs  w e  c oll ect. T h e 
p h ot gr a p hs will b e  st or e d usi n g a p artici p a nt n u m b er a n d 
n ot y o ur n a m e.  


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 6  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
O p ti c al C o h er e n c e T o m o gr a p h y ( O C T)  
T his  i n v ol v es  pl aci n g  a  h a n d h el d  pr o b e  g e ntl y 
a g ai nst  y o ur  s ki n  at  t h e  i m a gi n g  sit es  f or  2 -3 
mi n ut es. T his t ec h ni q u e us es n e ar i nfr ar e d li g ht, 
li k e t h at f o u n d i n t el evisi o n r e m ot es, t o sc a n j ust 
b e n e at h t h e s urf ac e of y o ur s ki n . W e will us e t w o 
diff er e nt t y p es of O C T m ac hi n e. Wit h t h e first  w e 
c a n  s e e  t h e  str uct ur e  of  t h e  s ki n,  i ncl u di n g  t h e 
s h a p e of bl o o d v ess els.  T h e s ec o n d is us e d  t o s e e 
t h e c o n n ecti v e fi br es (c oll ag e n) i n y o ur s ki n.   
 
F TI R s p e c tr os c o p y  
T his will i n v ol v e pl aci n g t h e d e vic e  bri efl y i n c o nt act wit h 
y o ur  f or e ar m.  T his d e vi ce  als o  us es  i nfr ar e d  li g ht  a n d 
c oll ects i nf or m ati o n o n y o ur  s ki n c o m p ositi o n.  
 
 
 
Tr a ns e pi d er m al w a t er l oss  ( T E W L) 
T his  will i n v ol v e  pl aci n g  a  pr o b e  o n  y o ur  s ki n  f or 
a p pr oxi m at el y  6 0  s ec o n ds . T h e  pr o b e  m e as ur es  h o w 
q uic kl y w at er is l ost t hr o u g h y o ur s ki n, w hic h i n dic at es h o w 
w ell it is f u ncti o ni n g as a b arri er  t o w at er a n d all er g e ns.  
 
 
S ki n r e d n ess  
W e will us e a pr o b e c all e d t h e M ex a m et er t o m e as ur e s ki n 
r e d n ess, t his si m pl y i n v ol v es pl aci n g (t o uc hi n g) t h e pr o b e 
a g ai nst  t h e  s urf ac e  of  t h e  s ki n  f or  a  f e w  s ec o n ds.  T h e 
m e as ur m e nt d o es n ot c a us e a n y r e d n ess. M e as ur e m e nts 
t a k e n at b as eli n e ( visit 1) pr o vi d e a r ef er e nc e p oi nt of h o w 
r e d  y o ur  s ki n  n or m all y  is.  All  s u bs e q u e nt  m e as ure m e nts 
ar e c o m p ar e d t o t his r ef er e nc e.  
 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 7  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
W h a t s a m pl e s will w e c oll e c t ?  
W e will c oll ect t h e f oll o wi n g tiss u e s a m pl es:  
M o u t h  s w a b 
W e will c oll ect a s a m pl e of y o ur s ali v a usi n g a 
b ucc al s w a b o n y o ur i n n er c h e e k s o t h at w e 
c a n o bt ai n y o ur D N A. B y a n al yzi n g a p art of 
y o ur  D N A  w e  c a n  d et er mi n e  w h et h er  y o u 
c arr y a n y of t h e g e n etic ris k f act ors c urr e ntl y 
li n k e d  t o a n  i ncr e as e d  ris k  of ecz e m a. W e 
w a nt t o d et er mi n e w h et h er c arri a g e of t h es e 
m ar k ers  aff ects  y o ur  r es p o ns e  t o  t h e 
tr e at m e nts,  a n d  t h er ef or e  w h et h er  g e n etic 
scr e e ni n g c o ul d h el p i nf or m tr e at m e nt c h oic es. Pl e as e n ot e t h at w e will n ot b e a bl e t o s h ar e 
y o ur i n di vi d u al r es ults of t h e g e n etic scr e e ni n g wit h y o u b ec a us e it is c urr e ntl y u ncl e ar w h at 
t h e r es ults m e a n. T his is b ec a us e t h e c a us es of ecz e m a ar e c o m pl ex, a n d w hil e s o m e g e n etic 
c h a n g es a p p e ar t o i ncr e as e ris k, m a n y p e o pl e wit h o ut ecz e m a c arr y t h e m t o o.  
T a p e - s tri p s a m pl es 
T his will i n v ol v e c oll ecti n g s urf ac e 
s ki n  s a m pl es fr o m  y o ur  f or e ar ms 
usi n g  s m all  stic k y -t a p e  discs  t o 
c oll ect o nl y t h e v er y t o p l a y ers of 
s ki n  c ells,  w hic h  ar e  alr e a d y  d e a d 
a n d a b o ut t o b e s h e d n at ur all y b y 
t h e b o d y. T h e s e ns ati o n is e q ui v al e nt t o t h e stic ki n g a n d r e m o v al of s ell ot a p e fr o m t h e s ki n. 
A s p eci al s pri n g -l o a d e d pl u n g er is us e d t o a p pl y t h e stic k y discs wit h a c o nsist e nt a m o u nt of 
pr ess ur e. W e will a n al ys e t h e disc s i n t h e l a b or at or y t o l o o k at t h e c o m p ositi o n of y o ur s ki n.  
W h a t a r e t h e p o s si bl e  b e n e fi t s o f t a ki n g p a r t ?  
T h er e ar e n o dir ect b e n efits t o y o u f or t a ki n g p art i n t his st u d y. H o w e v er, b y t a ki n g p art y o u 
will h el p us fi n d n e w w a ys of e v al u ati n g t h e eff ects of t o pic al tr e at m e nts o n t h e s ki n, w hic h 
c o ul d l e a d t o t h e i d e ntific ati o n a n d d e v el o p m e nt of s af er t o pic al tr e at m e nts a n d tr e at m e nt 
r e gi m e ns.  
E x p e ns es a n d r e m u n er a ti o n  
F or u n d ert a ki n g  t his st u d y, y o u will b e gi v e n £ 2 5 0  b y dir ect b a n k tr a nsf er  f or y o ur ti m e, a n d 
t o c o v er a n y ex p e ns es y o u m a y h a v e i nc urr e d. If y o u d o n ot w a nt t o pr o vi d e y o ur b a n k d et ails 
w e c a n pr o vi d e A m az o n Gift V o uc h ers i nst e a d. T h e £ 2 5 0 w o ul d n e e d t o b e d ecl ar e d f or t ax 
a n d b e n efits p ur p os es. T his is i n a d diti o n t o t h e t axi tr a nsf ers t o a n d fr o m t h e h os pit al, w hic h 
w e will arr a n g e a n d p a y f or.  
 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 8  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
A r e t h e r e a n y ri s k s ?  
W e d o n ot a ntici p at e a n y ris ks  ass oci at e d wit h t h e s ki n pr oc e d ur es, w hic h ar e all  n o n -i n v asi v e. 
A n y s ki n r e d d e ni n g t h at occ urs aft er t a p e -stri p pi n g is ex p ect e d t o dissi p at e i n a f e w d a ys. T h e 
st u d y tr e at m e nts ar e i n v esti g ati o n al m e dici n al pr o d ucts, a n d t h e ris ks ass oci at e d wit h t h eir  
us e i n t his st u d y ar e  c o m p ar a bl e t o t h e ris ks of st a n d ar d c ar e f or ecz e m a. Tr e at m e nt s p ecific 
si d e eff ects ar e d et ail e d i n t h e n ext s ecti o n. 
S o m eti m es p e o pl e h a v e all er gic r e acti o ns t o i n gr e di e nts t h at ar e i n t o pic al pr o d ucts. If y o u 
h a v e a n y  k n o w n all er gi es or s e nsiti viti es t o c o m m o n t o pic al pr o d ucts (i ncl u di n g cl e a ns ers), 
t oil etri es or t h eir c o m p o n e nts, or a d h esi v es, y o u s h o ul d n ot t a k e p art i n t his st u d y. It is v er y 
i m p ort a nt t o t ell t h e i n v esti g at or i m m e di at el y if y o u h a v e a n y k n o w n all er gi es or if y o u b e gi n 
t o h a v e a n all er gic r e acti o n. S o m e t hi n gs t h at h a p p e n d uri n g a n all er gic r e acti o n i ncl u d e a 
r ash o v er t h e w h ol e b o d y; s h ort n ess of br e at h; w h e ezi n g; s u d d e n dr o p i n bl o o d pr ess ur e; 
s w elli n g ar o u n d t h e m o ut h, t hr o at, or e y es; f ast p uls e; or s w e ati n g. If y o u ex p eri e nc e a n y of 
t h es e si d e eff ects, c o nt act y o ur d oct or or N H S dir ect i m m e di at el y.  
W h a t a r e t h e  s t u d y t r e a t m e n t s ?  
T h e st u d y tr e at m e nts ar e b ot h ‘t o pic al’ pr o d ucts, i nt e n d e d t o b e a p pli e d dir ectl y o nt o t h e 
s ki n. All p artici p a nts will r ec ei v e b ot h tr e at m e nts t o us e at t h e s a m e ti m e o n s e p ar at e ar e as 
of s ki n o n t h eir f or e ar ms. T h er e ar e n o ot h er st u d y tr e at m e nts.  At t h e e n d of t h e st u d y t h e 
tr e at m e nts m ust b e r et ur n e d, a n d will n ot t h er ef or e b e a v ail a bl e t o y o u f or c o nti n u e d us e.  
B e t a m e t h as o n e v al er a t e cr e a m  
B et a m et h as o n e v al er at e cr e a m is c urr e ntl y m ar k et e d i n t h e U K as B et n o v at e cr e a m b y Gl ax o 
W ellc o m e  U K  Lt d. 
E v er y  gr a m  of  cr e a m  c o nt ai ns  0. 0 0 1  gr a ms  of  t h e  acti v e  i n gr e di e nt, 
b et a m et h as o n e ( 0. 1 % w/ w) as v al er at e. It is wi d el y pr escri b e d b y h e alt hc ar e pr of essi o n als f or 
t h e  tr e at m e nt of  ecz e m a  i n  s h ort  c o urs es  of  n o  m or e  t h a n  4  w e e ks  d ur ati o n.  W e  ar e 
c o n d ucti n g t his st u d y b ec a us e t h e l o n g -t er m i n a p pr o pri at e us e of b et a m et h as o n e v al er at e 
c a n  c a us e  u n w arr a nt e d  s ki n eff ects  i ncl u di n g  s ki n  t hi n ni n g  ( atr o p h y) . T his  is  r el at e d  t o a 
l o w eri n g i n  t h e  l e v el  of  t h e  h or m o n e  c ortis ol  i n  t h e  bl o o d. D u e  t o  t h e  s h ort -d ur ati o n  of 
tr e at m e nt i n v ol v e d i n t his st u d y w e d o n ot ex p ect a n y irr e v ersi bl e s ki n t hi n ni n g t o occ ur, a n d 
w e’ll b e m o nit ori n g s ki n t hic k n ess cl os el y t hr o u g h o ut t h e st u d y f or y o ur s af et y.   
Li k e all m e dici n es, b et a m et h as o n e v al er at e  c a n c a us e si d e eff ects, alt h o u g h n ot e v er y b o d y 
g ets t h e m.  
•  V er y c o m m o n si d e eff e c ts  (t h es e m a y aff ect 1 i n 1 0 p e o pl e or m or e, or ≥1 0 %): n o n e;  
•  C o m m o n si d e eff e c ts  (t h es e m a y aff ect u p t o 1 i n 1 0 p e o pl e, or u p t o 1 0 %): a f e eli n g of 
b ur ni n g, p ai n, irrit ati o n or itc hi n g w h er e t h e cr e a m is a p pli e d.  
•  V er y r ar e si d e eff e c ts (t h es e m a y aff ect u p t o 1 i n 1 0, 0 0 0 p e o pl e, or u p t o 0. 0 1 %): a n 
i ncr e as e d ris k of i nf ecti o n; a n all er gic s ki n r e acti o n w h er e t h e cr e a m is a p pli e d ; r as h, itc h y 
b u m p y  s ki n  or  r e d n ess  of  t h e  s ki n ; t hi n ni n g  a n d  dr y n ess  of  y o ur  s ki n  a n d  it  m a y  als o 
d a m a g e  or  wri n kl e  m or e  e asil y ; str etc h  m ar ks  m a y  d e v el o p; bl o o d  v ess els  u n d er  t h e 
s urf ac e of y o ur s ki n ma y b ec o m e m or e n otic e a bl e;  a n i ncr e as e or r e d ucti o n i n h air gr o wt h 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 9  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
or h air l oss a n d c h a n g es i n s ki n c ol o ur ; w ei g ht g ai n, r o u n di n g of t h e f ac e ; d el a y e d w ei g ht 
g ai n  or  sl o wi n g  of  gr o wt h  i n  c hil dr e n ; b o n es  c a n  b ec o m e  t hi n,  w e a k  a n d  br e a k  e asil y ; 
cl o u d y l e ns in t h e e y e ( gl a uc o m a) ; a d ecr e as e d l e v el of t h e h or m o n e c ortis ol i n y o ur bl o o d ; 
i ncr e as e d bl o o d s u g ar l e v els or s u g ar i n t h e uri n e ; hi g h bl o o d pr ess ur e.  
•  N o t K n o w n  (fr e q u e nc y c a n n ot b e esti m at e d fr o m t h e d at a a v ail a bl e): bl urr e d visi o n. 
•  E F F E C T S  O N  P R E G N A N C Y  A N D  L A C T A TI O N: T h er e is li mit e d i nf or m ati o n fr o m t h e 
us e of b et a m et h as o n e v al er at e i n pr e g n a nt a n d br e astf e e di n g w o m e n. As a pr ec a uti o n, 
w o m e n w h o ar e pr e g n a nt or i nt e n di n g t o b ec o m e pr e g n a nt a n d br e astf e e di n g w o m e n will 
n ot b e i ncl u d e d i n t his st u d y.  
F or f urt h er i nf or m ati o n o n t o pic al c ortic ost er oi ds y o u c a n visit t h e N ati o n al Ecz e m a S oci et y 
w e b p a g e htt p:// w w w. ecz e m a. or g/c ortic ost er oi ds  
Cris a b or ol e oi n t m e n t  
Cris a b or ol e  oi nt m e nt  is  a  n e w  a nti -i nfl a m m at or y  tr e at m e nt  f or  ecz e m a.  E v er y  gr a m  of 
oi nt m e nt  c o nt ai ns  0. 0 2  gr a ms  of  t h e  acti v e  i n gr e di e nt  cris a b or ol e  ( 2 %). Cris a b or ol e  is  a 
p h os p h o di est er as e 4 ( P D E 4) i n hi bit or i n dic at e d f or t h e tr e at m e nt of mil d t o m o d er at e at o pic 
ecz e m a.  Cris a b or ol e  oi nt m e nt  is  n ot  c urr e ntl y  m ar k et e d  i n  t h e  U K,  h o w e v er  it is  c urr e ntl y 
m ar k et e d  i n  t h e  U nit e d  St at es  a n d  C a n a d a  u n d er  t h e  br a n d  n a m e  E ucris a,  a n d  w as  m ost 
r ec e ntl y a p pr o v e d f or m ar keti n g i n A ustr ali a a n d Isr a el . It is t h e i nt e nti o n of Pfiz er t o bri n g 
cris a b or ol e t o t h e U K p e n di n g l oc al r e g ul at or y a p pr o v al.  
Li k e all m e dici n es, cris a b or ol e c a n c a us e si d e eff ects, alt h o u g h n ot e v er y b o d y g ets t h e m.  
•  V er y c o m m o n si d e eff e c ts  (t h es e m a y aff ect 1 i n 1 0 p e o pl e or m or e, or ≥1 0 %): n o n e;  
•  C o m m o n si d e eff e c ts  (t h es e m a y aff ect u p t o 1 i n 1 0 p e o pl e, or u p t o 1 0 %): p ai n at t h e 
ar e a of a p pli e d st u d y m e dic ati o n;  
•  U n c o m m o n si d e eff e c ts  (t h es e m a y aff ect u p t o 1 i n 1 0 0 p e o pl e, or u p t o 1 %): w ors e ni n g 
at o pic d er m atitis or ecz e m a, itc hi n g at t h e ar e a of a p pli e d st u d y m e dic ati o n;  
•  R ar e si d e eff e c ts  (t h es e m a y aff ect u p t o 1 i n 1, 0 0 0 p e o pl e, or u p t o 0. 1 %): n o n e; 
•  Ot h er  t y p es  of  a p plic ati o n  sit e  s ki n  r e acti o ns  o bs er v e d  i n  pr e vi o us  cli nic al  st u di es  h a v e  
i ncl u d e d:  r e d n ess  ( er yt h e m a);  irrit ati o n;  itc hi n g  ( pr urit us);  i nf ect e d  or  i nfl a m e d  h air 
f ollicl es (f ollic ulitis); r e d n ess, s ki n b u m ps, b ur ni n g, sti n gi n g, s w elli n g, itc hi n g, o ozi n g a n d/ or 
cr usti n g of t h e s ki n ( d er m atitis); a n d p ai n.  
•  E F F E C T S O N P R E G N A N C Y A N D L A C T A TI O N : I n a ni m al st u di es, cris a b or ol e oi nt m e nt 
2 % di d n ot h a v e eff ects o n f ertilit y (t h e a bilit y t o  b ec o m e pr e g n a nt or m ai nt ai n pr e g n a nc y), 
birt h d ef ects or d eli v er y e v e nts ( d el a y e d birt h,  still b or n birt hs or s u d d e n n e w b or n d e at h). 
Cli nic al  st u di es  of pr e g n a nt  a n d  br e astf e e di n g  w o m e n  h a v e  n ot  b e e n  p erf or m e d  f or  
cris a b or ol e oi nt m e nt 2 %. W o m e n w h o ar e pr e g n a nt or i nt e n di n g t o b ec o m e pr e g n a nt a n d  
br e astf e e di n g w o m e n will n ot b e i ncl u d e d i n cli nic al st u di es.  
F or f urt h er i nf or m ati o n o n E ucris a y o u c a n visit htt ps:// w w w. e ucris a.c o m/  
T his c o m pl e t es P ar t 1  


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 1 0  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
If t h e i nf or m a ti o n i n P ar t 1 h as i n t er es t e d y o u a n d y o u ar e c o nsi d eri n g 
p ar ti ci p a ti o n, pl e as e r e a d t h e a d di ti o n al i nf or m a ti o n i n P ar t 2 b ef or e m a ki n g a n y 
d e cisi o n.  
P A R T  2  
W h a t i f r el e v a n t n e w i n f o r m a ti o n b e c o m e s a v ail a bl e ?  
S o m eti m es  w e  g et  n e w  i nf or m ati o n  a b o ut  t h e  tr e at m e nt  b ei n g  st u di e d.  If  t his  h a p p e ns, 
s o m e o n e fr o m t h e r es e arc h t e a m will t ell y o u a n d disc uss w h et h er y o u s h o ul d c o nti n u e i n t h e 
st u d y.   
W h o i s r e s p o n si bl e f o r m y p e r s o n al i n f o r m a ti o n ?  
T h e S h effi el d T e ac hi n g  H os pit als  ( S T H) N H S tr ust  is t h e s p o ns or f or t his st u d y b as e d i n t h e 
U nit e d Ki n g d o m . W e will b e usi n g i nf or m ati o n fr o m y o u  i n or d er t o u n d ert a k e t his st u d y a n d 
will act as t h e d at a c o ntr oll er f or t his st u d y. T his m e a ns t h at w e ar e r es p o nsi bl e f or l o o ki n g 
aft er y o ur i nf or m ati o n a n d usi n g it pr o p erl y. W e  will k e e p i d e n tifi a bl e i nf or m ati o n a b o ut y o u 
f or u p t o 1 5  y e ars aft er t h e st u d y h as fi nis h e d . 
H o w will w e u s e i n f o r m a ti o n a b o u t y o u ?   
W e will n e e d t o us e i nf or m ati o n fr o m y o u, a n d fr o m y o ur m e dic al r ec or ds, f or t his r es e arc h 
pr oj ect.   
T his i nf or m ati o n will i ncl u d e y o ur i niti als , N H S n u m b er , n a m e , a n d c o nt act d et ails.  P e o pl e 
will us e t his i nf or m ati o n t o d o t h e r es e arc h or t o c h ec k y o ur r ec or ds t o m a k e s ur e t h at t h e 
r es e arc h is b ei n g d o n e pr o p erl y. 
P e o pl e w h o d o n ot n e e d t o k n o w w h o y o u ar e will n ot b e a bl e t o s e e y o ur n a m e or c o nt act 
d et ails. Y o ur d at a will h a v e a c o d e n u m b er i nst e a d .  S o m e of y o ur i nf or m ati o n will b e s e nt t o 
Pfiz er (t h e F u n d er), b as e d i n t h e U nit e d St at es of A m eric a. T h e y m ust f oll o w o ur r ul e s a b o ut 
k e e pi n g y o ur i nf or m ati o n s af e.  
W e will k e e p all i nf or m ati o n a b o ut y o u s af e a n d s ec ur e.   
O nc e w e h a v e fi nis h e d t h e st u d y, w e will k e e p s o m e of t h e d at a s o w e c a n c h ec k t h e r es ults. 
W e will writ e o ur r e p orts i n a w a y t h at n o -o n e c a n w or k o ut t h at y o u  t o o k p art i n t h e st u d y. 
If y o u pr o vi d e y o ur c o ns e nt, T h e U ni v ersit y of S h effi el d will h ol d y o ur c o nt act d et ails f or u p 
t o 5 y e ars aft er t h e e n d of t h e st u d y s o t h at t h e y c a n s e n d y o u i nf or m ati o n a b o ut ot h er s ki n 
r es e arc h o p p ort u niti es wit h t h e S h effi el d Der m at ol o g y R es e arc h gr o u p. T his will b e d o n e b y 
e m ail; h o w e v er, i nf or m ati o n c a n b e s e nt o ut b y p ost if pr ef err e d. If at a n y ti m e y o u n o l o n g er 
wis h t o r ec ei v e t his i nf or m ati o n y o u c a n wit h dr a w b y e m ail ( s kinr es e arc h @s h effi el d. ac. u k ) or 
b y c o nt acti n g t h e st u d y t e a m. Y o u d o n ot n e e d t o pr o vi d e a r e as o n.  
 
 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 1 1  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
W h a t a r e y o u r c h oi c e s a b o u t h o w y o u r i n f o r m a ti o n i s u s e d ?  
•  
Y o u c a n st o p b ei n g p art of t h e st u d y at a n y ti m e, wit h o ut gi vi n g a r e as o n, b ut w e will 
k e e p i nf or m ati o n a b o ut y o u t h at w e alr e a d y h a v e.   
•  
If y o u c h o os e t o st o p t a ki n g p art i n t h e st u d y, w e w o ul d li k e t o c o nti n u e c oll ecti n g 
i nf or m ati o n a b o ut y o ur h e alt h fr o m y o ur h os pit al. If y o u d o n ot w a nt t his t o h a p p e n, 
t ell us a n d w e will st o p , u nl ess w e ar e n ot a bl e t o d o t his f or y o ur s af et y. W e will disc uss 
t his wit h y o u i n d et ail if t his sit u ati o n occ urs. 
•  
W e n e e d t o m a n a g e y o ur r ec or ds i n s p ecific w a ys f or t h e r es e arc h t o b e r eli a bl e. T his 
m e a ns t h at w e w o n’t b e a bl e t o l et y o u s e e or c h a n g e t h e d at a w e h ol d a b o ut y o u.  
W h e r e c a n y o u fi n d o u t m o r e a b o u t h o w y o u r i n f o r m a ti o n i s u s e d ?  
Y o u c a n fi n d o ut m or e a b o ut h o w w e us e y o ur i nf or m ati o n   
•  
at w w w. hr a. n hs. u k/i nf or m ati o n -a b o ut -p ati e nts/  
•  
b y as ki n g o n e of t h e r es e arc h t e a m  
•  
b y s e n di n g a n e m ail t o st h.i nf o g o v @ n hs. n et, or  
•  
b y ri n gi n g us o n 0 1 1 4 2 2 6 5 1 5 1 .  
Will m y t a ki n g p a r t i n t h e s t u d y b e k e p t c o n fi d e n ti al ?  
Y es. W e will f oll o w et hic al a n d l e g al pr actic e a n d all i nf or m ati o n a b o ut y o u will b e k e pt strictl y 
c o nfi d e nti al. A n y i nf or m ati o n/ d at a t h at l e a v es t h e h os pit al will h a v e y o ur n a m e a n d a d dr ess 
d el et e d, i ncl u d i n g d at a tr a ns mitt e d el ectr o nic all y. E ac h p artici p a nt will b e all oc at e d a u ni q u e 
st u d y n u m b er, w hic h will b e us e d f or r ec or di n g d e m o gr a p hic a n d st u d y d at a. All el ectr o nic 
d at a will b e st or e d o n a s ec ur e s er v er, m a n a g e d b y t h e U ni v ersit y of S h effi el d, a n d will b e 
i d e ntifi a bl e o nl y b y t h e u ni q u e st u d y n u m b er. Acc ess t o y o ur m e dic al r ec or ds h el d b y S h effi el d 
T e ac hi n g H os pit als N H S F o u n d ati o n Tr ust is r e q uir e d t o ass ess y o ur m e dic al hist or y, w h er e 
a v ail a bl e, a n d t o d oc u m e nt y o ur i n v ol v e m e nt i n a cli nic al tri al. W h er e p artici p a nts ar e n ot 
c urr e ntl y u n d er g oi n g tr e at m e nt at S h effi el d T e ac hi n g H os pit als N H S F o u n d ati o n Tr ust, a n e w 
s et of m e dic al n ot es will b e cr e at e d. St u d y d at a, i ncl udi n g t h e st u d y i m a g es, will n ot or di n aril y 
b e  st or e d  i n  t h e  m e dic al  n ot es,  u nl ess  p erti n e nt  t o  t h e  f oll o w -u p  of  a n  a d v ers e  e v e nt 
occ urri n g  d uri n g  y o ur  i n v ol v e m e nt  i n  t h e  st u d y. P ers o n al  c o nt act  d et ails  will  b e  r ec or d e d 
s e p ar at el y,  acc essi bl e  o nl y  t o  t h e  dir ect  st u d y  t e a m.  A n y  i nf or m ati o n  i ncl u d e d  i n  writt e n 
r e p orts/ pr es e nt ati o ns will n ot i d e ntif y y o u.  
W h a t will h a p p e n t o a n y s a m pl e s I gi v e ?  
Y o ur s a m pl es will b e tr e at e d as a gift. All s a m pl es c oll ect e d will b e l a b el e d o nl y wit h y o ur 
u ni q u e st u d y c o d e, i niti als a n d d at e of c oll ecti o n; t h e y will b e k e pt i n a s ec ur e l oc ati o n wit hi n 
T h e U ni v ersit y of S h effi el d M e dic al Sc h o ol/ R o y al H all a ms hir e H os p it al. Acc ess t o y o ur s a m pl es 
will b e r estrict e d t o m e m b ers of o ur r es e arc h t e a m o nl y. All s ali v a s a m pl es will b e d estr o y e d 
at t h e e n d of t h e st u d y. Wit h y o ur p er missi o n, e xtr act e d D N A s a m pl es a n d s u p erfici al s ki n 
s a m pl es (t a p e-stri ps) will b e k e pt f or a m a xi m u m of 1 0  y e ars u n d er t h e c ust o di a ns hi p of t h e 


Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 1 2  of 1 3  
P artici p a nt I nf or m ati o n S h e et | V ersi o n 4 : 2 8J a n 2 0 2 1  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
Pri nci p al I n v esti g at or. It is li k el y t h at t h es e s a m pl es will b e us e d t o s u p p ort f ut ur e st u di es , t his 
m a y i ncl u d e st u di es u n d ert a k e n b y t h e f u n d er, Pfiz er. Pfiz er w o ul d o nl y r ec ei v e a n o n y miz e d 
s a m pl es a n d  a p p r o pri at e  r es e arc h  et hics  c o m mitt e e  a p pr o v al  will  b e  s o u g ht.  S h o ul d  y o u 
c h o os e t o wit h dr a w fr o m t h e st u d y w e will d estr o y y o ur s a m pl e u p o n r e q u est.  
W h a t will h a p p e n t o t h e r e s ul t s o f t h e r e s e a r c h s t u d y ?  
W e will us e t h e i nf or m ati o n fr o m t his st u d y t o writ e s ci e ntific r e p orts a n d p u blic ati o ns , b ut 
t h e y will n ot i ncl u d e a n y i nf or m ati o n w hic h m a k es it p ossi bl e f or y o u t o b e i d e ntifi e d. W e will 
distri b ut e a s u m m ar y of o ur fi n di n gs t o all p artici p a nts at t h e cl os e of t h e st u d y.   
W h o i s o r g a ni si n g a n d f u n di n g t hi s r e s e a r c h ?  
T his st u d y is or g a nis e d b y r es e arc h ers at T h e U ni v ersit y of S h effi el d a n d S h effi el d T e ac hi n g 
H os pit als N H S F o u n d ati o n Tr ust. T h e st u d y is f u n d e d b y Pfiz er, w h o m a n uf act ur e cris a b or ol e 
oi nt m e nt . E m pl o y e es at Pfiz er h a v e r e vi e w e d t h e st u d y f or q u alit y  a n d will b e u p d at e d o n t h e 
pr o gr ess of t h e st u d y t hr o u g h o ut, h o w e v er as a n i n v esti g at or -l e d st u d y Pfiz er will h a v e n o 
dir ect i n v ol v e m e nt i n t h e c o n d uct of t h e st u d y. At t h e e n d of t h e st u d y t h e r es ults will b e 
s h ar e d wit h Pfiz er i n a f ull y a n o n y mise d f or m.  
T h e f ull st u d y titl e f or r ef er e nc e is “ V ali d ati o n of a n o v el c o m p osit e of s ki n bi o m ar k ers as a 
pri m ar y o utc o m e m e as ur e f or e v al u ati n g t h e s af et y of tr e at m e nts f or at o pic d er m atitis st u d y 
1: a r a n d o miz e d c o ntr oll e d tri al ( p h as e 3) c o m p ari n g t h e ef f ects of cris a b or ol e oi nt m e nt t o 
b et a m et h as o n e v al er at e cr e a m o n s ki n str uct ur e a n d f u ncti o n i n at o pic d er m atitis p ati e nts ”.  
W h o h a s r e vi e w e d t hi s s t u d y ?  
All r es e arc h i n t h e N H S is l o o k e d at b y a n i n d e p e n d e nt gr o u p of p e o pl e, c all e d a R es e arc h 
Et hics C o m m itt e e, t o pr ot ect y o ur s af et y, ri g hts, di g nit y a n d w ell b ei n g. T his st u d y h as b e e n 
r e vi e w e d,  a n d  gi v e n  a  f a v o ur a bl e  o pi ni o n  b y t h e  X X X X X X X X X X X X X X  R es e arc h  Et hics 
C o m mitt e e  ( R ef:  X X/ X X/ X X X X)  a n d  t h e  S h effi el d  T e ac hi n g  H os pit als  N H S  Tr ust  ( R ef:  S T H 
1 9 9 6 6 ). 
W h a t i f t h e r e i s a p r o bl e m ?  
If y o u h a v e a c o nc er n a b o ut a n y as p ect of t his st u d y, y o u s h o ul d s p e a k t o r es e arc h ers w h o 
will d o t h eir b est t o a ns w er y o ur q u esti o ns ( T el: X X X X X X X X X X X). If y o u r e m ai n u n h a p p y a n d 
wis h t o c o m pl ai n f or m all y, y o u c a n d o t his b y c o nt acti n g t h e P ati e nt S er vic es T e a m ( T h e R o y al 
H all a ms hir e H os pit al, Gl oss o p R o a d, S h effi el d, S 1 0  2J F; t el e p h o n e 0 1 1 4 2 7 1 2 4 0 0).  
I n t h e e v e nt t h at s o m et hi n g g o es wr o n g a n d y o u ar e h ar m e d d uri n g t h e r es e arc h t h e n y o u 
m a y h a v e gr o u n ds f or l e g al acti o n a n d c o m p e n s ati o n, b ut y o u m a y h a v e t o p a y y o ur l e g al 
c osts.  T h e  n or m al  N ati o n al  H e alt h  S er vic e  c o m pl ai nts  m ec h a nis ms  will  still  b e  a v ail a bl e  t o 
y o u.  
 
 


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H o w t o fi n d u s ?
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6 #( )&- # *N - *! & ' %! O # 2 )6! P )66 ) 8$ '-0 %! P #$ 5-& )6;! )!  8-6 %! 40 # 8! & ' %! (-& 2! # *! & ' %! D ' %44- %6 3! " % )( '- * +!
P #$ 5-& )6$! "0 1$&d$! ( % *&0 )6! ( ) 8 5 1$: M- *$ %0&!$-& %!$ 5 %(-4-(!6 #( )&- # *!3-0 %(&- # *$ N:!W #0! 8 #0 %! 3 %& )-6$! # *!
' # ,! & #! 4- * 3! & ' %! O # 2 )6! P )66 ) 8$ '-0 %! P #$ 5-& )6! 56 % )$ %! + #! & #! & ' % O # 2 )6! P )66 ) 8$ '-0 %! P #$ 5-& )6!
, % /$-& % @ '&& 5$aZZ , , ,:$& ': * '$: 1 .Z # 107 ' #$ 5-& )6$Z0 # 2 )67 ' )66 ) 8$ '-0 %7 ' #$ 5-& )6A  , ' %0 %! 2 # 1! ( ) *!
)6$ #! 4- * 3! 3 %& )-6$! 4 #0! 5 1 /6-(! &0 ) *$ 5 #0&! ) * 3! 5 )0 .- * +! @-4! 2 # 1! 3 # *d&!  , ) *&! 1$! & #! )00 ) * + %! )!
( # 8 56 % 8 % *& )0 2!& )Q-!4 #0! 2 # 1A! )$! , %66! )$! )!$-& %! 8 ) 5:
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S M A R T R es e ar c h er: - - - - - - - - - - - - -
C o n t a c t N u m b er: X X X X X X X X X X X
C o n t a c t e m ail: X X X X @s h effi el d. a c. u k
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P ri n ci p al I n v e s ti g a t o r: Mi c h a el C o r k
I n f o r m e d C o n s e n t F o r m
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Ski n bi o M A R k ers f or a t o pic ecz e m a  T h er a py ev al u ati o n ( SM A R T ) Tri al  
P a g e 2  of 2  
I nf or m e d C o ns e nt F or m | V ersi o n 1 . 0: 3 0  Oct 2 0 1 9  
 
I R A S 2 6 9 4 1 5  |  S T H 1 9 9 6 6  
7.  
[ O pti o n al] I gi v e my p er missi o n f or my D N A t o b e k e pt aft er t h e e n d 
of t his st u d y i n f ull y a n o n y mis e d f or m ( m e a ni n g t h at n o b o d y will b e 
a bl e t o i d e ntif y t h e s a m pl e as mi n e) f or u pt o 1 0 y e ars s o t h at it c a n 
b e us e d i n f ut ur e r es e arc h.  
¨  Y es  
¨  N o  
 
8.  
[ O pti o n al] I gi v e my p er missi o n f or my ‘ t a p e-stri p’ s ki n s a m pl es t o b e 
k e pt aft er t h e e n d of t his st u d y i n f ull y a n o n y mis e d f or m ( m e a ni n g 
t h at n o b o d y will b e a bl e t o i d e ntif y t h e s a m pl e as mi n e) f or u pt o 1 0 
y e ars s o t h at it c a n b e us e d i n f ut ur e r es e arc h.  
¨  Y es  
¨  N o  
 
9.  
[ O pti o n al] I a m h a p p y t o b e c o nt act e d b y t h e r es e arc h t e a m a b o ut 
ot h er r es e arc h st u di es b ei n g c o n d uct e d b y t h e S h effi el d D er m at ol o g y 
R es e arc h gr o u p wit hi n t h e n ext 5 y e ars. I u n d erst a n d t h at I m a y o pt 
o ut  of  a n y  f ut ur e  c o nt act  at  a n y  p oi nt  b y  i nf or m i n g  t h e  r es e arc h 
t e a m. 
¨  Y es  
¨  N o  
 
1 0.  I a gr e e t o t a k e p art i n t h e a b ov e st u d y.  
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
N a m e of p artici p a nt   
 
D at e   
 
 
Si g n at ur e                              
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
N a m e of p ers o n t a ki n g c o ns e nt  
D at e   
 
 
Si g n at ur e                              
 
W h e n c o m pl et e d: 1 f or p artici p a nt; 1 f or r es e arc h er sit e fil e; 1 t o b e k e pt i n m e dic al n ot es.  
 

Prot_000.pdf: 
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
0
1 0
�E pi d er m al t hi c k n e s s ( µ m)
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  

SAP_001.pdf: 
S M A R T – S ki n B arri er St u d y 
St atisti c al A n al y si s Pl a n v1. 2 
S S U 2 01 7/ 0 0 7  
1 6 A pril 2 0 21 
St ati sti c al A n al y si s Pl a n ( S A P) 
V ali d ati o n of a n o v el c o m p o sit e of s ki n bi o m a r k e r s a s a p ri m a r y o ut c o m e 
m e a s u r e f o r e v al u ati n g t h e s af et y of t r e at m e nt s f o r at o pi c d e r m atiti s: a 
r a n d o mi z e d c o nt r oll e d t ri al ( p h a s e 2) c o m p a ri n g t h e eff e ct s of c ri s a b o r ol e 2 % 
oi nt m e nt t o b et a m et h a s o n e v al e r at e 0.1 % c r e a m o n s ki n st r u ct u r e a n d 
f u n cti o n i n p a rti ci p a nt s wit h at o pi c d e r m atiti s. 
S ki n bi o M A R k e r s f o r at o pi c e c z e m a T h e r a p y e v al u ati o n 
N C T 0 4 1 9 4 8 1 4


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 2 of 20 
Contents 
Abbreviations .......................................................................................................................................... 3 
1. 
Introduction: ................................................................................................................................... 4 
2. 
Study Methods ................................................................................................................................ 4 
2.1 
Study Design ................................................................................................................................ 4 
2.2 
Randomisation ............................................................................................................................ 5 
2.3 
Sample size: ................................................................................................................................. 5 
2.4 
Timelines ..................................................................................................................................... 6 
3. 
Data Collection: ............................................................................................................................... 6 
4. 
Analysis Objectives: ........................................................................................................................ 7 
4.1 
Primary objective: ....................................................................................................................... 7 
4.2 
Secondary objective: ................................................................................................................... 7 
4.3 
Exploratory objectives: ............................................................................................................... 7 
5. 
Analysis Sets and Protocol Deviations ............................................................................................ 8 
6. 
Endpoints and Covariates ............................................................................................................... 8 
6.1 
Primary endpoints ....................................................................................................................... 8 
6.2 
Secondary endpoints .................................................................................................................. 8 
6.3 
Exploratory endpoints: ................................................................................................................ 9 
6.4 
Variables ...................................................................................................................................... 9 
7. 
Statistical Analyses ........................................................................................................................ 11 
7.1 
Primary Analysis ........................................................................................................................ 11 
7.2 
Secondary Analysis .................................................................................................................... 11 
7.3 
Exploratory Analysis .................................................................................................................. 12 
7.4 
Adverse event data: .................................................................................................................. 12 
7.5 
Multiplicity considerations........................................................................................................ 12 
7.6 
Missing and unusual data ......................................................................................................... 13 
7.7 
Interim Analysis: ........................................................................................................................ 13 
7.8 
Data Monitoring Committee (DMC): ........................................................................................ 14 
7.9 
Changes From Protocol ............................................................................................................. 14 
8. 
Transfer of documentation, data and reporting ........................................................................... 14 
9. 
List of Tables, Figures and Listings ................................................................................................ 17 
 
 
 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 3 of 20 
Abbreviations 
 
AD 
Atopic dermatitis 
ANCOVA 
Analysis of Covariance 
EASI 
Eczema Area and Severity Index  
FAS 
Full Analysis Set 
FTIR 
Fourier Transform Infrared 
ISGA 
Investigators Static Global Assessment 
NMF 
Natural moisturizing factor 
OCT 
Optical Coherence Tomography 
PPS 
Per protocol set 
PS-OCT 
Polarization sensitive OCT 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TCS 
Topical corticosteroid 
TEWL 
Trans-Epidermal Water Loss 
 
 
 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 4 of 20 
1. Introduction:  
This study aims to further develop and validate two non-invasive technologies for the 
assessment of early ‘sub-clinical’ skin changes associated with TCS adverse effects and to 
derive an optimum panel of safety biomarkers for use in future clinical trials of topical anti-
inflammatory treatments. In addition, this study aims to determine the relative local skin 
effects (as determined by early biomarkers of local skin changes) rather than clinical efficacy 
of crisaborole (2%) ointment compared to a potent TCS in participants with AD. 
 
2. Study Methods 
2.1 
Study Design 
This is an observer-blind, randomized within-subject controlled clinical trial. The participants 
will apply treatment on designated treatment areas (void of signs of AD) on their front volar 
forearm for 4 weeks, there will be a further 4 weeks in the study without treatment. Subjects 
will attend the study centre each working day of week 1 to allow for compliance monitoring 
including application supervision, product weighing and diary review. 
Participants will attend 8 clinic visits during the study: 
• 
Visit 1 (screening) will be performed at baseline (day 1) 
• 
Visit 2 will be performed after 1 day of treatment 
• 
Visit 3 will be performed after 2 days of treatment  
• 
Visit 4 will be performed after 3 days of treatment  
• 
Visit 5 will be performed after 4 days of treatment  
• 
Visit 6 will be performed after 14 days of treatment (day 15)  
• 
Visit 7 will be performed after 28 days of treatment (day 29) 
• 
Visit 8 will be performed after 28 days of treatment and 28 days of washout (day 57) 
 
There will be two treatments applied:  
  
crisaborole (2%) ointment  
  
betamethasone valerate (0.1%) cream  
The primary objective is superiority: that crisaborole use will result in less epidermal thinning 
than the equivalent regimen with betamethasone valerate. The secondary objectives are: 
investigating the difference between the two treatments on tolerability, skin barrier function, 
dryness and natural moisturising factor and the ability to detect sub-clinical changes 
associated with adverse effects. 
It is planned to recruit 37 adults (male and female, aged 18-65) with personal history of 
atopic dermatitis but no current eczema on the volar forearms and no possible allergy to the 
ingredients in the study medications (allowing for a 10% drop-out rate to meet the target of 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 5 of 20 
33 subjects). They will not be permitted to use topical product on the test area for 7 days 
prior to baseline or to use a tanning bed for 28 days prior to baseline.  
Subjects will remain in the study for 8-9 weeks. 
At each study visit, concomitant medication and any AEs are noted in the Case Report Form 
(CRF). The study medication will be collected and weighed in order to estimate cream 
consumption. 
Assessors will be blind to the treatment assigned to each site. Due the difference in 
consistencies between the two treatments (cream or ointment) subjects will not be blinded 
to the treatment assigned to each study site.  
2.2 
Randomisation 
Screening will take place either before or at the same visit as day 1. Those eligible to take part 
will be randomised on day 1 with each subject testing both treatments – one on each of the 
left or right lower volar forearm. The randomisation list will be provided by the SSU and the 
SSU will unblind the database after database lock. The interim analysis has been designed to 
be done on blinded data. 
The pharmacy and a statistician (independent of the study statistician) will have access to 
the randomisation master list. Since only the research team assessing the study endpoints 
are blind to the treatment allocation and participants are all prescribed both treatments, no 
emergency unblinding arrangements are necessary. 
2.3 
Sample size: 
The primary statistical analyses will compare the change in epidermal thickness from 
baseline to 28 days between treatments: betamethasone valerate cream vs crisaborole, 
utilising the within participant comparisons of left vs right forearm. Assuming that the change 
from baseline at day 28 in the betamethasone valerate group will be approximately -4.44μm 
and a standard deviation of 5 μm (for the change from baseline within each participant), to 
detect a reduction in this change of 80% to -0.88 μm in the crisaborole arm with 80% power, 
a parallel group study (one group for betamethasone valerate and one group for crisaborole) 
would require 33 participants in each group.  
The study described here is comparing within participants (left vs right arm) rather than a 
parallel group (between participants) design, however it is assumed that this within patient 
comparison will have greater power than the parallel group design.  This assumption is 
necessary because no information is available in the literature as to the standard deviation of 
the difference between change from baseline on the TCS arm and change from baseline on 
the crisaborole arm.  Assuming that the correlation between these two ‘change from 
baseline’ measures will be greater than zero then the within participant comparisons can be 
assumed to have greater power than a parallel group design. 
 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
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Statistical Services Unit, The University of Sheffield 
Page 6 of 20 
2.4 
Timelines 
 
Planned milestones are as follows; 
 
First subject in: December 2020 
 
Interim analysis: After 15th subject complete* (est. May 2021)  
 
Last subject complete: est. 30 September 2021 
 
Full database delivered to SSU: (est. 30 October 2021) 
 
Blind data review: SSU create tables: 6-8 weeks 
 
Team review blind outputs 
 
Data Base lock  
   
Statistical analysis: 6-8 weeks after database lock 
 
Statistical report: containing TFLs and brief text 
*Interim analysis to take place once 15 participants have had their final assessment at day 57. 
Final analysis will take place once all participants have had their final assessment at day 57 or 
have discontinued and the data has been fully cleaned and the database locked.   
Completion of the SAP, data cleaning and a blind review will take place prior to data base 
lock.  During blind review all decisions about protocol deviations (ITT and PP populations) 
and analyses (such as assumptions checking) will be made.  Once all these activities have 
taken place then the database will be locked and unblinded. 
 
3. Data Collection:  
Data is to be collected in a custom electronic data capture system designed by the Clinical 
Trials Research Unit (CTRU) within the University of Sheffield. Adverse events will be coded 
to MedDRA preferred terms & system organ class within the database. Data will be provided 
to the SSU as clean csv files. 
Data transfers between the study team and Pfizer will be in csv format, final data transfers 
(after final analysis) from the SSU to Pfzier will be in pre-agreed SAS format.  For further 
details of the transfer of documentation, data and reporting between the study team, the 
SSU and Pfizer see section 8. 
 
 
 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
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Statistical Services Unit, The University of Sheffield 
Page 7 of 20 
4. Analysis Objectives: 
4.1 
Primary objective: 
To determine whether twice daily treatment with crisaborole (2%) ointment, compared to 
betamethasone valerate (0.1%) cream, for up to 4 weeks is a cause of skin atrophy in patients 
with atopic dermatitis. 
4.2 
Secondary objective: 
To determine whether there is a difference between crisaborole (2%) ointment and 
betamethasone valerate (0.1%) cream on: 
• 
Kinetics of changes in epidermal thickness  
• 
Tolerability 
• 
Skin barrier function 
• 
Skin dryness 
• 
Levels of natural moisturising factor 
4.3 
Exploratory objectives: 
To investigate whether OCT-derived biomarkers (other than the established structural OCT 
biomarker) enable the accurate quantification of tissue changes (vascular and matrix) 
associated with epidermal atrophy in response to TCS treatment. Biomarker measurements 
from the images will include: 
• 
Superficial plexus depth (μm) from angiographic OCT images 
• 
Mean vessel diameter (μm) from angiographic OCT images 
• 
Vessel density (segments/mm2) from angiographic OCT images 
• 
Collagen matrix index from polarisation sensitive OCT images 
 
To investigate whether FTIR spectroscopy-derived biomarkers enable the accurate 
quantification of skin barrier condition and function in response to TCS treatment. 
Biomarker measurements from the spectra will include: 
• 
NMF levels in the skin 
• 
Lipid Structure 
 
To investigate the number of participants with FLG loss-of-function mutations and explore if 
there is any evidence of a relationship to treatment effects.  
 
To identify (by completing the objectives above) a panel of biomarkers that best 
characterises epidermal atrophy.  


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
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5. Analysis Sets and Protocol Deviations 
 
Full Analysis Set (FAS): All subjects who were randomised into the study. 
 
Per-protocol set (PPS): All participants who are deemed to have no major protocol 
violations that could interfere with the objectives of this study. This is a sub-population of the 
FAS. 
 
Safety set: All randomised participants who receive at least 1 dose of test or reference 
cream. 
 
All efficacy analyses and summaries will be performed on the FAS. If there are concerns 
about protocol deviations at the blind review, then a sensitivity analysis of the primary 
objective may be performed on the PPS.  
 
Safety summaries will be performed on the safety set. 
 
Prior to unblinding, a blind review of the data will be performed. The objective of the review 
is to identify protocol deviations and data queries and to make decisions regarding data 
analytical issues under blind conditions. Important violations of eligibility criteria and other 
deviations from the protocol will be assessed in cooperation with the study team. Important 
deviations from the protocol may lead to exclusion of a participant from the PPS.  All 
deviations will be discussed and agreed prior to the unblinding of the data. 
 
6. Endpoints and Covariates 
6.1 
Primary endpoints 
• 
Change in Epidermal thickness measured by structural OCT (day 29 - day 1) 
6.2 
Secondary endpoints 
• 
Epidermal thickness measured by structural OCT during and after 28 days treatment: 
o Change in epidermal thickness (day 15 - day 1) 
o Change in epidermal thickness (day 57 - day 29) 
• 
Erythema (visual redness) score during and after 28 days treatment: 
o Erythema score change from baseline (day 15, day 29, day 57) 
• 
Objective redness as assessed with a Mexameter during and after 28 days treatment  
o Objective redness change from baseline (day 15, day 29 and day 57) 
• 
Trans-Epidermal Water Loss during and after 28 days treatment 
o TEWL change from baseline (day 15, day 29, day 57) 
• 
Skin barrier integrity after 28 days treatment:  
o Difference in TEWLts20 between the two treatments (day 29) 
• 
Visual skin dryness during and after 28 days treatment:  
o Dryness change from baseline (day 15, day 29, day 57) 
• 
NMF at the end of treatment (quantified from superficial stratum corneum samples):  
o Difference between the two treatments (day 29)  
 
 


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6.3 
Exploratory endpoints:  
Angiographic OCT endpoints 
• 
Superficial plexus depth (μm) 
o Change from baseline/day 1 in superficial plexus measurement (day 15, day 29, 
day 57) 
• 
Mean blood vessel diameter (μm) 
o Change from baseline/day 1 in mean blood vessel diameter (day 15, day 29, day 
57) 
• 
Blood vessel density(segments/mm2) 
o Change from baseline/day 1 in blood vessel density (day 15, day 29, day 57) 
 
Polarisation sensitive OCT image (PS OCT) endpoints 
• 
Collagen matrix index 
o Change from baseline/day 1 in collagen matrix index (day 29) 
 
FTIR spectroscopy endpoints 
• 
Carboxylate levels  
o Change from baseline/day 1 in carboxylate levels (day 15, day 29, day 57) 
• 
Stratum corneum lipid structure (FTIR and tape stripping) 
o Difference between groups in stratum corneum lipid structure (day 29) 
• 
Number if FLG loss-of-function mutation carriers 
o Count result from saliva sample (day 1) 
• 
Descriptive statistics split by FLG mutation grouping  
of TEWL split by mutation grouping (day 1, day 15, day 29, day 57) 
o TEWL (day 1, day 15, day 29, day 57) 
o Epidermal thickness (day 1, day 15, day 29, day 57) 
6.4 
Variables 
Epidermal Thickness  
Triplicate measurements will be performed at each test site (upper part of the right and left 
volar at baseline (day 1), after 2 weeks treatment (day 15), after 4 weeks treatment (day 29) 
and 4 weeks after treatment cessation (day 57) using Structural OCT image capture at depth 
of focus 1.0mm and optical resolution of 7.5x5.0 μm. The average (mean) reading for each 
patient at each time point at each site will be used in the analysis.  
 
TEWL  
Duplicate measurements will be performed at each test site (upper part of the right and left 
lower volar forearm and lower part of the right and left lower volar forearm) at baseline 
(day 1), after 2 weeks treatment (day 15), after 4 weeks treatment (day 29) and 4 weeks after 
treatment cessation (day 57) using an AquaFlux condensing chamber probe. A fourth 
measurement may be taken if the technician feels that one of the previous readings was 
abnormal. The average reading for each patient at each time point at each site will be used in 
the analysis.  


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On the lower part of the right and left volar forearms, an alternative measurement of TEWL 
after tape-stripping will be done after 4 weeks treatment (day 29). This outcome is known as 
TEWLts20. 
 
Redness  
Visual scoring of the redness (erythema) of the subject’s skin by an expert will take place at 
baseline (day 1), after 2 weeks treatment (day 15), after 4 weeks treatment (day 29) and 4 
weeks after treatment cessation (day 57). Scores will be on a scale from 0 to 3 and will be 
graded by two observers independently. The upper and lower volar forearms on each side 
will be combined to give one overall result for the right and one overall result for the left. 
Objective scoring of the sites will also be measured using a mexameter.  Four repeats per site 
will be made; the average reading for each patient at each time point at each site (upper part 
of the right and left lower volar forearm and lower part of the right and left lower volar 
forearm) will be used in the analysis. A fourth measurement may be taken if the technician 
feels that one of the previous readings was abnormal. 
 
Dryness  
Visual scoring of the dryness of the subject’s skin by an expert will take place at baseline (day 
1), after 2 weeks treatment (day 15), after 4 weeks treatment (day 29) and 4 weeks after 
treatment cessation (day 57). Scores will be on a scale from 0 to 4 and will be graded by two 
observers independently. The upper and lower volar forearms on each side will be combined 
to give one overall result for the right and one overall result for the left. 
 
NMF levels  
Samples for analysis of stratum corneum NMF levels will be collected by tape stripping after 
4 weeks of treatment (single time point, day 29). One sample will be collected from each 
sampling site (tape-strips/discs 1-3 on lower right and left volar forearm).  The samples will 
be analysed separately. 
 
Product Consumption 
Product consumption will be based on the difference in weight of the ointment and cream 
between the start (day 1) and end (day 29) of treatment phase. 
 
Adverse Events 
Participants will record AEs throughout the study in their diaries with the information 
transferred to the CRF at day 29 and day 57.   
 
FLG loss-of-function mutations 
Saliva samples will be collected at baseline (day 1) to obtain genomic DNA for determination 
of participant FLG gene status. Samples will undergo DNA extraction and genotyping at the 


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University of Sheffield for the 5 common European loss-of-function FLG mutations that have 
been reported to confer increased AD risk. 
7. Statistical Analyses 
The primary and secondary analyses will identify where there is evidence of a difference 
between the two treatments in the change from baseline and which biomarkers are able to 
identify this difference in the clinical trial setting. Exploratory analyses will investigate 
whether a subset of the OCT endpoints can be used to non-invasively identify skin changes.  
 
Outcome and demographic data will be summarised at each time point using appropriate 
descriptive statistics such as N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile and maximum.   
7.1 
Primary Analysis 
The primary analysis of change in epidermal thickness over 28 days treatment will be 
estimated using a repeated measures mixed model with change from day 1 as the outcome, 
treatment, timepoint as  factors together with a treatment by timepoint interaction, subject 
as a random effect and baseline as a covariate.   The estimate of change from baseline to day 
29 from this model will be the primary outcome, the estimate of change from day 1 to day 15 
and change from day 29 to 57 will be secondary as described by in section 7.2. 
7.2 
Secondary Analysis 
The analysis of three of the secondary endpoints will use a repeated measures mixed  model 
with change from day 1 (to day 15, day 29, day 57) as the outcome, treatment, timepoint as  
factors together with a treatment by timepoint interaction, subject as a random effect and 
baseline as a covariate.  
The model will be used to estimate the difference between treatment arms for the change 
from baseline to day 29.   
If there is a significant difference observed in the change from baseline to day 29, then the 
change from day 1 to day 15,  and the change from day 29 to day 57 will also be assessed.  If 
there is no statistically significant difference in the change from baseline to day 29 then we 
will not test further timepoints. 
Summary statistics will be presented for all timepoints. 
 
This applies to: 
o Change in epidermal thickness (change from day 1 to day 15, and from day 29 
to day 57 as  secondary endpoints) 
o Change in redness/erythema  
o Change in Trans-Epidermal Water Loss (TEWL)  
o Change in visual skin dryness  
 
The Change in TEWLts20 after 28 days treatment will use an ANCOVA model with change from 
day 1 to day 29 as outcome, treatment as a factor, subject as a random effect and baseline as 
a covariate. The analysis of Natural Moisturising Factor after 28 days treatment (day 29) will 


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Statistical Services Unit, The University of Sheffield 
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use a paired analysis (such as a t-test, depending on the distribution of the data) unless it is 
necessary to adjust for any covariates, in which case an ANCOVA will be used. 
If any of the above models do not fit satisfactorily or appear to be over fitted the analysis may 
be changed to look at change from baseline to day 29 and change from day 29 to 57 
separately.  
 
Since these analyses are exploratory, no adjustment for multiplicity will be made. 
7.3 
Exploratory Analysis 
Discriminant analysis will be used to determine which of the new biomarkers provide the 
most informative and sensitive data pertaining to the atrophic changes induced by TCS 
treatment. This will be accomplished by assessing the ability of each biomarker to 
differentiate the skin of participants before and after treatment with the potent TCS, which 
is known to induce sub-clinical atrophic skin changes within the treatment window. 
 
The endpoints that will be explored this way will be: 
o Superficial plexus depth (μm) (day 1, day 15, day 29, day 57) 
o Mean blood vessel diameter (μm) (day 1, day 15, day 29, day 57) 
o Blood vessel density (day 1, day 15, day 29, day 57) 
o Collagen matrix index (day 1, day 15, day 29, day 57) 
o Carboxylate levels (day 1, day 15, day 29, day 57) 
o Stratum corneum lipid structure (day 29) 
 
Furthermore, summaries of the key outcomes (TEWL and epidermal thickness) by visit 
(day 1, day 15, day 29) will be made split by FLG loss-of-function mutation carriers. 
 
Exposure and Compliance 
A summary of the number of treatment days and the used weight per treatment day by 
treatment willl be provided. 
7.4 
Adverse event data: 
 
All Adverse Events will be summarized for all subjects enrolled in the study – both the 
number of participants with an AE and the total number of AEs. AEs will be tabulation by 
system organ class and by preferred term, as well as severity and relationship to treatment. 
Finally, those AEs which are specifically recorded as related to one of the test sites, the AEs 
will be summarised by test site. A listing, by participant number, will be produced to show 
the AEs at the worst severity and worst relationship to treatment. 
7.5 
Multiplicity considerations 
All analyses in this SAP will be carried out with a two sided 5% significance level.   
Secondary analyses are considered to be exploratory and so no adjustment will be made for 
multiplicity. 


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7.8 
Data Monitoring Committee (DMC): 
No DMCs are planned for this trial. 
7.9 
Changes From Protocol 
The interim analysis described in section 7.7 was not included in the protocol. 
8. Transfer of documentation, data and reporting 
Data, documentation and reporting will be shared between the Study team, CTRU, SSU and 
Pfizer as detailed below. The transfers will use a mutually agreeable electronic transmission 
method that is demonstrated to be compatible with uploading to the targeted Pfizer 
database or Pfizer systems and that protects the security and integrity of the data.  All 
deliverables provided to Pfizer will be written in English. 
Documentation 
• 
Monthly status reports will be provided to Pfizer by the study team in Excel Format, 
SAS Format, or XPT Format to include: 
o monthly updates of first participant first visit, participant screened, and 
randomized to date, screen failures to date 
o Participants completed; and 
o any other information as may reasonably be requested by Pfizer 
• 
At the time of study reporting the SSU will provide listings (pdf document) by Study 
subject, for all enrolled Study subjects (not including screen failures) for the 
following variables as a minimum: 
o subject no.,  
o enrollment date,  
o randomization date,  
o dosing date 
• 
The study team will provide the follow documents to Pfizer and the SSU in the form 
of one or more Portable Document Format (“PDF”) files and as they become 
available: 
o annotated CRFs 
o an electronic “Data Dictionary” consisting of all versions of the CRFs used in 
the Study, annotated with variable names and corresponding datasets 
o documentation of dictionary coding versions used to code medications and 
SAEs/AEs 
o Any derivations used at the point of data entry or during data cleaning 
o TMF-associated documentation, including, but not limited to: 
 
, blank/template CRF,  
 
CRF approval(s),  
 
clinical data change report,  
 
all versions of CRF completion guidelines,  
 
completed CRFs,  
 
database entry and database user acceptance testing documentation,  
 
data management plan(s) (inclusive of edit checks),  


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 
data review plan(s) and database release documentation, 
 
any other documentation as may reasonably be requested by Pfizer 
 
• 
The SSU will provide SAP for review and at sign off (plus if any amendments are 
required) 
o Any derivations used for the analysis will be included in the SAP/added to an 
appendix of the SAP as appropriate 
o relevant statistical analysis assumptions or plans will be included in the 
SAP/added to an appendix of the SAP as appropriate 
Clinical Datasets 
A “Clinical Dataset” consists of all Study Data (with certain personal identifiers removed) 
available to Trust at the time of transfer.  Clinical Datasets may include raw datasets and/or 
analysis datasets.  Trust will transfer Clinical Datasets and in the form of SAS 
Export/Transport file format (XPT) files or CSV files as detailed below. 
Test transfers 
Prior to transfer of a given Clinical Dataset to Pfizer, the study team will transfer test data 
to support the effective transfer of such Clinical Dataset.  A test data set will consist of 
complete “dummy” data for at least 5 hypothetical or actual Study subjects.  Pfizer will 
perform certain checks on test data to determine if the transmission meets Pfizer 
requirements in content and process and if the data will load successfully into the target 
Pfizer database.  Trust will work with Pfizer if changes are needed in the data formatting or 
transmission process to ensure data quality and usability.  Trust will transfer additional sets 
of test data if needed after such changes are made, as well as if there are any changes in the 
Study variables or data collection tools during the Study.  Transfers from the study team 
will be of RAW data in csv format. 
When a test transfer is available it will be provided to the SSU by the study team. 
Data transfers 
The study team will transfer a Clinical Dataset to Pfizer: after fifteen (15) of subjects dosed 
and after study completion.  
At the time of study reporting (when the final analysis is complete) the SSU will provide 
clinical datasets in SAS format.  A test transfer can be done in advance, however, there may 
be small changes to variables up until the final analysis is agreed. 
Data cleaning and validation 
Pfizer, the study team and the SSU will alert each other promptly if they discover that any 
data within a Clinical Dataset fails to meet appropriate quality standards.  This may include 
data queries from Pfizer or the SSU that the study team will investigate and resolve. 
 


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Results Summary 
The SSU will provide tables and listings to the study team and Pfizer following the final 
analysis, the format of these will be agreed in advance and will include: 
o subject population summaries 
o efficacy results 
o safety results 
o the SSU will advise on statistical interpretation of primary results 
In addition, the study team may provide commentary on the objectives and study design and 
clinical interpretation. 
Timelines for the delivery of the tables and listings will be agreed between the study team, 
the SSU and Pfizer. 
 
Study Report 
o Whilst the SSU will input and advise with respect to the statistical design, 
methodology and interpretation the study team will be responsible for writing the 
study report. 
o A draft of the written Study Report will be delivered to Pfizer in accordance with the 
information and formatting as agreed to by the study team and in accordance with 
ICH-E3 guidelines.  The Study Report will reflect the results of the Study as a 
whole.  Study team will provide Pfizer with an opportunity to review and comment 
on the draft Study Report for at least thirty (30) days after Pfizer’s receipt of the 
draft Study Report, and Trust and Principal Investigator will consider in good faith any 
comments reasonably 
o Within five (5) months after the last subject’s last visit or database lock or upon early 
termination of the study, whichever occurs first, the study team will provide Pfizer 
with the final Study Report.  In case of early termination of the study (before Study 
Completion), the Study Report will include, at minimum, the Study Results through 
the date of termination.  Unless otherwise agreed in writing, The Trust may submit 
the Study Report to applicable regulatory authorities. 
o Unless otherwise agreed by Pfizer, the Study Report will address: 
o Ethics 
o Investigators and Study administration  
o Study objectives 
o investigational plan 
o Study subjects 
o efficacy evaluation 
o Drug compliance/adherence evaluation 
o safety evaluation 
o discussion and overall conclusions; supportive tables, figures and graphs; 
o biomarker findings; and 
o any other information as may reasonably be requested by Pfizer. 
 
 
 


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9. List of Tables, Figures and Listings  
 
Tables 
14.1.1 
Disposition (Full Analysis Set)  
14.1.2 
Important PDs (Full Analysis Set) 
14.1.3 
Patients excluded from analysis populations (Full Analysis Set)  
14.1.4 
Demographic data (Full Analysis Set) 
14.1.5 
Baseline eczema history (Full Analysis Set) 
14.1.6 
Medical History (Full Analysis Set) 
14.1.7 
Temperature and humidity during skin assessments (Full Analysis Set) 
14.2.1 
Epidermal thickness. (Full Analysis Set) 
14.2.1.1 
Change in epidermal thickness during and after 4 weeks of treatment (day 
15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.1.2 
Analysis of epidermal thickness change (day 15 – day 1, day 29 – day 1, day 
57 – day 1) (Full Analysis Set) 
Note for this table and similar tables for the secondary endpoints – only 
those comparisons carried out will be included – see section 7.2 
14.2.2 
TEWL (g/m2h) (Full Analysis Set) 
14.2.2.1 
Change in TEWL (g/m2h) during and after 4 weeks of treatment (day 15 – 
day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.2.2 
Analysis of change in TEWL (day 15 – day 1, day 29 – day 1, day 57 – day 1) 
(Full Analysis Set) 
14.2.3 
TEWLts20 (g/m2h) (Full Analysis Set) 
14.2.3.1 
Change in TEWLts20 (g/m2h) after 4 weeks of treatment (day 29) (Full 
Analysis Set) 
14.2.3.2 
Analysis of change in TEWLts20 following 4 weeks of treatment(Full Analysis 
Set) 
14.2.4 
NMF (Full Analysis Set) 
14.2.4.1 
Analysis of NMF (day 29) (Full Analysis Set) 
14.2.5 
Investigator visual scores for redness (Full Analysis Set) 
14.2.5.1 
Change in visual score for redness during and after 4 weeks of treatment 
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.5.2 
Analysis of change in visual score for redness (day 15 – day 1, day 29 – day 
1, day 57 – day 1) (Full Analysis Set) 
14.2.6 
Objective Redness (Mexameter) (Full Analysis Set) 
14.2.6.1 
Change in Objective Redness (Mexameter) during and after 4 weeks of 
treatment (day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.6.2 
Analysis of change in Objective Redness (Mexamater) (day 15 – day 1, 
day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.7 
Dryness(Full Analysis Set) 
14.2.7.1 
Change in Dryness during and after 4 weeks of treatment (day 15 – day 1, 
day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.7.2 
Analysis of change in dryness (day 15 – day 1, day 29 – day 1, day 57 – day 1) 
(Full Analysis Set) 
14.2.8 
Superficial plexus depth (μm) (Full Analysis Set) 
14.2.8.1 
Change from baseline in superficial plexus depth (μm) (day 15 – day 1, day 
29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.9 
Mean blood vessel diameter (μm) (Full Analysis Set) 
14.2.9.1 
Change from baseline in mean blood vessel diameter (μm) (day 15 – day 1, 
day 29 – day 1, day 57 – day 1) (Full Analysis Set) 


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14.2.10 
Blood vessel density (segments/m2) (Full Analysis Set) 
14.2.10.1 
Change from baseline in blood vessel density (segments/m2) (day 15 – 
day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.11 
Collagen matrix index (Full Analysis Set) 
14.2.11.1 
Change from baseline in collagen matrix index (day 15 – day 1, day 29 – day 
1, day 57 – day 1) (Full Analysis Set) 
14.2.12 
Carboxylate levels (FTIR) (Full Analysis Set) 
14.2.12.1 
Change from baseline in carboxylate levels (FTIR – indirect NMF) (day 15 – 
day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
14.2.13 
Stratum corneum lipid (Full Analysis Set) 
14.2.13.1 
Change from baseline in stratum corneum lipid (day 15 – day 1, day 29 – 
day 1, day 57 – day 1) (Full Analysis Set) 
14.2.14 
Summary of FLG (Full Analysis Set) 
14.2.14.1 
Summary of epidermal thickness by mutation status(Full Analysis Set) 
14.2.14.1.1 
Analysis of change in epidermal thickness (day 29 – day 1) within mutation 
status (Full Analysis Set) 
14.2.14.2 
Summary of TEWL (g/m2h) by mutation status(Full Analysis Set) 
14.2.14.2.1 
Analysis of change in TEWL (g/m2h) (day 15 – day 1, day 29 – day 1, day 57 – 
day 1) within mutation status (Full Analysis Set) 
14.2.15 
Total Product consumption (Safety Analysis Set) 
14.3.1 
Number of patients experiencing AEs (Safety Analysis Set) 
14.3.2 
Adverse Events by system organ class and preferred term (Safety Analysis 
Set) 
14.3.x  
Adverse Events - further tables as appropriate (Safety Analysis Set) 
BDR1.1 
Summary of epidermal thickness by location (Full Analysis Set) 
BDR1.2 
Summary of epidermal thickness change by location (day 29 – day 1) (Full 
Analysis Set) 
BDR1.3 
Summary of epidermal thickness change after treatment cessation by 
location (day 57 – day 29) (Full Analysis Set) 
BDR2.1 
Summary of TEWL (g/m2h) by location (Full Analysis Set) 
BDR2.2 
Summary of TEWL (g/m2h) change by location (day 15 – day 1, day 29 – 
day 1, day 57 – day 1) (Full Analysis Set) 
BDR3.1 
Summary of TEWL ts20 (g/m2h) by location (Full Analysis Set) 
BDR3.2 
Summary of TEWL ts20 (g/m2h) change by location (day 29 – day 1) 
BDR4.1 
Summary of NMF by location (Full Analysis Set) 
BDR4.2 
Summary of NMF change by location (day 15 – day 1, day 29 – day 1, day 57 
– day 1) (Full Analysis Set) 
BDR5.1 
Summary of visual scores for redness (erythema) by location (Full 
Analysis Set) 
BDR5.2 
Summary of visual scores for redness (erythema) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR6.1 
Summary of Objective redness (Mexameter) by location (Full Analysis Set)
BDR6.2 
Summary of Objective redness (Mexameter) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR7.1 
Summary of Dryness by location  (Full Analysis Set) 
BDR7.2 
Summary of Dryness change by location (day 15 – day 1, day 29 – day 1, 
day 57 – day 1) (Full Analysis Set) 
BDR8.1 
Summary of Superficial plexus depth (μm) by location(Full Analysis Set) 
BDR8.2 
Summary of Superficial plexus depth (μm) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR9.1 
Summary of Mean blood vessel diameter (μm) by location (Full Analysis 
Set) 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 19 of 20 
BDR9.2 
Summary of Mean blood vessel diameter (μm) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR10.1 
Summary of blood vessel density (segments/m2) by location (Full Analysis 
Set) 
BDR10.2 
Summary of blood vessel density (segments/m2) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR11.1 
Summary of collagen matrix index by location (Full Analysis Set) 
BDR11.2 
Summary of collagen matrix index change by location (day 15 – day 1, day 
29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR12.1 
Summary of carboxylate levels (FTIR) by location (Full Analysis Set) 
BDR12.2 
Summary of carboxylate levels (FTIR) change by location  
(day 15 – day 1, day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
BDR13.1 
Summary of stratum corneum lipid by location (Full Analysis Set) 
BDR13.2 
Summary of stratum corneum lipid change by location (day 15 – day 1, 
day 29 – day 1, day 57 – day 1) (Full Analysis Set) 
 
 
 
 
Listings 
 
16.2.1 
Discontinued patients (All patients) 
16.2.2 
Protocol deviations (Full Analysis Set) 
16.2.3 
Patients excluded from analysis populations (All patients) 
16.2.4.1 
Demographic data (Full Analysis Set) 
16.2.4.2 
Baseline eczema history (Full Analysis Set) 
16.2.4.3 
Medical history (Full Analysis Set) 
16.2.4.4 
Patient routine (Full Analysis Set) 
16.2.5 
Cream consumption (Full Analysis Set) 
16.2.6.1 
Epidermal thickness (Full Analysis Set) 
16.2.6.2 
TEWL (Full Analysis Set) 
16.2.6.3 
Investigator visual scores for redness (Full Analysis Set) 
16.2.6.4 
Objective erythema (Full Analysis Set) 
16.2.6.5 
Objective Redness (Mexameter) (Full Analysis Set) 
16.2.6.6 
TEWLts20 (Full Analysis Set) 
16.2.6.7 
Skin surface dryness (3D skin images) (day 29 – day 1) (Full Analysis Set) 
16.2.6.8 
Superficial plexus depth (Full Analysis Set) 
16.2.6.9 
Blood vessel diameter (Full Analysis Set) 
16.2.6.10 
Blood vessel density (Full Analysis Set) 
16.2.6.11 
Collagen matrix index (Full Analysis Set) 
16.2.6.12 
Carboxylate levels (Full Analysis Set) 
16.2.6.13 
Stratum corneum lipid (Full Analysis Set) 
16.2.6.14 
TEWLts5 (Full Analysis Set) 
16.2.6.14 
TEWLts10 (Full Analysis Set) 
16.2.6.14 
TEWLts15 (Full Analysis Set) 
16.2.6.15 
Patient tolerability scores (VAS) (Full Analysis Set) 
16.2.6.16 
Total Cream consumption (Full Analysis Set) 
16.2.6.17 
NMF (Full Analysis Set) 
16.2.6.18 
FLG (Full Analysis Set) 
16.2.7 
AEs (Safety Analysis Set) 
 
 
 


SMART – Skin Barrier Study 
 
Statistical Analysis Plan v1.2 
SSU2017/007  
 
16 April 2021 
Statistical Services Unit, The University of Sheffield 
Page 20 of 20 
Figures: 
Figure 14.2.1.1 
Epidermal thickness by visit (day 1, day 15, day 29, day 57) (Full Analysis Set) 
Figure 14.2.2.1 
Erythema (visual redness) by visit (day 1, day 15, day 29, day 57) (Full Analysis 
Set) 
Figure 14.2.3.1 
Objective redness (mexameter) (day 1, day 15, day 29, day 57) (Full Analysis 
Set) 
Figure 14.2.4.1 
TEWL (g.m2h) by visit (day 1, day 15, day 29, day 57) (Full Analysis Set) 
Figure 14.2.7.1 
Skin surface dryness (μm) (day 1, day 15, day 29, day 57) (Full Analysis Set) 
Figure 14.2.8.1 
NMF levels at day 29(Full Analysis Set) 
Figure 14.2.9.1 
Superficial plexus depth (μm) (day 1, day 15, day 29, day 57) (Full Analysis Set) 
Figure 14.2.10.1 
Mean blood vessel diameter (μm) (day 1, day 15, day 29, day 57) (Full Analysis 
Set) 
Figure 14.2.11.1 
Blood vessel density (segments/mm2) (day 1, day 15, day 29, day 57) (Full 
Analysis Set) 
Figure 14.2.12.1 
Collagen matrix index (day 1, day 29) (Full Analysis Set) 
Figure 14.2.13.1 
Carboxylate levels (day 1, day 15, day 29, day 57) (Full Analysis Set) 
Figure 14.2.14.1 
Stratum corneum lipid structure (day 29) (Full Analysis Set) 
Figure 14.2.15.1 
Epidermal thickness split by FLG mutation (day 1, day 15, day 29, day 57) (Full 
Analysis Set) 
Figure 14.2.16.1 
TEWL split by FLG mutation (day 1, day 15, day 29, day 57) (Full Analysis Set)